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Core of Self Common Gut Problems GIT Two The Gastrointestinal Tract & the Core of Self 2 CNS/ Brain ANS ANS Immune Enteric Nervous System Afferent and Efferent Endocrine Oesophagus Liver Pancreas Gallbladder Stomach Small Intestine Large Intestine Appendix [email protected] Rectum 2/02/15 MIND OF THE GUT; THE EFFERENT & AFFERENT NERVOUS SYSTEMS, THE VAGAL SYSTEM & THE MICROBIOME 3 Brains 4 In mammals there exist two brains of almost equal importance to the individual. One is the cranial brain, the instrument of volitions, of mental progress and physical protection. The other is the abdominal brain, the instrument of vascular and visceral function. It is the automatic, vegetative, the subconscious brain of physical existence. In the cranial brain resides the consciousness of right and wrong. Here is the seat of all progress, mental and moral . . . However, in the abdomen there exists a brain of wonderful power maintaining eternal, restless vigilance over its viscera. It presides over organic life. It dominates the rhythmical function of viscera. . . . The abdominal brain is a receiver, a reorganiser, an emitter of nerve forces. It has the power of a brain. It is a reflex centre in health and disease. . . . (Robinson, 1907, pp. 123-126). [email protected] 2/02/15 • For Robinson, the abdominal brain is centred in the solar plexus (Fig. 1). The abdominal brain is the primary control center of an extensive peripheral nervous system containing a number of "little brains." Anatomically, this peripheral system is roughly equivalent to the autonomic nervous system. [email protected] 5 2/02/15 Gut-Brain Trade-off 6 More effective nutrient gathering Higher Diet Quality Cooking reduces bulk and creates greater nutritional assimilation [email protected] Increased Energy Availability Smaller Gut Larger Brain Increased efficiency: 5% used in assimilation 2/02/15 Gut-Brain Axis 7 Communications along the brain-gut axis (GBA) involve neural pathways as well as immune and endocrine mechanisms. The two branches of the autonomic nervous system are integrated anatomically and functionally with visceral sensory pathways, and are responsible for the homeostatic regulation of gut function. The autonomic nervous system is also a major mediator of the visceral response to central influences such as psychological stress and other central factors. [email protected] 2/02/15 Mind in the Belly 8 We speak of gut reactions and the truth of the ‘instinctive’ response; this ‘feeling response’ is directly related to our enteric (ENS) and vagal (VNS) nervous systems and, the ancient and primordial response to attack and danger. Our gut feeling is an important component in the personal self, to knowing one self. The ENS is of special interest because it is the only substantial grouping of neurons outside the central nervous system that form circuits capable of autonomous reflex activity. [email protected] 2/02/15 Microbiota-Brain-Nervous System Interactions 9 The gut–brain axis (GBA) is a bi- directional communication system through which the brain modulates gastrointestinal function and through which gut function is monitored by the brain. Neural, endocrine and immunological mechanisms underlie gut–brain interactions (Bienenstock & Collins, 2010). [email protected] 2/02/15 Bowel and Behaviour 10 The enteric microbiota interacts with the host to form essential relationships that govern homeostasis. Despite the unique enteric bacterial fingerprint of each individual, there appears to be a certain balance that confers health benefits. A decrease in the desirable gastrointestinal bacteria will lead to deterioration in gastrointestinal, neuroendocrine or immune relationships and ultimately disease. Specific modulation of the enteric microbiota may be a useful strategy for stress-related disorders and for modulating the co-morbid aspects of GI disorders such as IBS and IBD (2011, doi:10.1111/j.1365-2982.2010.01664.x). [email protected] 2/02/15 Bowel and Behaviour 11 Collins et al., (2012) have described the recent advances in the understanding of how the intestinal microbiota communicates with the brain via the gut-brain axis (GBA) to influence brain development and behaviour. They also reviewed how this extended communication system might influence a broad spectrum of diseases, including irritable bowel syndrome, psychiatric disorders and demyelinating conditions such as multiple sclerosis (doi: 10.1038/nrmicro2876). Microbial-based therapeutic strategies to aid in the treatment of mood disorders was studied by Forsythe & Kunze (2013, doi: 10.1007/s00018-012-1028-z). [email protected] 2/02/15 GBA 12 The GBA has been implicated in primary psychiatric and in functional and inflammatory gastrointestinal (GI) diseases. Psychiatric co-morbidity occurs in up to 60% of these GI disorders (Whitehead et al, 2002). The brain is aware of the introduction of pathogenic microbes into the gastrointestinal tract. This results in brain stem nuclei becoming activated and, in some instances, associated with the development of anxiety-like behaviour (Lyte et al, 2006). [email protected] 2/02/15 GBA 13 The ENS is an extensive network of neurons widely dispersed throughout the gut that coordinate to regulate gastrointestinal events such as peristalsis, blood flow, secretion, and absorption (Costa and Brookes, 1994). The ENS can influence the CNS both through nerve reflexes and the production of neuropeptides. It is estimated that 80% of vagal fibres are visceral afferents (Davenport, 1978). Recent work has also shown a vast overlap of neuropeptide activity in the gut and the brain (Pert et al., 1985). The ENS is an active area in physiologic research with more than 1000 articles on MEDLINE since 1985. [email protected] 2/02/15 ENS 14 The Enteric Nervous System (ENS) is present in all vertebrates, has these functions: to regulate the normal activity of the digestive system and prepare it for whatever its future may hold: our "Gut Reaction”, which is the feedback loop to the CNS. Many of its structures and chemicals parallel those of the CNS. It has sensory and motor neurons, information processing circuits, and the glial cells. It uses the major neurotransmitters: dopamine, serotonin, acetylcholine, nitric oxide and norepinephrine. It even has benzodiazepines, chemicals of the family of psychoactive drugs that includes Valium and Xanax. [email protected] 2/02/15 ENS 15 When the brain signals danger, it activates mast cells in the lining of the small intestine and/or colon to release histamine and other chemicals. These chemicals trigger an inflammatory response inside the GIT, attracting immune cells from the bloodstream into the area and the body is ready for trauma. But when this inflammatory response gets out of control one may develop IBS, IBD, reflux, ulcers, 'leaky gut' and even cancer. Cytokines can and do pass through the BBB and induce ‘anxiety-like’ feelings [email protected] 2/02/15 ENS 16 • The enteric nervous system (ENS) exerts a profound influence on all digestive processes, namely motility, ion transport associated with secretion and absorption, and gastrointestinal blood flow. • Some of this control emanates from connections between the digestive system and central nervous system, but the digestive system is endowed with its own, local nervous system (Bowen 2006). • The ENS is capable of autonomous functions such as the coordination of reflexes (Dorland's n.d.). [email protected] Vagus nerves Preganglionic sympathetic Postganglionic sympathetic Preganglionic parasympathetic Postganglionic parasympathetic Intrinsic enteric neurons Afferents Sympathetic chain T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 S2 S3 S4 Vagus nerves Splanchnic nerves Celiac or superior mesenteric ganglia Celiac ganglion Mesenteric nerves following blood vessels Superior mesenteric ganglion Inferior mesenteric ganglion Mesentery Pelvic nerves Serosa Longitudinal muscle Myenteric plexus Circular muscle Submucous plexus Muscularis mucosae Mucosa 2/02/15 ENS 17 Evidence is accumulating to suggest that gut microbes (microbiota) may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain. There is an increasing and intense current interest in the role that gut bacteria play in maintaining the health of the host. There are rapidly coalescing clusters of evidence which point to the possibility that variations in the composition of gut microbes may be associated with changes in the normal functioning of the nervous system (Forsythe et al, 2010). [email protected] 2/02/15 Peristalsis 18 Peristalsis is a manifestation of two major reflexes within the enteric nervous system that are stimulated by a bolus of foodstuff in the lumen. Mechanical distension and perhaps mucosal irritation stimulate afferent enteric neurons. These sensory neurons synapse with two sets of cholinergic interneurons, which lead to two distinct effects: One group of interneurons activates excitatory motor neurons above the bolus - these neurons, which contain acetylcholine and substance P, stimulate contraction of smooth muscle above the bolus. Another group of interneurons activates inhibitory motor neurons that stimulate relaxation of smooth muscle below the bolus. These inhibitor neurons appear to use nitric oxide, vasoactive intestinal peptide and ATP as neurotransmitters. [email protected] 2/02/15 Afferent & Efferent 19 The gastrointestinal tract is in two way communication with the CNS. Afferent neurons convey information about the state of the gastrointestinal tract. Some of this reaches consciousness, including pain and discomfort from the gut and the conscious feelings of hunger and satiety, which are integrated perceptions derived from the gastrointestinal tract and other signals (blood glucose, for example). Other afferent signals, concerning, for example, the nutrient load in the small intestine, or the acidity of the stomach, do not normally reach consciousness. In turn, the CNS provides signals to control the intestine, which are, in most cases, relayed through the ENS. [email protected] 2/02/15 ENS 20 The ENS is an extensive network of neurons widely dispersed throughout the gut that coordinate to regulate gastrointestinal events such as peristalsis, blood flow, secretion, and absorption (Costa and Brookes, 1994). The ENS can influence the CNS both through nerve reflexes and the production of neuropeptides. It is estimated that 80% of vagal fibres are visceral afferents (Davenport, 1978). Recent work has also shown a vast overlap of neuropeptide activity in the gut and the brain (Pert et al., 1985). The ENS is an active area in physiologic research with more than 600 articles on MEDLINE since 1985. [email protected] 2/02/15 Vagal Nervous System 21 Stimuli that are interpreted by the brain as extreme or threatening, regardless of their modality, elicit an immediate stereotypic response characterised by enhanced cognition, affective immobility, vigilance, autonomic arousal and a global catabolic state. The brain differentially activates a subset of vagal and sacral parasympathetic efferents that mediate the gut responses to stress (Habib et al. 2001). The vagal nerve also activates heart rate, respiration, epigastric motility and expression. [email protected] 2/02/15 Vagal Nervous System 22 The VNS affects heart rate, digestion, Vagus Nerve (X): Schema respiration rate, salivation, perspiration, and diameter of the pupils, micturition, and sexual arousal. Whereas most of its actions are involuntary, some, such as breathing, work in tandem with the conscious mind. Posterior nucleus of vagus nerve (parasympathetic and visceral afferent) Glossopharyngeal nerve (IX) Solitary tract nucleus (visceral afferents including taste) Meningeal branch of vagus nerve Auricular branch of vagus nerve Spinal tract and spinal nucleus of trigeminal nerve (somatic afferent) Auditory (pharyngotympanic, Eustachian) tube Levator veli palatini muscle Nucleus ambiguus (motor to pharyngeal and laryngeal muscles) Salpingopharyngeus muscle Cranial root of accessory nerve* (see next plate) Palatoglossus muscle Vagus nerve (X) Palatopharyngeus muscle Jugular foramen Superior pharyngeal constrictor muscle Superior ganglion of vagus nerve Inferior ganglion of vagus nerve Stylopharyngeus muscle Middle pharyngeal constrictor muscle Inferior pharyngeal constrictor muscle Cricothyroid muscle Trachea Esophagus Right subclavian artery Right recurrent laryngeal nerve Heart Hepatic branch of anterior vagal trunk (in lesser omentum) Celiac branches from anterior and posterior vagal trunks to celiac plexus Pharyngeal branch of vagus nerve (motor to muscles of palate and pharynx; sensory to lower pharynx) Communicating branch of vagus nerve to carotid branch of glossopharyngeal nerve Pharyngeal plexus Superior laryngeal nerve: Internal branch (sensory and parasympathetic) External branch (motor to cricothyroid muscle) Superior cervical cardiac branch of vagus nerve Inferior cervical cardiac branch of vagus nerve Thoracic cardiac branch of vagus nerve Left recurrent laryngeal nerve (motor to muscles of larynx except cricothyroid; sensory and parasympathetic to larynx below vocal folds; parasympathetic, efferent, and afferent to upper esophagus and trachea) Celiac and superior mesenteric ganglia and celiac plexus Pulmonary plexus Cardiac plexus Hepatic plexus Esophageal plexus Gallbladder and bile ducts Anterior vagal trunk Liver Gastric branches of anterior vagal trunk (branches from posterior trunk behind stomach) Pyloric branch from hepatic plexus Vagal fibers (parasympathetic motor, secretomotor, and afferent fibers) accompany superior mesenteric artery and its branches usually as far as left colic (splenic) flexure Pancreas Duodenum Small intestine Ascending colon Efferent fibers Cecum Afferent fibers Appendix Parasympathetic fibers © Elsevier, Inc. - Netterimages.com [email protected] 2/02/15 Vagus 23 The vagus nerve, also known as the tenth cranial nerve. In Latin, 'vagus' means 'wandering', and the nerve was so named due to its meandering and multi-branched route through the body; it originates at the brain stem and travels through the chest where it spreads out in multiple directions to innervate organs in the neck, thorax and abdomen, effectively connecting your brain to your lungs, digestive tract and, most notably, your heart. The vagus assists the adrenal glands during 'fight or flight' situations by stimulating the release of epinephrine in the brain. It is the vagus nerve which activates the PNS to calm the body after the perceived danger has passed, slowing the heart rate so that normal bodily functions, such as digestion, can resume. [email protected] 2/02/15 Vagal Nervous System 24 It traditionally has been divided by subsystems, the parasympathetic nervous system and sympathetic nervous system and more recently the vagus and enteric systems. Porges (1995) has shown clear evidence that the third, more modern branch of the ANS; the vagus nerve is a survival value specific to more sophisticated animals especially primates. “Social Nervous System” is the proposed term for this third branch of the ANS [email protected] 2/02/15 Vagal Tone 25 Vagal tone is proposed as a novel index of stress vulnerability and reactivity with applications in all branches of medicine and measurement of cardiac vagal tone is a method to assess on an individual basis both the stress response and the vulnerability to stress (Porges 1992). Cardiac vagal tone is proposed as a novel index of stress and stress vulnerability in mammals (Porges 1995). [email protected] 2/02/15 Vagal Tone 26 Vagal tone (VT), an index of autonomic flexibility, is linked to social and psychological well-being. The association between VT and well-being reflects an "upward spiral" in which autonomic flexibility, represented by VT, facilitates capitalising on social and emotional opportunities and the resulting opportunistic gains, in turn, lead to higher VT. Adults who possessed higher initial levels of VT increased in connectedness and positive emotions more rapidly than others. Furthermore, increases in connectedness and positive emotions predicted increases in VT, independent of initial VT level (Kok & Fredrickson, 2010). [email protected] 2/02/15 Vagal Tone 27 Psychophysiology emphasises a continuity between neuro- physiological and psychological processing. Psychophysiologists assume that the nervous system provides the functional units for the bidirectional transduction of psychological and physiological processes. Thus, from a psychophysiological perspective, it is possible to link psychological processes with neuro-physiological processes and brain structures (Porges 1995). [email protected] 2/02/15 Vagal Tone 28 The mammalian vagus is neuroanatomically linked to the cranial nerves that regulate social engagement via facial expression and vocalization. As the autonomic nervous system changed through the process of evolution, so did the interplay between the autonomic nervous system and the other physiological systems that respond to stress, including the cortex, the HPA axis, the neuropeptides of oxytocin and vasopressin, and the immune system (Porges 2001). [email protected] 2/02/15 Sensory System: Afferent Others Impact on us Parasympathetic Regulatory Functions: “Vagal Brake” Heart Cardiac Regulation, Heart Rate & Blood Pressure Lungs Respiratory Regulation Middle Ear Isolating Human Voices Pharynx & Larynx Speaking & Swallowing Oesophagus, Stomach & Intestines Feelings of Hunger & Satiation; Craving Swallowing & Digestion Motility/Peristalsis Kidney, Gallbladder, Pancreas, Liver From: Cozolino 2006 29 Motor System: Efferent Impact on Others Vagal Tone Higher Vagal Tone Lower Vagal Tone Self Regulation Irritability Self Soothing Behavioural Problems Control of Emotions (not Emotional Dysregulation suppression) Reliable Autonomic Response Suppression of Heart Rate Enhanced Attention Positive Social response Increased Behavioural Engagement Consistent Caretaking/ Secure Attachment 30 Distractibility Hyper-reactivity to Environmental & Visceral Stimuli Withdrawal Poor Impulse Control Insecure Attachment From: Cozolino 2006 2/02/15 Polyvagal Theory & Social Nervous System 31 The mammalian vagus is neuroanatomically linked to the cranial nerves that regulate social engagement via facial expression and vocalisation. The Polyvagal Theory provides neurobiological explanations for two dimensions of intimacy: courting and the establishment of enduring pair-bonds. The establishment of enduring pair-bonds is dependent upon a co-opting of the visceral vagus from an immobilisation system associated with fear and avoidance to an immobilisation system associated with safety and trust. [email protected] 2/02/15 Polyvagal Theory & Social Nervous System 32 The theory proposes that the phylogenetic development of the mammalian vagus is paralleled by a specialised communication, via oxytocin and vasopressin, between the hypothalamus and the medullary source nuclei of the visceral vagus. The third stage, unique to mammals, is characterised by a myelinated vagus that can rapidly regulate cardiac output to foster engagement and disengagement with the environment (Porges 1998). The fear of intimacy, fear of bonding = IBS [email protected] 2/02/15 “Insult” Social Nervous System Behavioural/Psychological Outcomes Social Communication & Regulation Hyper-arousal Hyper-vigilance Hypertension Gut Problems Anxiety Disorders Mobilisation Hypotension Vasovagal Syncope Fibromyalgia Immobilisation Avoidant Social Withdrawal Affect Limitations Self-Medication From: Porges 2003 33 Dissociative States Suicide Risk Cardiac Vagal Tone 34 Infants with higher baseline cardiac vagal tone were rated in the laboratory as showing fewer negative behaviours and were less disrupted by the experimental procedure. Infants who were able to decrease cardiac vagal tone during the laboratory assessment were rated on maternal report temperament scales as having longer attention spans, and being more easily soothed (Huffman et al, 1998). [email protected] 2/02/15 Vagal Tone 35 There have been a growing number of reports demonstrating disordered autonomic function in subgroups of functional bowel patients (Jorgensen et al, 1993). While a number of different methods were used to assess autonomic function, they generally point to decreased vagal (parasympathetic) outflow or increased sympathetic activity in conditions usually associated with slow or decreased gastrointestinal motility. Under certain conditions, altered autonomic balance (including low vagal tone and increased sympathetic activity) may also alter visceral perception (Kamath et al, 1993). [email protected] 2/02/15 Vagal Tone & Acupuncture 36 Acupuncture-induced balance of the autonomic nervous system activities is one of its key mechanisms. 1) regulating cardiac sympathetic-beta-adrenergic receptor activity and myocardial intracellular GTP-binding protein (Gs)adenylylcyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase (PKA) signalling, and 2) balancing cardiac sympathetic and vagal nerve activities ( http://www.ncbi.nlm.nih.gov/pubmed/24684118). Acupuncture may be effective in patients with functional gastrointestinal (GI) disorders because of its effects on GI motility and visceral pain (2013, doi: 10.1016/ B978-0-12-411545-3.00014-6). [email protected] 2/02/15 Vagal Tone & Acupuncture 37 An analysis by da Silva & Dorsher (2014) demonstrated marked correspondences of the indications for those lateral head and neck acupoints to the clinical effects (beneficial and adverse) documented for the VNS device in the medical literature. This clinical correspondence, in conjunction with the anatomic proximity of the acupoints to the vagus nerve in the lateral neck, strongly suggests that vagus nerve (and hence the autonomic nervous system) stimulation is fundamental in producing the clinical effects of the acupoints (doi: 10.1089/acm.2012.1022). [email protected] 2/02/15 Vagal Tone & Acupuncture 38 The effect of auricular acupuncture (AA) applied to the "Shenmen" and "Point Zero" points on the postoperative heart rate variability (HRV) was studied by Arai et al., (2013, doi: 10.1155/2013/945063). AA kept the low frequency (LF)/high frequency (HF) ratio at lower levels and HF at higher levels during postoperative period in the patients who had undergone hemicolectomy. They concluded AA is a diagnostic and treatment system based on normalising the body's dysfunction, and has been applied for pain relief, relaxation. These techniques would modulate the autonomic nerve system [email protected] 2/02/15 Vagal Tone & Acupuncture 39 Acupuncture manipulation significantly decreased low frequency components (LF) of both HR variability (HRV) and systolic blood pressure (SBP). Changes in HF (index of parasympathetic activity) and total power (overall activity of the autonomic nervous system) of HRV were positively correlated. ANS changes induced by manipulation inducing specific acupuncture sensations might be mediated through the central nervous system, especially through the forebrain as shown in EEG changes, and are beneficial to relieve chronic pain by inhibiting sympathetic nervous activity (Auton Neurosci. 2007 May 30;133-2). [email protected] 2/02/15 Darwinian Perspective 40 Ethanol and caffeine are two of the oldest human drugs. Their pervasive integration into the modern human diet may reflect behavioural attempts to correct maladaptation induced by evolutionary displacement of the autonomic system. Caffeine effectively exploits a pre-existing association between adrenergic activity and cognitive readiness. Ethanol may have emerged as a dietary means to buffer the maladaptive chronic sympathetic activation and fear response associated with stressful lifestyles and the social phobias associated with the dissolution of kin networks (Med Hypotheses. 2007;68(1):31-6). [email protected] 2/02/15 G.I. Disorders Weakens Liver Qi Stagnation Stomach & Spleen Qi Xu Encourages Blood Xu Stress Generates Heat Blood Stasis Yin Xu Generates Damp Phlegm Damp Diet Antibiotics Damp Heat 41 2/02/15 The Gut and its Function 42 The average adult human is, in essence, a 10-meter-long tube. The inner lining of this tube—the gut—absorbs nutrients and defends against would-be pathogens, yet the number of microorganisms it accepts and even embraces is higher than the number of cells making up our entire body. Its tissues are wreathed in sensory cells and awash in hormones relaying information back and forth. What goes on within the gut is still largely mysterious, and in this issue we explore some of its most interesting secrets (Simpson et al, 2005). [email protected] 2/02/15 Gut & Immunity 43 Eighty percent of the human immune system resides in the gastrointestinal tract. Alongside it are the trillions of symbiotic bacteria, fungi and other single-celled organisms that make up our guts’ microbiomes. Normally everyone wins: The microorganisms benefit from a home and a steady food supply; we enjoy the essential assistance they provide in various metabolic and digestive functions. Our microbiomes also help calibrate our immune systems, so our bodies recognise which co-inhabitants should be there and which should not (Scientific American, Oct 8 2014). [email protected] 2/02/15 Gut & Immunity 44 The gut represents a unique dilemma for the immune system. It has the largest surface of the body harbouring numerous species of microorganisms. T helper and cytotoxic T cells obtain their antigen experience in the gut associated lymphatics after migration from the thymus. Evidence suggests a CD8 positive T cell that directly migrates to the intestinal epithelium increasing the role of the thymus in shaping intestinal immunity (2005 doi: 10.1136/gut.2005.087288) [email protected] 2/02/15 Gut & Immunity 45 The thymus is the major primary immune tissue for the production of functional T lymphocytes in vertebrates. However, its evolutionary origin is unknown. It has recently been shown that the generation of local T cells also occurs in gut-associated lymphoid tissues (GALT). This suggests that the thymus and GALT have similar functions and that they might be evolutionarily related. The thymus may have evolved from mucosa-associated lymphoid tissues (MALT) (Matsunaga T & Rahman, 2001) [email protected] 2/02/15 Gut & Stress 46 Certain exteroceptive stressful life events have been associated with the onset or symptom exacerbation in some of the most common chronic disorders of the digestive system, including functional gastrointestinal disorders (FGD), inflammatory bowel disease (IBD), gastrooesophageal reflux disease (GORD), and peptic ulcer disease (PUD). Early life stress in the form of abuse plays a major role in the susceptibility of individuals to develop functional as well as IBD later in life (Mayer, 2000). [email protected] 2/02/15 Gut & Stress 47 IBS is characterised by an over-activation of the HPA axis and a proinflammatory cytokine increase (Dinan et al, 2000). Low HPA axis and locus ceruleus–norepinephrine (LC/NE) activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli are pathophysiologic effects of the dysregulation of the stress response, which may result in vulnerability to several disease entities, such as anxiety or depression and chronic inflammatory processes including GI function (Tsigos & Chrousos 2002). [email protected] 2/02/15 Gut & Stress 48 Levels of stress, gynaecological events, bowel, and psychological symptoms in Chinese women of reproductive age who experienced both diarrhoea-predominant irritable bowel syndrome (D-IBS) and premenstrual syndrome were studied. The results revealed that compared to D-IBS patients, the patients in the overlapping syndromes group had increased stress and gynaecological events and more severe bowel and psychological symptoms. Overlapping syndromes were associated with repeated episodes of longer duration and delayed recovery (2014, doi: 10.1097/SGA. 0000000000000067). [email protected] 2/02/15 FGID 49 The clinical definition of FGID corresponds to how these patients present, it has proved difficult to apply in the search for the pathophysiological factor(s) potentially involved in these conditions. While much remains to be done in that regard, it is increasingly accepted that these conditions are multifactorial, and that the symptoms experienced by two individual patients, although somewhat similar, may in fact result from a number of different aetiologies (Tougas G Gut 2000;47:iv78-iv80). [email protected] 2/02/15 FGID 50 In recent years, we have undergone a substantial shift in our conceptual definitions of what constitutes functional bowel disorders and IBS. In general, we now view these conditions as a group of disorders or clinical entities characterised by the presence of, to a varying degree, chronic pain, discomfort, and disordered gastrointestinal function. functional disorders must to some extent involve the brain as well as the gut. Secondly, if visceral factors such as an infectious event in the gut affect the cortical response to visceral stimuli, and if conversely, psychological events can alter the function of the gut, gut-brain and brain-gut communication must be one of the important modulators involved [email protected] 2/02/15 FGID 51 Functional gastrointestinal disorders (FGIDs) can affect any part of the gastrointestinal (GI) tract, including the oesophagus, stomach and intestines. They are disorders of function, not structural or biochemical abnormalities. As a result, x-rays, blood tests and endoscopies can show essentially normal results. FGIDs are also not psychiatric disorders, although stress and psychological difficulties can make FGID symptoms worse. [email protected] 2/02/15 Three Primary Features of FGID 52 Motility is the muscular activity of the GI tract. Normal peristalsis is an orderly sequence of muscular contractions from the top to the bottom. In FGIDs, the motility is abnormal - there can be muscular spasms that can cause pain, and the contractions can be very rapid (fast motility is diarrhoea) or very slow (slow motility is constipation). Sensation is how the nerves of the GI tract respond to stimuli (for example, digesting a meal). In FGIDs, the nerves are sometimes so sensitive that even normal contractions can bring on pain or discomfort. [email protected] 2/02/15 Three Primary Features of FGID 53 Brain-gut dysfunction relates to the disharmony in the way the brain and GI system communicate. With FGIDs, the regulatory conduit between the brain and gut function may be impaired and this can lead to increased pain and bowel difficulties which can be worsened by stress. There is evidence that a brain to gut pathway may account for GI symptoms in some FGIDs, but other evidence points to the gut being the primary driver of symptoms via the gut to brain connections through cytokines. [email protected] 2/02/15 Biopsychosocial Model of FGID 54 The biopsychosocial model of FGID supports the concept that early life events, such as genetic and environmental factors, play an important role in increasing susceptibility to gut dysfunction, including the development of visceral hypersensitivity. [email protected] 2/02/15 FGID 55 Koloski et al., (2012) found a FGID diagnosis at baseline to be significantly associated with higher levels of anxiety and depression. FGIDs in the community are chronic and while there is a waxing and waning of symptoms they do not usually disappear on their own. Second, in the FGIDs, including IBS and functional dyspepsia, the hypothesis that early identification and treatment of psychological distress in patients presenting with abdominal pain like symptoms will help prevent the subsequent development of persistent FGIDs. [email protected] 2/02/15 Brain-Gut Axis 56 There is a bidirectional relation between the central nervous system and the digestive tract. Numerous data argue for a dysfunction of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS). Visceral hypersensitivity is peripheral and/or central in origin and may be the consequence of digestive inflammation or an anomaly of the nociceptive message treatment at the spinal and/or supraspinal level. Stress is involved in the genesis and maintenance of IBS. Disturbances of the autonomic nervous system are observed in IBS as a consequence of brain-gut axis dysfunction. [email protected] 2/02/15 GORD etc. 57 Altered autonomic function may be involved in gastrointestinal conditions, such as gastro-oesophageal reflux disease and neuropathic upper gastrointestinal motility disorders (Ogilive et al., 1985). More interestingly, such vagal abnormalities have also been identified in patients with functional gut disorders, including functional dyspepsia and colonic inertia(Haug et al., 1994) Aggarwal et al (1994) have shown convincingly that a subgroup of patients with IBS also showed various autonomic abnormalities. Patients with increased sympathetic activity and low vagal tone tended to have constipation, whereas diarrhoea prone patients primarily showed increased parasympathetic activity. Depression/anxiety [email protected] 2/02/15 FGID 58 The dietary carbohydrate fructose can be incompletely absorbed in the small intestine and is sometimes associated with gastrointestinal symptoms that include motility disturbances and abdominal pain. Fructose malabsorption has been well documented in variable but similar proportions of healthy and populations with functional gastrointestinal disorders. Restricting dietary fructose intake and other poorly absorbed short-chain carbohydrates and polyols remains an efficacious approach for managing FGIDs [email protected] 2/02/15 FGID 59 It is increasingly perceived that gut host–microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. [email protected] 2/02/15 IBS 60 Irritable Bowel Syndrome (IBS) is the most common digestive complaint, suffered by one in seven adults. It can occur at any age, but most likely between the ages of 20-60, with women being more susceptible than men. Sufferers report feeling pain in the belly, bloating and wind; and bouts of either diarrhoea or constipation or they may alternate (classified as IBS-D, IBS-C or IBS-A, respectively). As a functional gastrointestinal disorder (FGID), IBS has no known organic cause, a diagnosis of IBS is usually made by exclusion; when nothing else can be found. [email protected] 2/02/15 Habba Syndrome or IBS 61 Sometimes patients are diagnosed with IBS. This can be a “catch all” or “wastebasket” diagnosis. When patients are tagged with an IBS diagnosis, they can be dissatisfied and continue to change physicians in hopes of getting relief. Habba Syndrome can cause chronic diarrhoea or three or more bowel movements per day for at least three months. The diarrhoea is mostly after meals. The Habba Syndrome is a dysfunction of the gall bladder. There is inappropriate bile in the gastrointestinal tract. It can cause painful stools which are watery and without blood. Most of the patients have normal gallbladder ultrasounds. [email protected] 2/02/15 Habba Syndrome- Bile Acid Sequestrants 62 Studies have shown that the resin gum guggul, can decrease elevated lipid levels. The stereoisomers Eand Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR) [email protected] Zlim Trim Citrus Aurantium Synephrine (standardised) Hydroxycitric acid (HCA) Garcinia 0.5-2% E & Z Gugglesterones (Guggul) forskohlii extract, standardised to contain '185 forskolin' L-Tyrosine 2/02/15 IBS 63 Several conditions may present themselves as IBS, including coeliac disease, fructose malabsorption, mild infections, parasitic infections like giardiasis, several inflammatory bowel diseases, bile acid malabsorption, functional chronic constipation, small intestinal bacterial overgrowth, and chronic functional abdominal pain. The most common theory for IBS is that it is a disorder of the interaction between the brain and the gastrointestinal tract, although another common theory is that for at least some individuals with IBS there are abnormalities in the gut flora which results in inflammation and altered bowel function. [email protected] 2/02/15 Serotonin (5-HT) & IBS 64 Serotonin is an important gastrointestinal signalling molecule. It is a paracrine messenger utilised by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonergic signalling abnormalities have been putatively implicated in the pathogenesis of functional bowel diseases (Gershon & Tack, 2007). [email protected] 2/02/15 Serotonin (5-HT) & IBS 65 Serotonin exerts its effects via neurocrine, paracrine, and endocrine pathways. Recent studies have demonstrated that serotonin, acting primarily through 5-HT3 and 5-HT4 receptors, is intricately involved in initiating the peristaltic reflex and facilitating intraluminal secretions. GI motor activity and sensory dysfunction in patients with IBS may be a result of alterations in serotonin levels or associated 5-HT receptors. Serotonin agonists (for constipation IBS) and antagonists (for diarrhoeal IBS) may offer new treatments that normalise GI motor and sensory functions in patients with disorders of GI function. [email protected] 2/02/15 Da Jian Zhong Tang 66 Pericarpium Zanthoxyli Bungeani (hua jiao) Rhizoma Zingiberis Officinalis (gan jiang) Radix Ginseng (ren shen) Saccharum Granorum (yi tang) [email protected] Daikenchuto (Da-Jian- Zhong-Tang) dosedependently improved delayed gastrointestinal transit by acting as a 5-HT antagonist (Tokit et al., 2007) 2/02/15 Suan Zao Ren Tang 67 Semen Zizyphi Spinosae (suan zao ren) Radix Ligustici Wallichii (chuan xiong) Sclerotium Poriae Cocos (fu ling) Rhizoma Anemarrhenae Asphodeloidis (zhi mu) Radix Glycyrrhizae Uralensis (gan cao) [email protected] One ingredient of suanzaorentang, zizyphi spinosi semen, exhibits binding affinity for serotonin (5hydroxytryptamine, 5-HT) receptors, 5-HT(1A) and 5-HT(2), and for GABA receptors (Yi et al., 2007). 2/02/15 Ban Xia Hou Pu 68 Rhizoma Pinelliae Ternatae (ban xia) Cortex Magnoliae Officinalis (hou po) Sclerotium Poriae Cocos (fu ling) Rhizoma Zingiberis Officinalis (sheng jiang) Folium Perillae Frutescentis (zi su ye) [email protected] Magnolia bark (PMB) & Poria (PPO) were the two principal components of polysaccharides elevating 5-HT levels. BanxiaHoupu decoction attenuated abnormalities in the serotonergic and dopaminergic system functions (Yi et al., 2009) 2/02/15 IBS 69 RASCIBLY for Gut Harmony is a 20-herb Chinese medicinal formula that offers beneficial effects in patients with IBS. Studies showed that this brilliant product, a combination of 20 key botanicals, potently inhibited proinflammatory cytokines, macrophage marker nitric oxide synthase and decreased pro-inflammatory cytokine secretion from JAWS II dendritic cells. RASCIBLY also blocked the drop in transepithelial electric resistance and significantly suppressed the up-regulation of key inflammatory cytokines in inflamed colon. [email protected] 2/02/15 Panaxea RASCIBLY Angelicae Dahuricae Radix (Bai Zhi) Artemisiae Scopariae Herba (Yin Chen) Atractylodis Macrocephalae Rhizoma (Bai Zhu) Aucklandiae Radix (Mu Xiang) Bupleuri Radix (Chai hu) Citri Reticulatae Pericarpium (Chen Pi) Codonopsis Radix (Dang Shen) Coicis Semen (Yi Yi Ren) Coptidis Rhizoma (Huang Lian) Fraxini Cortex (Qin Pi) Glycyrrhizae Radix et Rhizoma (Zhi Gan Cao) [email protected] 70 Magnoliae Officinalis Cortex (Hou Po) Paeoniae Alba Radix (Bai Shao) Plantaginis Semen (Che Qian Zi) Phellodendri Amurensis Cortex (Guan Huang Bo) Pogostemonis Herba (Guang Huo Xiang) Poria (Fu Ling) Saposhnikoviae Radix (Fang Feng) Schisandrea Chinensis Fructus (Wu Wei Zi) Rhizoma Zingiberis Praeparatum (Pao Jiang) 2/02/15 SIBO 71 SMALL INTESTINE BACTERIAL OVERGROWTH [email protected] 2/02/15 SIBO not IBS 72 Here are the top 6 symptoms of SIBO: 1. 2. 3. 4. 5. 6. Abdominal bloating and distension Constipation Diarrhoea Abdominal pain or discomfort Acid reflux or heartburn Excessive gas or belching [email protected] 2/02/15 Here are six signs you might have SIBO 73 1. 2. 3. 4. 5. 6. You notice that fibre worsens your constipation. You notice an improvement in IBS symptoms when taking antibiotics. You feel more gas and bloating when you take probiotics that contain pre-biotics. You are coeliac or gluten intolerant and do not have 100% resolution of symptoms on a gluten-free diet. You develop chronic symptoms of gas, bloating, constipation or diarrhoea after taking pain medications, like opiates. Your blood work shows chronically low iron [email protected] 2/02/15 SIBO 74 The small intestine contains less than 10,000 bacteria per millilitre of fluid when compared with the large intestine at least 1,000,000,000 bacteria per millilitre of fluid and the types of bacteria normally present in the SI are different from those in the LI. SIBO is not caused by a single type of bacteria, but is an overgrowth of the various types of bacteria that should normally be found in the LI or a local SI overgrowth. SIBO may significantly interfere with digestion of food and absorption of nutrients, primarily by damaging the mucosal lining the small bowel. Additionally, this damage to the small bowel mucosa can lead to leaky gut [email protected] 2/02/15 SIBO 75 Patients with underlying SIBO have significant delays in small bowel transit time (SBTT) as compared with those without. The association between prolonged SBTT and positive lactulose breath testing (LBT) may be useful in identifying those patients with SIBO diagnosed by LBT and potentially target therapeutic option. Small bowel transit specifically predisposes to the development of SIBO (J Clin Gastroenterol. 2014 Oct 14). Low ileocaecal junction pressures (IJP) is significantly associated with SIBO (2014, doi: 10.1007/ s10620-014-3166-7). [email protected] 2/02/15 Risk factors for SIBO 76 Low stomach acid Irritable bowel syndrome Long-standing Coeliac disease Crohn’s disease Prior bowel surgery Diabetes mellitus (type I and type II) Multiple courses of antibiotics Organ system dysfunction, such as liver cirrhosis, chronic pancreatitis, or renal failure [email protected] 2/02/15 SIBO 77 The number of people with SIBO in the general population remains unknown. Some studies suggest that between 6 to 15% of healthy, asymptomatic people have SIBO, while up to 80% of people with irritable bowel syndrome (IBS) have SIBO (Gastroenterol Hepatol 2007). Antibiotics are often used to treat SIBO. However, studies show that despite treatment with antibiotics, recurrence develops in almost half of all patients within one year. Herbal therapies are at least as effective as rifaximin for resolution of SIBO. Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy (Global Advances. May 2014, Vol.3, No 3). [email protected] 2/02/15 SIBO 78 Extrinsic factors that alter the gut microbiome and may influence the development of small intestine bacterial overgrowth: FODMAPs (fructose, lactose, galactans, fructans, sugar alcohols) Proton pump inhibitors Anti-motility agents Fibre Prebiotics Probiotics Antibiotics [email protected] 2/02/15 How do we treat SIBO? 79 1. Diet options Paleo diet or autoimmune paleo diet Low FODMAP diet (http://www.taste.com.au/news+features/ articles/2752/low+fodmaps+diet) GAPS Diet (http://www.gapsdiet.com/ INTRODUCTION_DIET.html) Avoid all alcohol Use caution with probiotics/prebiotics Use caution with fermented foods as they can increase histamine [email protected] 2/02/15 How do we treat SIBO? 80 2. Antimicrobial herbs Berberine Epi-Gastro Formula ¡ Increases pepsin and enhances protein absorption Increases gastric emptying time Emodin AntiBioBotanical Scutellaria baicalensis extract baicalein (Kim et al., 2009) Genistein Phellodendron chinensis (huang bai) [email protected] 2/02/15 Panaxea Emodin 81 Emodin can enhance the function of small intestinal peristalsis of mice by mechanisms of promoting secretion of motilin, lowering the content of somatostatin and inhibiting Na+-K+-ATPase activity of small intestinal mucosa. Emodin increased the content of motilin, while reduced the content of somatostatin in the small intestine significantly (World J Gastroenterol. 2005 May 28;11:20). Emodin can inhibit the apoptosis of intestinal mucosa cells and up-regulate the serum leptin content to protect the intestinal barrier function and prevent the translocation of bacteria and endotoxin (2009, doi: 10.3736/ jcim20091215). [email protected] 2/02/15 FODMAPs 82 FODMAPs is an acronym that stands for Fermentable Oligo-, Di- and Mono-saccharides, and Polyols. This term was coined by a group of researchers who theorise that foods that contain these forms of carbohydrates exacerbate the symptoms of some digestive disorders, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). These substances are poorly absorbed by the small intestine and thus it is theorised that they may contribute to digestive difficulties in some people due to the processes of fermentation and/or osmosis. [email protected] 2/02/15 Panaxea Genistein 83 Genistein at low doses (0.1 mg/kg) had mild anti- inflammatory effects in ileitis (Crohn's ileitis is a type of Crohn's disease affecting the ileum). Therapeutic benefit included a reduction in nitric oxide production, granulocyte infiltration and improved mucosal architecture. Genistein, at low doses, also appeared to attenuate immunohistochemical staining for inducible nitric oxide synthase (iNOS) and nitrotyrosine (1998, doi: 10.3181/00379727-217-44244). SIBO might be a cause cause ileitis, particularly in women [email protected] 2/02/15 SIBO or IBD 84 SIBO represents a frequently ignored complication in Crohn’s Disease (CD), often mimicking an acute flare. The symptoms of SIBO can be difficult to differentiate from those caused by the underlying disease. People with Crohn’s disease have a predisposition to SIBO mostly due to altered motility from structures, fistulas or surgery. Several studies found that SIBO was present in 23 to 34% Crohn’s patients tested. [email protected] 2/02/15 Leaky Gut 85 While SIBO usually manifests with local GI symptoms, a leaky gut will manifest with complaints that affect the immune system throughout the body. Keep in mind that it is not uncommon to have both SIBO and leaky gut simultaneously. And very often, if you have SIBO for a long period of time, you will develop a leaky gut. About half of the patients diagnosed with SIBO will also have leaky gut. Most of the time if SIBO is treated, leaky gut will heal itself [email protected] 2/02/15 Panaxea Gut Clear 86 Uncaria rhynchophylla Coix lacryma-jobi (yi ren) (gou teng) Flos Chrysanthemi Indici (ye ju hua) Citrus aurantium (zhi ke) Trichosanthes kirilowii (tian hua fen) Angelica Dahurica (bai zhi) Agastache rugosa (huo xiang) Tribuli terretris (bai ji li) [email protected] Mentha haplocalyx (bo he) Hordeum vulgare (Mai Ya) Magnolia Flower (hou po hua) Atractylodes lancea (cang zhu) 2/02/15 Gut Clear Continued 87 Pueraria lobata (ge gen) Coptis chinensis (huang lian) Aucklandia lappa (mu xiang) Grapefruit Seed (pu tao zi) Asafoetida (Ferula Foetida) Gum Resin (60 to 75 percent concentrate) (a wei) [email protected] Indications Irritable bowel syndrome (IBS) Gut dysbiosis Small intestine bacterial overgrowth (SIBO) Diarrhoea / Constipation Low IgA response 2/02/15 IBD 88 CROHN'S DISEASE & ULCERATIVE COLITIS [email protected] 2/02/15 IBD 89 Cramping Irregular bowel habits, passage of mucus without blood or pus Weight loss Fever, sweats Malaise, fatigue Arthralgias Growth retardation and delayed or failed sexual maturation in children Extra-intestinal manifestations (10-20%): Arthritis, uveitis, or liver disease Grossly bloody stools, occasionally with tenesmus: Typical of UC, less common in CD Perianal disease (eg, fistulas, abscesses): Fifty percent of patients with CD [email protected] 2/02/15 IBD 90 Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. Inflammatory bowel disease (IBD) is not a single condition. It is the term for a group of disorders that cause prolonged inflammation of the digestive tract and the two most common types are ulcerative colitis and Crohn’s disease. There is no single cause although many suspect heredity, immune disregulation, stress, smoking and alcohol, gender and age, and geographical location as urban areas and industrialised countries have a higher risk. (no dirt to eat) [email protected] 2/02/15 IBD 91 We could be "poisoning the world with our McDonalds’ and fatty fried foods," says Balfour Sartor, MD, chief medical advisor for the Crohn’s & Colitis Foundation of America. "We’re purifying water, embarking on sanitation, and dramatically changing the environment. Any one or a combination of these factors could be affecting this.” Crohn's disease was more common in subjects whose first houses had a hot-water tap (odds ratio 5·0, 95% Cl 1·4– 17·3) and separate bathroom (3·3, 1·3–8·3) (1994, DOI: 10.1016/S0140-6736(94)91841-4). [email protected] 2/02/15 IBD 92 Literature suggests that the hygiene hypothesis and its association with decreased microbial exposure in childhood probably plays an important role in the development of IBD. The most promising factors that may potentially be associated with development of IBD include H pylori exposure, helminths, breastfeeding and sibship. Improved hygiene is believed to result in a limited exposure to micro-organisms. Such exposure is thought to be necessary in programming the immune system of the gut and mitigating its future inflammatory responses, perhaps even resulting in CD when the immune system is challenged (Am J Gastroenterol. 2006 May;101,5). [email protected] 2/02/15 IBD & Stress 93 Stress-exposed subjects demonstrated increased risk of clinical episodes of disease when compared with unexposed subjects (RR = 2.6, 95% CI: 1.3–4.9). Elevated effect measures were highest for the domain of health-related stress (RR = 3.8, 95% CI: 1.5–9.9). In the multiple regression analysis, major stress events remained the most significant indicator of disease activity in the presence of the co-variables considered (1991, DOI: 10.1080/08964289.1991.9937553. There is consistent evidence for a contribution of psychological factors to IBD disease course, especially stress in UC and depressive symptoms in CD (2008, DOI http://dx.doi.org/10.2174/156652408784533832. [email protected] 2/02/15 IBD & Vagus Nerve 94 The Inflammatory Reflex (IR) describes an interaction between the vagus nerve and peripheral macrophages, which result in attenuation of proinflammatory cytokine release in response to systemic exposure to bacterial endotoxin. The vagus nerve plays a counter-inflammatory role in acute colitis via a macrophage-dependent mechanism. The identification of a counter-inflammatory neural pathway opens new therapeutic avenues for treating acute exacerbations of inflammatory bowel disease (Ghia et al, 2006). [email protected] 2/02/15 NSAIDs & IBD 95 Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are known to disrupt the intestinal epithelial barrier. This disruption may alter the interaction between gut microbes and immune cells and, secondarily, may raise risk for inflammatory bowel disease. NSAIDS is associated with a small increase for the incidence of ulcerative colitis (Ann Intern Med. 2012 http://www.annals.org/content/156/5/350.full) [email protected] 2/02/15 Vitamin D 96 In epidemiological studies serum levels below 30 nM of 25- OHD3, the precursor of the active vitamin D metabolite 1,25-(OH)2D3, were consistently associated with incidence of colorectal cancer. The active vitamin D metabolite possesses antimitotic, pro-differentiating and proapoptotic capacity in vivo and in vitro. VDR-mediated signaling antagonising TNF-α and IL-6 receptor-activated pro-inflammatory and proliferative intracellular pathways, may prevent development of IBD and colitis-associated colorectal cancer (2011, DOI: 10.1016/j.mce.2011.07.022). [email protected] 2/02/15 IBD 97 The commensal intestinal microbiota drive the inflammation associated with Crohn's disease. However, bacteria such as bifidobacteria appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduced proportions of interleukin (IL)-6 to reduce disease activity in patients with Crohn's disease (Benjamin et al, 2011). [email protected] 2/02/15 IBD 98 Stools from 109 patients with inflammatory bowel disease (13.4%) contained C. difficile or its toxin, an incidence similar to the stools of 99 control patients with diarrhoea (11.9%), but significantly higher than the stools of 77 control patients with a normal bowel habit (1.4%) (Greenfield et al, 1983). C difficile colitis has doubled in North America over the past 5 years and recent reports have demonstrated an increase in incidence and severity of these infections in patients with inflammatory bowel disease (IBD; Crohn's disease, ulcerative colitis) (Issa et al, 2008). [email protected] 2/02/15 C. difficile 99 The annual rate of disease has risen more than 20-fold due to use of proton-pump inhibitors (PPIs). In a case-control analysis, older age, prior hospitalisation, and antibiotic use all correlated strongly with increased risk for Clostridium Difficile-Associated Diseases/Diarrhoea (CDAD). Gastric-acid suppression has been associated with an increased risk for bacterial enteric infections such as salmonellosis, and several studies now suggest that it also heightens risk for CDAD (Hookman P & Barkin, 2006). [email protected] 2/02/15 C. difficile 100 There are new data on the aetiology of and potential risk factors for Clostridium difficile infection (CDI); controversial issues include specific antimicrobial agents, gastric acid suppressants, potential animal and food sources of C. difficile, and the effect of the use of alcoholbased hand hygiene agents (Freeman et al, 2010). The epidemiology of CDI has changed dramatically during this millennium. [email protected] 2/02/15 C. Difficile Infection 101 In humans the disease pseudomembranous colitis, caused by Clostridium difficile, is almost always a consequence of antibiotic treatment. In humans it has been shown that administering faecal enemas derived from a healthy human adult can reverse C. difficile infection (CDI). In chickens it has long been known that dosing newly hatched chicks per Os with faecal suspension from adult hens can prevent the establishment of salmonellae in the gut. [email protected] 2/02/15 C. Difficile Infection 102 Faecal transplantation through colonoscopy seems to be an effective treatment for recurrent CDI and also for recurrent CDI caused by the virulent C. difficile 027 strain. During the first 12 weeks after faecal transplantation, symptoms resolved in all patients who did not have strain 027 C. difficile infections. Of 36 patients with 027 C. difficile infection, 32 (89%) had a favourable response (2012. http://dx.doi.org/10.1053/j.gastro.2011.11.037) [email protected] 2/02/15 Autism & C. Difficile 103 Novel findings associated with alterations in nicotinic acid metabolism within autistic individuals showing increased urinary excretion of N-methyl-2-pyridone-5-carboxamide, N-methyl nicotinic acid, and N-methyl nicotinamide indicate a perturbation in the tryptophan−nicotinic acid metabolic pathway. These biochemical changes are consistent with some of the known abnormalities of gut microbiota found in autistic individuals. Children with autism are producing toxins that might interfere with brain development. One of the compounds identified in the gut is C. Difficile (Yap et al 2010), [email protected] 2/02/15 Blastocystis hominis 104 Case reports and series have suggested a pathogenic role of B. hominis in causing intestinal inflammation. Also some studies have suggested that inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are associated with B. hominis infection (Ustün & Turgay, 2006). Blastocystis is a very peculiar organism in that it especially likes grains. Many people with Blastocystis may have grain allergies or difficulties tolerating grains. [email protected] 2/02/15 Reduced Firmicutes in CD 105 The role of the intestinal microbial community (microbiota) in the onset and chronicity of Crohn's disease (CD) is strongly suspected, mainly represented by the phyla Bacteroidetes and Firmicutes. Among the Firmicutes, 43 distinct ribotypes were identified in the healthy microbiota, compared with only 13 in CD. The reduced complexity of the bacterial phylum Firmicutes is a signature of the faecal microbiota in patients with CD (Manichanh et al, 2006). [email protected] 2/02/15 IBD 106 Despite extensive research, the exact cause of Crohn’s disease remains unknown. People with Crohn’s have various mutations (NOD2, ATG16L1, IL-23, IL12B, STAT3 and NKX2-3) in their genes that healthy people don’t have. Expression of the altered genes affects how bacteria interact with the intestinal surface and how our immune system interacts with these adherent bacteria. One thing is clear – People with Crohn’s have an altered microbiome, suffering a 50% decrease in the diversity of gut microbes including the loss of bacterial species Bacteriodes, Eubacterium and Lactobacillus [email protected] 2/02/15 IBD 107 The composition of the intestinal microflora has been proposed as an important factor in the development of inflammatory bowel diseases (IBD). Antibiotics have the potential to alter the composition of the intestinal microflora. There is a strong association between antibiotic use and CD in childhood. [email protected] 2/02/15 Panaxea Gut Bug 108 Sophorae Flavescentis (Ku Sclerotium Poriae (Fu Shen Gen) Corneum Gigeriae Galli (Ji Nei Jin) Sargento Doxae (Hong Ten) Stemonae (Zhi Bai Bu) Arecae Catechu (Bing Lang) Quisqualis (Shi Jun Zi) Glycyrrhizae (Gan Cao) Ling) Pericarpium Citri Reticulatae (Chen Pi) Dioscorea Bulbiferous Huang Yao Zi) Testa Dolichoris (Bian Dou) Atractylodis Macrocephalae (Bai Zhu) Saussureae Lappae (Mu Xiang) [email protected] 2/02/15 Panaxea UC 109 Scutellaria baicalensis Purges Toxic Heat and (contains extract berberine regulates Damp (BE) Ulcerative Colitis Glycyrrhiza uralensis (contains Crohn’s Disease extract glycyrrhizin (GL) Gastrointestinal Pinellia Tuber (ban xia) Inflammatory Disorders Scutellaria Root (huang qin) Inflammatory Bowel Panax Ginseng, red (ren shen) Disease standardised ginsenosides Zizyphus jujuba (da zao) Glycyrrhiza uralensis (zhe gan cao) Coptis japonica (huang lian) [email protected] 2/02/15 IBD 110 Higher scores of neuroticism, depression, inhibition, and emotional instability, are typical for many patients with chronic diseases and nonspecific for chronic gastroenterological disorders. Patients with chronic gastrointestinal disorders have impaired health-related quality. Psychological treatment in IBD achieved lower demands for health care rather than a reduction of anxiety or depression. Psychotherapy with chronic gastrointestinal disorders could lead to improve the course of the disease, changing psychological factors such as depression and dysfunctional coping and improving the patient's quality of life. [email protected] 2/02/15 IBD & Depression 111 Psychological factors such as a depressive mood associated with anxiety and impaired QOL may exert a negative influence on the course of IBD. Therefore, assessment and management of psychological distress should be included in clinical treatment of patients with IBD. Depression was found in 28% of patients, and 59% experienced at least one relapse during the 18 months of follow-up (Mittermaier et al, 2004). [email protected] 2/02/15 IBD & Depression 112 Depression may coexist with Crohn’s disease more often than would be expected by chance. Clinical and experimental evidence indicates that intestinal inflammatory conditions can be exacerbated by depression. The tonic counter-inflammatory influence mediated by the vagus nerve in experimental colitis provides a potential link between behaviour and gut inflammation. Depressive-like behaviours in mice increased susceptibility to intestinal inflammation by interfering with the tonic vagal inhibition of pro-inflammatory macrophages and produced a vulnerability to colitis by a mechanism involving parasympathetic transmission (Ghia et al, 2008). [email protected] 2/02/15 Treatments 113 IBD Panaxea UC regulates intestinal hormones somatostatin, motilin, and gastrin. Down-regulates pro-inflammatory cytokine levels in the colon, including TNF, IFN-γ, Keratinocyte chemoattractant (KC), and IL-17 and increases regulatory cytokine IL-10. Suppresses inflammatory bowel disease (IBD) and significantly reduces colonic damage. ¡ Panaxea Curcumin is an adjunct to treatment protocols for IBS, Crohn’s disease, Ulcerative colitis, Diabetes, Alzheimer's, RA & Cancer. ¡ Panaxea ICC reduces various inflammatory mediators, including interleukin-6 (IL-6), IL-1 beta, TNF-alpha, prostaglandin E2 and leukotrienes. ¡ [email protected] 2/02/15 Panaxea UC 114 Scutellaria baicalensis Panax Ginseng, red (contains extract berberine (BE) Glycyrrhiza uralensis (contains extract glycyrrhizin (GL) Pinellia Tuber (Bàn Xià) Scutellaria Root (Huáng Qín) (Hong Rén Shēn) standardised ginsenosides Zizyphus jujuba (Dà Zǎo) Glycyrrhiza uralensis (Zhì Gān Cǎo) Coptis japonica (Huáng Lián) [email protected] 2/02/15 IBD 115 Using IBD as a model of inflammation, we explore the principal complementary and alternative medicine treatments that show promise in this regard, namely, resveratrol, green tea, curcumin, boswellia, fish oil, vitamin D, and probiotics (Clarke JO & Mullin, 2008). These compounds have the ability to modulate the immune system and disrupt the proinflammatory cascade through a variety of mechanisms, including antioxidant effects, alterations in cell signalling (in particular the nuclear factor (NF)-κB pathway), cytokines, proinflammatory mediators, and disruption of bacterial flora. [email protected] 2/02/15 Panaxea Puerarin 116 Oxidative stress is believed to be a key factor in the pathogenesis and perpetuation of the mucosal damage in IBD. In addition, neutrophils and monocytes in patients with active IBD have been shown to produce higher concentrations of oxygen-derived free radicals than those in controls. Malondialdehyde (MDA), Glutathione (GSH) levels in the gut mucosa and histological analysis were measured in tissue samples. Compared with model control group, puerarin group showed significantly lower mucosal MDA and higher mucosal GSH levels after 2 and 8 hr. Puerarin can maintains GSH levels and reduced lipid peroxidation and partly by decreasing Caspase-3 expression (Liu & Chen, 2009) [email protected] 2/02/15 Puerarin 117 Contemporary pharmacological research has demonstrated that puerarin, the most important phytoestrogen extracted from Pueraria lobata, has protecting functions on the cardiovascular system, nervous system, osteoporosis, liver injury, and inflammation in vivo and in vitro. Most of these research studies focused on inhibiting oxidative stress and apoptosis through regulating various bio-activators and signal pathways (2014, doi: 10.1016/ S1875-5364(14)60064-9). Mucosal iNOS gene expression decreased significantly in puerarin high-treated group (Liu & Chen, 2005) [email protected] 2/02/15 IEC Apoptosis 118 Intestinal epithelial cells derive from stem cells at the base of the crypt and migrate along the crypt-lumen axis. Their life is terminated as they reach the luminal surface where they detach and are shed. Intestinal epithelial cells show evidence of apoptosis in the region of shedding, and cell death is thought to resemble a form of apoptosis called detachment-induced cell death, or anoikis (Grossmann et al, 1998). They have a lifespan of about 4 weeks (Histology. n.d.) [email protected] 2/02/15 IEC Apoptosis 119 Intestinal epithelial cell (IEC) apoptosis contributes to the development of ulcerative colitis (UC), an inflammatory bowel disease (IBD) that affects the colon and rectum. Therapies that target the inflammatory cytokine TNF have been found to inhibit IEC apoptosis in patients with IBD, although the mechanism of IEC apoptosis remains unclear (Qiu et al, 2011). [email protected] 2/02/15 Advanced Mucosal Healing 120 Advanced mucosal healing (MH) is a complex phenomenon viewed as a succession of steps necessary to restore tissue structure and function. These steps include epithelial cell migration and proliferation, cell differentiation, restoration of epithelial barrier functions, and modulation of cell apoptosis. Data suggest that supplementation with specific amino acids including arginine, glutamine, glutamate, threonine, methionine, serine, proline, and the amino acid-derived compounds, polyamines can favourably influence MH. [email protected] 2/02/15 Advanced Mucosal Healing 121 Short-chain fatty acids, which are produced by the microbiota from undigested polysaccharides and proteinderived amino acids, also exert beneficial effects on the process of intestinal MH in experimental models as well as endogenous prostaglandin synthesis. Among micronutrients, several vitamin and mineral deficiencies with different frequencies have been observed in patients with inflammatory bowel diseases and supplementation with some of them (vitamin A, vitamin D3, vitamin C, and zinc) are presumed to favour MH (Inflamm Bowel Dis. 2014 Sep 9). [email protected] 2/02/15 Colo-Rectal Cancer 122 [email protected] 2/02/15 Panaxea Artesunate (oral & IM) 123 Artesunate significantly inhibited both the invasiveness and anchorage independence of colon cancer SW620 cells in a dose-dependent manner. The protein level of intercellular adhesion molecule 1 (ICAM-1) was down-regulated as relative to the control group. Artesunate could potentially inhibit invasion of the colon carcinoma cell line SW620 by down-regulating ICAM-1 expression (Fan, Zhang, Yao & Li, 2008). MDR: Artesunate acts via p53-dependent and- independent pathways in isogenic p53+/+ p21WAF1/CIP1+/+, p53-/p21WAF1/CIP1+/+, and p53+/+ p21WAF1/CIP1-/- colon carcinoma cells (Efferth et al., 2003). [email protected] 2/02/15 Panaxea Ai Di Injection 124 There are significant differences in clinical benefit response and KPS score with Ai Di Injection (ADI). In addition, adverse gastrointestinal reactions and the incidence of leukopenia were lower than that of the control group. Aidi injection, combined with FOLFOX4, is associated with reduced toxicity of chemotherapy, enhanced clinical benefit response, and improved quality of life in patients with advanced colorectal cancer (Xu, Huang, Li, Li, & Tang, 2011). [email protected] 2/02/15 Ai Di Injection (ADI) 125 Mylabris phalerata (ban mao) Panax ginseng (ren shen) Astragalus membranaceus (huang qi). 50-100ml once daily: 10 days as a course of treatment. Single application: 15 days as a cycle, with 3 days interval., 2 cycles as a course of treatment. [email protected] When combined with radiotherapy or chemotherapy: treatment is synchronised to radiotherapy or chemotherapy. Application before or after the surgery: 10 days as a course of treatment. 2/02/15 Panaxea CRC 126 Herba Hedyotiolis Diffusae CRC combined with chemotherapy significantly (Bai Hua She She Cao) increased 1- and 3-year survival Flos Lonicerae Japonicae rate. The combined therapy (Jin Yin Hua) significantly slowed colorectal Radix Scutellariae cancer progression and improved Baicalensis (Huang Qin) quality of life. Herba Solani Nigri (Long It had positive effects in immunoKui) regulation. Caulis Sargentodoxae (Hong CRC as an adjunctive therapy also Teng) had significant advantages in reducing the adverse effects of Fructus Sophorae Japonicae chemotherapy (Zhong et al., Immaturus (Huai Jiao) 2012). Radix Sanguisorbae Officinalis (Di Yu) [email protected] 2/02/15 Probiotics 127 [email protected] 2/02/15 Caesarean & Gut Health 128 Children born by caesarean are 26% much more likely to be admitted to hospital with gastrointestinal disease or 12% more likely for chest infections than those born vaginally. These babies miss out on picking up important gut bacteria when passing through the vagina. 626,700 births were tracked in NSW, Australia from 2001-2008 as reported in the journal Archives of Diseases in Childhood (Roberts et al, 2012) [email protected] 2/02/15 Probiotics in Pregnancy 129 Neonates of mothers who received a probiotic had higher cord blood (CB) IFN-γ levels, and a higher proportion had detectable blood IFN-γ levels, compared with the placebo group. This suggests that supplementation with probiotics in pregnancy has the potential to positively influence foetal immune parameters as well as immunomodulatory factors in breast milk (Prescott SL, et al. 2008) [email protected] 2/02/15 Alimentary System Plants Soil Plants Genetics Faeces Age Environment Stress Diet Antibiotics Chemicals NSAIDS Intestinal Flora Eubiosis Health Mammals Dysbiosis Un-health Disease The intestinal flora influence the immune system and regulate the body's ability to cleanse itself of waste products i.e. detoxification. A harmonised and balanced flora will contribute to a better absorption of nutrients, such as minerals, trace elements, vitamins and amino acids. © DR.D.Weber 2012 130 2/02/15 Panaxea ProB)Plus 131 Astragalus Polysaccharide (APS) Germinated barley foodstuff (GBF) Probiotic Blend Lactobacillus plantarum Lactobacillus rhamnosus Lactobacillus paracasei Lactobacillus salivarius Bifidobacterium infantis Bifidobacterium bifidum [email protected] Maintains and stabilises gut microflora. Increases microflora after antibiotic therapy. Modulates systemic immunity and intestinal microbiota. Reduces colonic mucosal inflammation. 2/02/15 ProB)Plus 132 Symptoms associated with intestinal flora imbalance such as: diarrhoea, constipation, bloating and flatulence. Colonic mucosal inflammation. Irritable Bowel Syndrome Inflammatory Bowel Disease Acute diarrhoea Antibiotic-induced diarrhoea [email protected] 2/02/15 ProB)Plus 133 Based on findings by Aiba et al (1998), L. salivarius was found to be a potentially effective probiotic against H. pylori. L. plantarum produces antimicrobial substances. These antimicrobial substances have shown significant effect on Gram-positive and Gram-negative bacteria (Kleerebezem et al, 1995). Intestinal colonisation by TNFαinhibitory L. paracasei reduced intestinal inflammation in H. hepaticus-challenged IL-10-deficient mice and had a direct modulation of mucosal inflammatory responses (Peña et al, 2005). [email protected] 2/02/15 ProB)Plus 134 There is an important role of bacteria in the bidirectional communication of the gut–brain axis and certain organisms prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression. L. rhamnosus reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus reduced stress-induced corticosterone and anxiety, and depressionrelated behaviour via the vagus nerve (Bravo et al, 2011). [email protected] 2/02/15 ProB)Plus 135 Astragalus polysaccharide had promoting growth action to probiotics (Liu et al, 2005) and all the tonic traditional Chinese medicines have a certain modulation in dysbacteria (Shi et al, 2005). Chinese herbal medicines may replace the using of antibiotic to play an important role on intestinal microecology balance (Li et al, 2003). Probiotics and Astragalus polysaccharides (APS) can modulate systemic immunity and intestinal microbiota. Results showed that probiotics combined with APS administration displayed synergistic modulation effects on immunity and intestinal microbiota (Li et al, 2008). [email protected] 2/02/15 ProB)Plus 136 Germinated barley foodstuff (GBF) reduces colonic mucosal inflammation. GBF effectively prevents colitis-related dysplasia and inflammatory change in chronic and subacute colitis models by modulating the intestinal environment as a prebiotic. This prebiotic might contribute to the prevention of mucosal damage including colorectal cancers (Komiyama et al, 2011). GBF significantly elevated faecal acetic acid and n-butyric acid levels. GBF tended to increase the number of eubacteria and that of bifidobacteria (Araki et al, 2000). [email protected] 2/02/15 Stomach Disorders 137 GASTRO-OESOPHAGEAL-REFLUX DISORDER GASTRIC ULCER, GASTRIC BLEEDING, GASTRITIS, GASTRIC CANCER, OESOPHAGEAL ADENOCARCINOMA [email protected] 2/02/15 GORD 138 Gastro-oesophageal reflux disease is a chronic symptom of mucosal damage caused by stomach acid coming up from the stomach into the oesophagus. GORD is usually caused by changes in the barrier between the stomach and the oesophagus, including abnormal relaxation of the lower oesophageal sphincter, which normally holds the top of the stomach closed or impaired expulsion of gastric reflux from the oesophagus. GORD is more common in the Western world than in Asia, and the low rate of incidence relative to prevalence reflects its chronicity. [email protected] 2/02/15 GORD 139 The most-common symptoms of GORD are: Heartburn and regurgitation Less-common symptoms include: Pain with swallowing/sore throat (odynophagia) Increased salivation (also known as water brash) Nausea Chest and upper back pain Dry cough Factors that have been linked with GORD, but not conclusively: Obstructive sleep apnea Gallstones, which can impede the flow of bile into the Duodenum, which can affect the ability to neutralise gastric acid [email protected] 2/02/15 Causes of GORD 140 Being overweight but not high fat food consumption is implicated as causes of reflux disease. Other factors associated with reflux disease hospitalisation included age, low recreational activity, and history of doctor-diagnosed arthritis. In practice the treatment of GORD is oriented toward the individual patient's symptoms, and includes offering reasonable advice on how to adapt to personal dietary intolerance and lifestyle factors. [email protected] 2/02/15 PPI 141 A recent study determined that proton pump inhibitors (PPIs), drugs used to treat chronic acid reflux, cause the constriction of blood vessels. The finding raises concern that long term use of PPI drugs such as omeprazole and lansoprazole will lead to high blood pressure and a weakened heart. PPIs suppressed the enzyme DDAH, dimethylarginine dimethylaminohydrolase. That caused an increase in the blood levels of ADMA (asymmetric dimethylarginine), an important chemical messenger. They found ADMA in turn suppressed the production of another chemical messenger, nitric oxide (NO). [email protected] 2/02/15 PPI 142 In 2009 a staggering 113.4 million prescriptions for proton pump inhibitors (PPIs) are filled, making this class of drugs, at $13.9 billion in sales, the third highest seller in the United States. It should come as no surprise that PPIs have been shown to be overprescribed; between 53% and 69% of PPI prescriptions are for inappropriate indications (Arch Intern Med. 2010;170(9):747-748). It has been proposed that long-term acid suppression in the presence of H. pylori infection accelerates the development of atrophic gastritis, which may lead to gastric cancer (www.gesa.org.au/members_guidelines/helicobacter/ index.htm). [email protected] 2/02/15 PPI 143 Most of patients with GORD have a sleep disorder. Melatonin has an inhibitory action on gastric acid secretion and seems to control the lower oesophageal sphincter. Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. Omeprazole (one of the PPIs) and melatonin have similarities in their chemical structures (2010 doi: 10.4292/wjgpt.v1.i5.102) [email protected] 2/02/15 Melatonin 144 Excess alcohol consumption and stress are suggested to be key elements in the development of gastrointestinal disorders (Konturek et al. 2011). Dysfunction of the small intestinal barrier function with increased permeability is a common clinical observation in patients with inflammatory bowel syndrome (IBS) and alcoholic liver disease (Sommansson et al. 2013). Therapeutic administration of melatonin has shown to be beneficial, and clinical studies have demonstrated attenuated abdominal pain in IBS (Song et al. 2005). [email protected] 2/02/15 Melatonin 145 Melatonin is a circulating hormone released from cells in the pineal gland and from enterochromaffin cells in the gastrointestinal tract. The hormone is a close derivative of serotonin, and circulating levels are high at night and low during the day. Hence, the classical function of melatonin is as a regulator of circadian and seasonal rhythms. Besides this, melatonin has been demonstrated to have multiple other functions. It affects the cardiovascular system and immune system and is involved in regulation of body fat mass, insulin secretion and metabolism of glucose and lipids (2014, DOI: 10.1111/apha.12364). [email protected] 2/02/15 Melatonin 146 The work by Sommansson et al. (2014) for the first time establishes beneficial effects of oral application of melatonin on tissue damage in the small intestine. Melatonin is a cheap and non-toxic molecule that has great potential to have beneficial effects on public health, not only on gastrointestinal disorders but also metabolic diseases (Song et al. 2005, Mulder et al. 2009, Nduhirabandi et al. 2012). [email protected] 2/02/15 PPI & SIBO 147 Small intestinal bacterial overgrowth (SIBO) occurs due to alteration of the microbiota within the upper gastrointestinal tract. Proton pump inhibitor (PPI) therapy has been suggested as a risk factor for SIBO. PPIs exacerbate NSAID-induced intestinal damage at least in part because of significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be a viable option for reducing the incidence and severity of NSAID enteropathy. [email protected] 2/02/15 GORD/Reflux 148 Panaxea Core)Ease ¡ CORE)EASE is based on a classical formula sometimes referred to as CALM THE STOMACH POWDER. It has the advantage over the classical formula in including a group of isolates. This combined with herbs facilitates faster and more effective clinical outcomes. ¡ CORE)EASE is an antiinflammatory & carminative and has powerful effects on two systems: Gastro-Intestinal and Gynaecological. CORE)EASE acts on the whole digestive system, removing obstruction and stagnation by elimination via the intestines. [email protected] 2/02/15 GORD/Reflux 149 Panaxea ZJP (Ethanol extraction only) ¡ Huang Lian (coptis rhizome) 85.7% ¡ Wu Zhu Yu (evodia fruit) 14.3% ¡ The anti-inflammatory properties of ethanol extract from ZJP might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1β, and TNF-α expression through preventing the nuclear translocation of the NF-κB p50 and p65 subunits in RAW 264.7 cells. In addition, these results provided evidence to understand the therapeutic effects of ZJP on gastritis, gastric ulcer, and other inflammatory diseases in clinic. Stomach ‘Cold’ ¡ Ethanol extract from ZJP produced antidepressant-like effect and the possible mechanism, at least in part, is via the central monoaminergic neurotransmitter system and 5-HT plays a major role [email protected] 2/02/15 H. pylori 150 H. pylori is one of humanity’s old friends and companions: the bacteria has been in human stomachs for at least 50,000 years, and probably longer. Roughly fifty percent of all humans carry it (Science. 2003 Mar 7;299:5612). Interestingly, the percentage of infected people has been decreasing since the 1950s, with richer countries having much lower rates than the rest of the world. In the US, less than 25 percent of adults and only about 5 percent of all school children are infected. [email protected] 2/02/15 H. pylori 151 Every infected person harbour their own individual H. pylori strain, but strains can undergo genetic alteration in vivo, driven by an elevated mutation rate and frequent intraspecific recombination. This genetic variability, which affects both housekeeping and virulence genes, has long been thought to contribute to host adaptation (2007, doi: 10.1038/nrmicro1658). Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases (2009, doi:10.1172/JCI38605). [email protected] 2/02/15 H. pylori 152 In spite of being a highly prevalent bacterium in the gastric mucosa, only 15 % of carriers develop overt disease. Bacterial pathogenesis is believed to arise from an interaction of strain-specific immunity-mediating capabilities and the host susceptibility. In a healthy host, the H. pylori strains that are asymptomatically tolerated are those with the ability to invade the mucous layer as well as those that inhibit the ability of epithelial cells to secrete defensin and chemoattractants (Wendelsdorf et al. Immunology Conference 2011). [email protected] 2/02/15 H. pylori 153 Since the 1950s, the number of patients with allergies, asthma or autoimmune diseases has sky-rocketed. Children without Helicobacter in their stomachs are more likely to suffer from skin allergies or hay fever. The bacteria also seem to provide a certain protection against coeliac conditions, also wheat FODMAPs intolerance. The bacteria might even manipulate our appetite: the New York based doctor Martin Blaser assumes a connection between its eradication and the growing obesity problem worldwide. [email protected] 2/02/15 Chronic Atrophic Gastritis 154 When severe inflammation of gastric membrane destroys gastric mucosal epithelial cells, gastric glandular cells are destroyed and eventually replaced by intestinal-type epithelial cells with high cell proliferative rate and fibrosis. Then chronic atrophic gastritis with intestinal metaplasia and dysplasia, an important causative factor for gastric cancer, occurs. Intestinal metaplasia disturbs the cell proliferation and apoptosis in normal gastric mucosa and increases incidence of gastric cancer which is the second most common cause of cancer deaths worldwide. [email protected] 2/02/15 Chronic Atrophic Gastritis 155 53 Chinese medicinal herbs and prescriptions were investigated for chronic atrophic gastritis (CAG), Panax notogenseng and Magnolia officinalis were discovered to be sensitive, Prunus mume and Corydalis Yanhusuo were moderate sensitive, and Coptis chinensis and Rheum palmatum highly sensitive to HP. Decoction of Clearing up the Heat and Relieving the Blood Stasis (CHRBS) was used to treat 70 CAG patients with Stomach Heat Syndrome. The effective rate of gastroscopic examination was 85.7% (Zhang et al, 1995) [email protected] 2/02/15 Zhu Yu Tang (CHRBS) 156 Semen Persicae (Tao Ren) Poria (Fu Ling) Flos Carthami (Hong Hua) Caulis Spatholobi (Ji Xue Rhizoma Sparganii (San Leng) Rhizoma Curcumae (EZhu) Rhizoma Chuanxiong (Chuan Xiong) Radix Salviae Miltiorrhizae (Dan Shen Radix Angelicae Sinensis (Dang Gui) Radix Paeoniae Alba (Bai Shao) [email protected] Teng) Sanguis Draconis (Xue Jie) Ramulus Cinnamomi (Gui Zhi) Ramulus Mori (Sang Zhi) Rhizoma Cimicifugae (Sheng Ma) Flos Caryophylli (Ding Xiang) 2/02/15 Zhu Yu Tang (CHRBS) 157 Rhizoma et Radix Notopterygii (Qiang Huo) Rhizoma Cyperi (Xiang Fu) Rhizoma Alpiniae Officinarum (Gao Liang Jiang) Radix Gentianae Macrophyllae (Qin Jiao) Rhizoma Corydalis (Yan Hu Suo) Cortex Moutan (Mu Dan Pi) [email protected] Radix Cyathulae (Chuan Niu Xi) Semen Nelumbinis (Lian Zi) Fructus Jujube (Da Zao) Radix Glycyrrhizae (Gan Cao) Fructus Liquidamberis (Lu Lu Tong) 2/02/15 Weiqi Decoction Radix Angelicae Sinensis (dang gui) 20g Radix Astragali (huang qi) 25g Radix Codonopsis (dang shen) 20g Rhizoma Curcumae Ezhu 25g Fructus Aurantii (zhi qiao) 25g Fructus Akebiae (ba yue zha) 25g Herba Taraxaci (pu gong ying) 50g [email protected] 158 Inhibits AGS cell proliferation through G2/ M arrest due to downregulation of cyclin B1 protein expression, and promotes apoptosis by caspase-3 and mitochondria-dependent pathways (Chin J Integr Med 2014 Jun;20,6) 2/02/15 Panaxea Epi-Gastro Enzyme Formula 159 Radix Linderae (wu yao) Hypochlorhydia Flos Lonicera (jin yin hua) SIBO Endothelium Corneum Gigeriae Galli (ji nei jin) Alpha-Amylase Tryptin Protease Lipase Bromelain Papain Pepsin Cellulase [email protected] Gastric Ulcer Poor protein absorption Pepsin deficiency Slow gastric emptying time 2/02/15 Insulin Resistance 160 Extragastric or extraintestinal manifestations of Helicobacter pylori has been linked with insulin resistance (IR). The metabolic syndrome consists of several known factors which include IR, abnormal fat metabolism, hypertension, abdominal obesity, proinflammatory and prothrombotic state. H. pylori infection and metabolic syndrome both show increase in prevalence with age, and since IR is a key factor in the pathogenesis of metabolic syndrome, research of a possible correlation between H. pylori infection and IR has intensified in the last decade (doi: 10.3748/ wjg.v20.i16.4607). Research has demonstrated a direct link between H. pylori infection and IR [email protected] 2/02/15 H. Pylori infection Chronic Inflammation Psychophysical Factors Gastric Hormones Leptin Ghrelin Gastrin Somatostatin Inflammatory Cytokines IL-1β, TNF, CRP Insulin Resistance Insulin Secretion T2DM [email protected] 161 2/02/15 H. pylori 162 Helicobacter pylori (H. pylori) has been conclusively related to several gastro-duodenal diseases. The possible role of the bacterium in the development of extragastric manifestations has been investigated. Controversial findings of H. pylori seroprevalence have been obtained in patients with bronchial asthma, lung cancer, pulmonary tuberculosis, sarcoidosis, cystic fibrosis, chronic bronchitis and bronchiectasis. In the past few years, a variety of extradigestive disorders, including cardiovascular, skin, rheumatic and liver diseases, have been associated with H. pylori infection. [email protected] 2/02/15 H. pylori 163 Heimesaat et al., (2014) investigated microbiota changes along the entire GI tract after infection with H. pylori. Comprehensive cultural analyses revealed that severe gastric diseases such as atrophic pangastritis and precancerous transformations were accompanied by elevated luminal loads of E. coli and enterococci in the caecum. This leads to distinct shifts of the microbiota composition in the distal uninflamed GI tract. Hence, H. pylori induced immunopathogenesis of the stomach, including hypochlorhydria and hypergastrinaemia, might trigger large intestinal microbiota changes. [email protected] 2/02/15 H. pylori 164 The role of Helicobacter pylori (HP) in some digestive diseases (gastritis, ulcer, gastric cancer, MALT lymphoma) is well known. It has also involved in respiratory disorders (chronic obstructive pulmonary disease, bronchiectasis, lung cancer, pulmonary tuberculosis, bronchial asthma); vascular disorders (ischaemic heart disease, stroke, primary Raynaud phenomena, primary headache); autoimmune disorders (Sjogren syndrome, Henoch-Schonlein purpura, autoimmune thrombocytopenia, autoimmune thyroiditis, Parkinson's disease, idiopathic chronic urticaria, rosacea, alopecia areata); other disorders (iron deficiency anaemia, growth retardations, liver cirrhosis). [email protected] 2/02/15 Panaxea Helico)X 165 Coptis Chinensis Rhizoma (Huang Lian ) Rheum Palmatum Rhizoma (Da Huang) Heydyotidis Diffusa Herba (Bai Hua She She ) Radix Pseudoginseng (San Qi ) Salvia Miltiorrhiza Radix (Dan Shen ) Magnolia Officinalis Cortex (Hou Po) Pueraria Lobata Radix (Ge Gen) [email protected] Chicken Gizzard (Ji Nie Jin ) Paeoniae Lactiflorae Radix (Bai Shao) Prunus Mume Fructus (Wu Mei ) Codonopsis Pilosula, Radix (Dang Shen ) Astragalus Membranaceus Radix (Huang Qi ) Cinnamom Cassia Ramulus (Gui Zh) Olibanum Gummi (Boswelia Carterii) (Ru Xiang )_(fried w/ vinegar) 2/02/15 Panaxea Pure)arin 166 Puerarin significantly attenuates gastric mucosal damage induced by water-immersion stress, inhibits gastric motility, specially decreases the index of gastric motility and percentage of gastric contraction time and numbers of violent contraction. The gastric mucosal blood flow and NO level in gastric mucosal were enhanced. Puerarin exerts a significant protective effect on waterimmersion stress-induced gastric mucosal damage by relaxing the vessels, increasing NO level in gastric mucosal, increasing regional gastric mucosal blood flow and inhibiting gastric motility (Wang et al, 2006). [email protected] 2/02/15 Peptic Ulcer 167 A clinical study involving 30 cases of peptic ulcer, the patients took 12 sea buckthorn oil capsules daily for one month. A curing rate of 76.6 % and a total effective rate of 96.7 % were reported. Sea buckthorn oil was also used as an adjuvant treatment of 116 peptic ulcer patients, 71 with duodenal ulcer and 45 with gastric ulcer (AGROFood Industry Hi-Tech, 2003 Vol. 53, No.3). Oral application of sea buckthorn oil relieved pain and accelerated the repair process of gastric and duodenal epithelial tissue and mucosa. [email protected] 2/02/15 SSRIs, Alcohol & Gastric Bleeding 168 SSRI users had a 50% increased risk for upper gastrointestinal bleeding (UGIB) compared with nonusers. Both antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) increased the risk for a bleeding episode; the concomitant use of both with SSRIs resulted in a nine-fold elevated risk for UGIB (2014, http://dx.doi.org/10.1016/j.cgh.2014.06.021). Ethanol has experimentally been shown to be "ulcerogenic," independent of gastric intraluminal pH. Ethanol remains ulcerogenic despite anti-secretory doses of H2-receptor antagonists. Low-dose alcohol stimulates acid secretion, an effect possibly mediated by histamine or gastrin. High-dose alcohol reduces intraluminal acid by damaging mucosa. Ethanol is capable of increasing gastric mucosal permeability (Emerg Med Clin North Am, 1990). [email protected] 2/02/15 SSRIs & Gastric Bleeding 169 SSRI users had a 50% increased risk for upper gastrointestinal bleeding (UGIB) compared with nonusers. Both antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) increased the risk for a bleeding episode; the concomitant use of both with SSRIs resulted in a ninefold elevated risk for UGIB (2014, http://dx.doi.org/ 10.1016/j.cgh.2014.06.021). [email protected] 2/02/15 Gastric Bleeding 170 Banxia-baizhu-tianma-tang (BCT) protects the gastric mucosa against ethanol-induced gastric injury by increasing the antioxidant status. Shin et al., (2013) suggest that BCT could be developed as an effective drug for the treatment of gastric injury caused by alcohol intake. BCT reduced ethanol-induced haemorrhage, hyperaemia, and loss of epithelial cell in the gastric mucosa. BCT reduced the increased lipid peroxidation associated with ethanol-induced acute gastric lesions, and increased the mucosal GSH content and the activities of antioxidant enzymes (2013, doi: 10.1186/1472-6882-13-170). [email protected] 2/02/15 Ban Xia Bai Zhu Tian Ma Tang 171 Pinelliae Tuber (ban xia) Gastrodiae Rhizoma (tian Citri Unshius Pericarpium ma) Ginseng Radix (ren shen) Astragali Radix (huang qi) Alismatis Rhizoma (ze xie) Zingiberis Rhizoma (sheng jiang & gan jiang) Phellodendri Cortex (huang lian) (wen zhou migan) Hordei Fructus Germinatus (mai ya) Atractylodis Rhizoma Macrocephalae (bai zhu) Massa Medicata Fermentata (shen qu) Poria Sclerotium (fu ling) Atractylodis lancea (cang zhu) [email protected] 2/02/15 Panaxea Emodin 172 Several studies done in China demonstrate the protective effect of Radix et Rhizoma Rhei (da huang) and its component Emodin on gastric bleeding. Three groups, namely, Rheum officinale Baill, Rheum palmatum L, and Rheum tanguticum Maxim were studied. The time taken for the stool occult blood changing from positive into negative was 57.1, 53.4, and 56 hours respectively. This shows that they are efficient in curing the upper digestive tract bleeding (Zhong Xi Yi Jie He Za Zhi. 1983 Jul;3(4):251-2; Zhong Xi Yi Jie He Za Zhi. 1988 Jun; 8(6):344-6, 324-5,Zhong Xi Yi Jie He Za Zhi. 1990 Mar; 10(3):150-1, 131-2). [email protected] 2/02/15 Thyroid & Stomach 173 In rats dietary iodides are able to defend brain cells from lipid peroxidation (Katamine et al, 1985). In normal thyroid hormonogenesis, iodide in giving its electron to oxygen reduces H2O2 by peroxidase activity. The remaining iodine readily iodinates the tyrosine and so neutralises its own high oxidant power. The stomach and the thyroid share iodide concentrating ability and many morphological and functional similarities such as cell polarity and apical microvilli, similar organspecific antigens and associated autoimmune diseases (Roitt et al, 1988). [email protected] 2/02/15 Thyroid & Gut 174 The thyroid gland is, embryogenetically and phylogenetically, derived from the primitive gut, and we may consider the thyroid cells as primitive gastroenteric cells, which, during evolution, migrated and specialised in the uptake of iodide and in the storage and elaboration of iodine compounds (Venturi & Venturi, 1999). [email protected] 2/02/15 Panaxea Thyrocaps 175 Supplies L-Tyrosine for thyroxine production Increases thyroxine production Increases T4 to T3 conversion Increases thermogenesis Increases mitochondrial activity Relieves symptoms of hypothyroidism such as fatigue, depression, weight gain and dry skin [email protected] 2/02/15 Thyrocaps 176 L-Tyrosine Coleus forskohlii (contains extract 20% of Forskolin) Cordyceps (contains extracts 0.15% adenosine & 5% mannitol) Guggul (guggulipid extract standardized to 10% guggulsterones, containing 0.5-2% E- and Z-guggulsterones) [email protected] Forskolin may increase thyroid through the activation of the betanaphthylamidase enzyme which functions to raise cyclic adenosine monophosphate (cAMP) levels. This in turn stimulates the release of thyroid hormone (TSH) 2/02/15 Gastric Cancer 177 A combination of chemotherapy with oral administration of YWKL Formula significantly increased the survival of stage IV gastric cancer patients. Orally administration with YWKLF had anti-tumour cell activity. Li et al., (2008) observed that sera from rabbits administered with YWKLF induced the apoptosis of MGC-803 cells by causing the loss of mitochondrial membrane potential, increasing the expression of Fas protein and Bax mRNA, as well as down-regulating Fas-L mRNA. [email protected] 2/02/15 YWKL (Gastric Cancer) Formula 178 Codonopsis pilosula (Dang Shen) Astragalus membranaceous (Huang Qi) Paeonia alba (Bai Shao) Dioscorea opposita (Shan Yao) Cyperus rotundus (Xiang Fu) Citrus reticulata (Chen Pi) [email protected] Activates major apoptotic pathways 2/02/15 Gastric Cancer 179 Treating advanced stomach cancer, with the combination of Kangai injection and chemotherapy, may decrease the adverse effects of chemotherapy on patients′ cellular immune functions and other side effects, and thereby, improve the quality of life of patients (Wu & Yang, 2007). Expressions of Tenascin-C are down-regulated when gastric cancer MGC-803 cells were treated with Shenqi Fuzheng injection at high concentration, therefore the invasiveness of gastric tumours may be reduced (Ma et al., 2013). [email protected] 2/02/15 Shen Qi Fu Zheng 180 Codonopsis pilosula (dang shen) Astragalus membranaceus (huang qi) [email protected] Shenqi-Fuzheng injection plus chemotherapy can improve cellular immune function, tolerance of chemotherapy, and reduce toxicity in patients with advanced gastric cancer (Yin & Jiang, 2013). 2/02/15 Gastric Cancer 181 The control group was treated by chemotherapy and the treatment group by chemotherapy and Yiqi Bushen Oral Liquid. The relapse and metastatic rate of the treatment group was remarkably lower than that of the control group. The Karnofsky score, peripheral blood and immune function were all remarkably improved in comparison with the control group. Yiqi Bushen oral liquid, combined with chemotherapy, has an effective function in down-regulating stomach metastasis after surgery, increasing chemo-sensitivity, decreasing adverse reactions, improving quality of life, and improving immune function of patients (Liu et al., 2008). [email protected] 2/02/15 Panaxea Yiqi Bushen Liquid 182 Astragali Radix (huang Scutellariae barbatae qi) Poria (fu ling) Ligustri lucidi Fructus (nu zhen zi) Lycii Fructus (gou qi zi) Sclerotium Polypori Umbellati (zhu ling) Curcumae Rhizoma Ezhu (e zhu) Herba (ban zhi lian) Actinidiae Chinensis Radix (teng li gen) Coicis Semen (yi ren) Caulis Aristolochiae Manshuriensis (ba yue zha) Jujubae Fructus (da zao) Glycyrrhizae Radix preparata (zhi gan cao) [email protected] 2/02/15 Oesophageal Adenocarcinoma (OA) 183 Participants who took 1 or more multivitamin pills/day had a significantly decreased risk of tetraploidy and OA compared to those not taking multivitamins. Significant inverse associations were also observed between risk of OA and supplemental vitamin and vitamin E. In this cohort study, use of multivitamins and single antioxidant supplements was associated with a significantly reduced risk of OA and markers of neoplastic progression among individuals with Barrett's oesophagus (Dong et al., 2008). [email protected] 2/02/15 Oesophageal Adenocarcinoma (Syndrome differentiation) 184 For obstruction of Phlegm and qi: Xuan Fu Dai Zhe Tang combining Li Ge Hua Tan Wan (Lin Zongguang) For obstruction of stagnant Blood and Phlegm: Qi Ge San combining Tao Hong Yin and Li Ge Hua Tan Wan For Fluid injury and stagnant Blood accumulation: Sha Shen Mai Dong Tang combining Tong You Tang (Lin Zg, 2004). [email protected] 2/02/15 Oesophageal Adenocarcinoma 185 For the middle and advanced stage, in combination with chemotherapy or radiotherapy Shen Zhu Fu Zheng Tang: huang qi, dang shen, bai zhu, fu ling, dan shen, chuan xiong, di long, xi xue teng, gan cao (Fu Js, 2008) For the advanced stage, which is not suitable for surgery, chemotherapy, or radiotherapy Fu Zheng Xiao Ai Tang: dang shen, dang gui, sheng di, shi hu, tian hua fen, san qi, wei ling xian, jiang can, ban xia, fu ling, chai hu, bai zhu, gan cao (Liu & Zhang, 2008) [email protected] 2/02/15 Oesophageal Adenocarcinoma (Treatment according to different principles) 186 Methods of clearing ‘Phlegm’ and removing ‘Stagnant Blood’ for the middle and advanced stage Formula: zhi ban xiao, zhi nan xing, qing meng shi, lu feng fang, dan shen, yi yi ren, chuan xiong, fu ling (Gao & Shen, 2007) For the advanced stage, as the main treatment Ding Xiang Tou Ge Tang: ding xiang, sha ren, sheng huang qi, bai hua she she cao, xia ku cao, zhi ban xia, zhi nan xing, sheng wa leng zi, ji xing zi, qiang lang chong, zhi shou gong, wei ling xian, shi da chuan, lu feng fang, quan xie, wu gong (Xu & Zhong, 2006). [email protected] 2/02/15 Pancreatitis 187 PANCREATIC ENZYMES (ESPECIALLY TRYPSIN) THAT DIGEST FOOD ARE ACTIVATED IN THE PANCREAS INSTEAD OF THE DUODENUM [email protected] 2/02/15 Panaxea Berberine 188 Berberine attenuates intestinal barrier dysfunction and ameliorates intestinal mucosal barrier damage and membrane permeability associated with severe acute pancreatitis (SAP). Although berberine exerted minimal effects on tight junction proteins in the ilea of SAP rats, it was observed to significantly inhibit SAP-induced MLC phosphorylation (2014, doi: 10.3892/mmr.2014.1996). Berberine showed preferential selectivity toward pancreatic cancer cells compared to normal ones (2010, DOI: 10.1055/ s-0030-1249931). [email protected] 2/02/15 Panaxea Emodin 189 Serum levels of amylase, tumour necrosis factor-alpha (TNF-α), angiotensin II (AngII), maleic dialdehyde (MDA), glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and C-reactive protein (CRP), intestinal secretory IgA (SIgA), pancreatic and hepatic myeloperoxidase (MPO) activity as well as plasma levels of D-lactate and endotoxin were measured. Emodin-assisted early enteral nutrition (EAEEN) could significantly ameliorate these parameters and prevent pancreas and liver from serious damage (2007, doi: 10.1155/2007/29638). [email protected] 2/02/15 Emodin 190 Emodin and somatostatin analogs can be used the management of acute pancreatitis, which might be ascribed to the upregulation of TGFβ1 and EGF gene expression, which subsequently increases DNA synthesis and protein content and thus accelerates pancreatic repair and regeneration (Pancreas. 2002 Aug;25(2):154-60). Emodin enhances cytokine TGFβ1 gene expression, regulates cell growth and differentiation, stimulates the formation of extracellular matrix components, increasing DNA synthesis and protein content, to take part in pancreatic repairing and remodeling (http:// www.ncbi.nlm.nih.gov/pubmed/12577439). [email protected] 2/02/15 Gardenia jasminoides 191 Gardenia jasminoides (zhi zi) remarkably reduced the serum amylase and myeloperoxidase levels of both serum and pancreatic tissue as well as the level of TNF-alpha and IL-6 as well as reducing injury by oxygen-free radicals, NO and endotoxins (Chin J Integr Tradit West Med 1996; 16:355-7). Gardenia can lower vasopermeability and inflammation, improve pancreatic haemodynamics, protect the function of the cellular membrane and alveolar subcellular organelles, strengthen the defence mechanism and inhibit the release of pancreatic enzymes and biotic active factors (J Hepatopancreatobiliary Surg 2003; 15:156-7). [email protected] 2/02/15 Salvia miltiorrhiza 192 Salvia miltiorrhiza (dan shen) can alleviate pathological changes in the pancreas due to its inhibitory effect on initial neutrophilic granulocyte and endotheliocyte adhesion by decreasing IL-1, IL-6 and TNF-α levels in the blood, pancreatic enzyme production and phospholipase A activation (Chin J Pract Chin Modern Med 2004; 4:1969-71). A significant difference in the incidence of complications, frequency of surgery and average hospital stay has been reported by Zhang et al. between the salvia miltiorrhizatreated group and the control group (J Jiangsu University (Med Edition) 2004; 14:406-9). [email protected] 2/02/15 Panaxea Silibinin 193 Silibinin effectively inhibited the pancreatic carcinoma AsPC-1, BxPC-3 and Panc-1 cells’ proliferation and caused apoptosis. Silibinin induced a decrease in S phase and cell cycle arrest in G1 phase in AsPC-1 cells, but had no obvious changes in BxPC-3 and Panc-1 cell cycle (2011, doi: 10.3390/ijms12084861). Silibinin may protect pancreatic exocrine cells (Cell Mol Life Sci. 1997;53: 917–920). Silibinin is thought to be an antioxidant, a cell membrane stabiliser, a general "hepatoprotectant", and a compound that helps to conserve intracellular glutathione levels and encourage cellular growth and regeneration. [email protected] 2/02/15 Pancreatitis 194 Acanthopanax (wu jia pi) led to apparently a higher serum NO level and superoxide dismutase activity in the treated group in relation to the severe acute pancreatitis group, and a notable decline in serum amylase as well as a decreased pathological state of the pancreas (Zhang, JOP. J Pancreas 2007). Baicalin has a protective effect on multiple organs of a severe acute pancreatitis rat model similar to that of octreotide (ibid) Panax Notoginoside has been found to downgrade the serum amylase level in severe acute pancreatitis and the positive incidence of germiculture for the pancreas, liver, spleen, lung and mesenteric lymph nodes; it protects the intestinal mucosal barrier, inhibits enteric bacterial translocation and lessens pathological injury (Chin J Bases Clin Gen Surg 2004) [email protected] 2/02/15 Panaxea CelProtect 195 Radix Pueraria lobata (Ge Gen) contains Daidzein Semen Sojae Praeparatum (Dan Dou Chi) contains Glycitein Sojae Praeparatum (Dan Dou Chi) contains Genistein Radix Scutellariae Baicalensis (Huang Qin) contains Baicalein Radix Scutellariae Baicalensis (Huang Qin) contains Baicalin Fructus Gardeniae Jasminoidis (zhi zi) contains Jasminoidin [email protected] Anti-inflammatory Enhances immunologic functions Inhibits angiogenesis Anti-tumoural 2/02/15 Microbiome 196 GUT/MICROBIOME CO-EVOLUTION [email protected] 2/02/15 Evolution of Microbiome 197 Ley et al., (2006, DOI: 10.1016/j.cell.2006.02.017) argue that the microbial diversity of the human gut is the result of coevolution between microbial communities and their hosts. They suggest that the peculiar structure of microbial diversity in the human gut resulted from natural selection operating at two levels. Host level, “top-down” selection on the community favours stable societies with a high degree of functional redundancy. An opposing “bottom-up” force is selection pressure driving microbial cells to become functionally specialised [email protected] 2/02/15 Microbial Diversity 198 Ley et al., suggest the idea that microbial community structure should be considered as a factor that can influence predisposition to specific diseases in certain host contexts. We need to monitor human “microevolution” during this period of profound social, economic, and ecological change, and, hopefully, help us forecast changes in our disease susceptibility. [email protected] 2/02/15 Evolution of Microbiome 199 Humans are ecosystems containing trillions of microorganisms, but the evolutionary history of this microbiome is obscured by a lack of knowledge about microbiomes of African apes. Moeller et al., (2014 doi: 10.1073/pnas.1419136111) sequenced the gut communities of hundreds of chimpanzees, bonobos, and gorillas and developed a phylogenetic approach to reconstruct how present-day human microbiomes have diverged from those of ancestral populations. Human microbiomes have lost ancestral microbial diversity while becoming specialised for animal-based diets [email protected] 2/02/15 Evolution of Microbiome 200 In the distinct habitats of the gut, environmental filtering and competitive exclusion between microbes are the driving factors shaping microbial diversity. Specialists have smaller genomes than generalists, and microbes with environmental reservoirs have large accessory genomes. A shift toward a Neolithic diet increased loads of simple carbohydrates and selected for their increased breakdown and absorption in the small intestine. Humans who outcompeted microbes for the new substrates obtained more energy from their diets (2011, doi: 10.1146/ annurev-micro-090110-102830) [email protected] 2/02/15 Evolution 201 If one looks at the gut microbiome as a major, if not dominant, component of the DNA of a host animal, then changes in the gut microbiome can quite naturally lead to new adaptations and speciation just like changes in nuclear genes. Dr. Seth Bordenstein adheres to this view and suggests that the gut microbiome must be considered a major portion of the genetics of an animal, in combination with the nuclear genome and organelles – what is now called a hologenome. The changes in the gut microbiome can promote the evolution of one species, the microbiome into two species; the micro-biomes and the host. [email protected] 2/02/15 Microbiome 202 Individual human health is determined by a complex interplay between genes, environment, diet, lifestyle, and symbiotic gut microbial activity. Here, we demonstrate a new "nutrimetabonomic" approach in which spectroscopically generated metabolic phenotypes are correlated with behavioural/psychological dietary preferences. Data suggest that specific dietary preferences can influence basal metabolic state and gut microbiome activity that in turn may have long-term health consequences to the host (J Proteome Res. 2007 Nov;6:11). [email protected] 2/02/15 Diet & Microbiota 203 Diet is a major force that shapes the composition and activity of the gut microbiota. This is evident from alterations in gut microbiota composition after weaning or drastic dietary changes. Owing to the complexity of the microbiota, interactions of intestinal bacteria with the host are difficult to study (2013, doi: 10.3920/BM2012.0029). As diet appears to play a predominant role in shaping the microbiota and promoting obesity-associated dysbiosis, parallel initiatives are required to elucidate dietary patterns and diet components (e.g., prebiotics, probiotics) that promote healthy gut microbiota (2013, doi: 10.1016/j.mam. 2012.11.001). [email protected] 2/02/15 Microbiome & Obesity 204 Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behaviour to increase their fitness, sometimes at the expense of host fitness. Microbes may do this through two potential strategies: (i) generating cravings for foods that they specialise on or foods that suppress their competitors, or (ii) inducing dysphoria until we eat foods that enhance their fitness (2014, DOI: 10.1002/bies.201400071). Conventional wisdom often blames unhealthy eating on a lack of willpower. However, binge eating is not just a matter of mental control (Int J Eat Disord. 1995 Jul;18:1) food cravings are unlike other cravings. [email protected] 2/02/15 Microbiome & Obesity 205 Obesity-related disorders derive from a combination of genetic susceptibility and environmental factors. Recent evidence supports the role of gut microbiota in the pathogenesis of obesity, type 2 diabetes mellitus, and insulin resistance by increasing energy harvest from diet and by inducing chronic, low-grade inflammation. Several studies describe characteristic differences between composition and activity of gut microbiota of lean individuals and those with obesity (2012, doi: 10.1016/j.gtc. 2012.08.009). [email protected] 2/02/15 Microbiome & Obesity 206 A large cohort study (n = 64,580) in the US found an increased risk of obesity in children aged 2–5 years who had been exposed repeatedly to broad-spectrum antibiotics in their first 24 months (four or more episodes) (rate ratio [RR] 1.11, 95% confidence interval [CI] 1.02 to 1.21) (JAMA Pediatr 2014;168:1063–9). A review of antibiotic use in infants and delayed health effects found the use of antibiotics resulted in a change in gut microbiota (BJOG 2006;113:758–65). In a study of 14 infants' gastrointestinal microbial communities over the first year of life, use of antibiotics was associated with a sudden change in the density or composition of the microbiota (PLoS Biol 2007;5:e177). [email protected] 2/02/15 Immune System & Gut Microbiome 207 Rich and balanced bacterial communities seem to be perceived as "self" and induce a quick maturation of the immune system and gut responses (induction of regulatory T cells and IgA), while a poor and unbalanced bacterial community is apparently perceived as "non-self" and induces responses aimed at eliminating it (T cells with inflammatory properties and IgG or IgE responses (2014; doi: 10.1016/j.immuni.2014.05.016). New insights from DNA sequence-based analyses of gut microbial communities and a renewed interest in mucosal immunology suggest that the microbiome represents an important environmental factor that can influence autoimmune disease manifestation. [email protected] 2/02/15 Microbiome & Immunity 208 Evidence suggests that when our resident biota are out of balance, they contribute to numerous diseases, including diabetes, rheumatoid arthritis, autism and multiple sclerosis (MS) by inciting rogue immune activity that can spread throughout the body and brain. A single-celled organism called methanobrevibacteriaceae that activates the immune system is enriched in the gastrointestinal tracts of MS patients whereas bacteria that suppress immune activity are depleted. Preliminary findings indicate that in MS, gut microbiome composition is significantly altered, with enrichment for microbiota known to be associated with gastrointestinal infectious processes (Tremlett H, et al., 2014). [email protected] 2/02/15 Microbiome & Immunity 209 Several studies have shown that gut bacteria have a role in diabetes. As healthy infants approach the toddler stage, their microbiomes become healthier and more stable, whereas, children who are destined for autoimmunity develop a microbiome that is less diverse and stable. Hence, the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. Bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children (The ISME Journal 2011 doi:10.1038/ismej.2010.92). [email protected] 2/02/15 Microbiome & RA 210 A newly published study found that the onset of rheumatoid arthritis (RA) could be partly mediated by specific intestinal bacteria. Scher et al., (2013) found that patients with newly diagnosed rheumatoid arthritis had more of a species of bacteria called Prevotella copri in their guts compared to healthy individuals or patients with chronic, treated RA. The presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects (doi: 10.7554/eLife.01202). © DR.D.Weber 2012 2/02/15 Microbiome & RA 211 The production of cross reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints (2006,doi:10.1136/gut. 2005.076901). New insights from DNA sequence-based analyses of gut microbial communities and a renewed interest in mucosal immunology suggest that the microbiome represents an important environmental factor that can influence autoimmune disease manifestation such as RA (2011, doi: 10.1038/nrrheum.2011.121. [email protected] 2/02/15 Periodontal Disease & RA 212 New-onset rheumatoid arthritis (NORA) patients exhibit a high prevalence of periodontal disease (PD) at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota of NORA patients is similar to chronic RA (CRA). Prevotella and Leptotrichia species are the only characteristic taxa in the NORA group irrespective of PD status. The role of A. geminatus and Prevotella/ Leptotrichia species in this process merits further study (2012, doi: 10.1002/art.34539). [email protected] 2/02/15 [email protected] 213 2/02/15 The extrinsic sensory innervation of the gastrointestinal tract is the conduit through which the gut and the central nervous system communicate. The hindbrain receives information directly from the bowel via the vagus nerve, while information from spinal afferents arrives in the central nervous system through the dorsal root ganglia. [email protected] 214 2/02/15 Dysbiosis 215 LEAKY, CREAKY AND THE PERMEABLE GUT [email protected] 2/02/15 Dysbiosis 216 Craven et al., (2012) sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis. Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, (Adherent-invasive Escherichia coli (AIEC) irrespective of trigger and genotype. The identification of CCR2 chemokine (C-C motif) as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for Crohn’s Disease (doi:10.1371/journal.pone.0041594). [email protected] 2/02/15 Dysbiosis The relationship between 217 Normal Flora Dysbiosis the human host and her army of microbes is described by the Greek word, symbiosis, which means "living together". When symbiosis benefits both parties, it is called mutualism. When symbiosis becomes harmful, it is called dysbiosis. The first line of protection against dysbiosis and intestinal toxicity is strict control of intestinal permeability, the ability of the gut to allow some substances to pass through its walls while denying access to others. © DR.D.Weber 2012 2/02/15 [email protected] 218 2/02/15 Gut Permeability 219 Increased epithelial permeability may be important in the development of chronic gut T cell–mediated inflammation. CD4 T cells activated by gut antigens in Peyer's patches migrate to the lamina propria (LP). In healthy individuals, these cells die by apoptosis. Increased epithelial permeability may allow sufficient antigen to enter the LP to trigger T cell activation, breaking tolerance mediated by immunosuppressive cytokines and perhaps T regulatory cells. Pro-inflammatory cytokines then further increase epithelial permeability, setting up a vicious cycle of chronic inflammation (MacDonald & Monteleone, 2005). © DR.D.Weber 2012 2/02/15 Cholecystokinin Gall Bladder contraction Gastrointestinal Motility Pancreatic Exocrine Secretion Secretin Pancreatic Exocrine Secretion GIP Incretin Activity Motilin Gastrointestinal Motility Ghrelin Hunger Growth Hormone Release Gastrin Acid Secretion Insulin & Glucagon Glucose Homeostasis Pancreatic Polypeptide Gastric Motility Satiation Amylin Glucose Homeostasis Gastric Motility GLP-1 Incretin Activity Satiation GLP-2 Gastrointestinal Motility and Growth Oxyntomodulin Satiation Acid Secretion PYY Satiation Enteric Endocrine System Gut Feeling © DR.D.Weber 2012 220 2/02/15 EES 221 The second of the two systems that control digestive function is the endocrine system, which regulates function by secreting hormones. The gastrointestinal tract is the largest endocrine organ in the body and the endocrine cells within it are referred to collectively as the enteric endocrine system. The secretion of hormones is in response to fairly specific stimuli and they stop secreting when those stimuli are no longer present. In most cases these endocrine cells respond to changes in the environment within the lumen of the digestive tube. [email protected] 2/02/15 Paracrine Molecules 222 PM can affect energy balance and impact obesity and other diseases of the organs mentioned before (autism, depression, allergy, diabetes, inflammatory bowel disease, and so on). These molecules will also affect host biology, possibly at the interface between microbial populations and the gutassociated immune system. It is known that the microbiota exerts important effects on the maturation of the mammalian immune system, so the small molecules in the intestine could be used to modulate these relationships in controlled ways. [email protected] 2/02/15 MAJOR ACTIVITY STIMULI FOR RELEASE Stimulates gastric acid secretion proliferation of gastric epithelium Presence of peptides and amino acids in lumen Cholecystokinin Stimulates secretion of Pancreatic enzymes and emptying of the GB Presence of fatty acids and amino acids in Small Intestine Secretin Stimulates secretion of water and bicarbonate from Pancreas and bile ducts Acidic pH in lumen of SI Ghrelin Strong stimulant for appetite and feeding; potent stimulator of hGH Secretion peaks prior to feeding and diminishes with gastric filling Motilin Involved in stimulating general patterns of motility in Stomach and SI Secretion is associated with fasting Gastric Inhibitory Polypeptide Inhibits gastric secretion and motility and potentiates release of insulin in response to blood glucose concentration Presence of fat and glucose in SI HORMONE Gastrin [email protected] 223 2/02/15 HCA 224 The pH in the fundus can be on the order of 1–2. With this low pH, pepsinogen, secreted by chief cells is converted to pepsin. Pepsin breaks down protein-containing foods in the fundus into peptides and amino acids, and calcium and vitamin B12 are released. These food components arrive in the antrum, where they induce the production of the hormone gastrin. Gastrin travels via the blood to the fundus to increase hydrochloric acid secretion. Gastrin also enhances closure of the pylorus and oesophageal sphincter. Local histamine secretion sensitises parietal cells to the effects of activation the vagus nerve and of gastrin. [email protected] 2/02/15 HCA 225 Hydrochloric acid constitutes the majority of gastric acid, the human digestive fluid. In a complex process and at a large energetic burden, it is secreted by parietal cells. Finally, the stomach secretes intrinsic factor, which is required for vitamin B12 absorption in the intestine. Vitamin B12 is a large molecule, and requires intrinsic factor to protect it from destruction by the stomach. [email protected] 2/02/15 H. Pylori 226 From approximately age 35 most people begin to secrete less stomach acid and by their 50's, it is estimated that over 50% have low stomach acid. People with a history of HP infection and/or who have long-term use of protein pump inhibitor (PPI) medications are likely to have hypochlorhydria. In Western countries the prevalence of HP infections roughly matches age (i.e., 20% at age 20, 30% at age 30, 80% at age 80 etc). [email protected] 2/02/15 Neuropeptide Transmitters 227 In humans, eradicating H. pylori affects the regulation of two hormones produced in the stomach and involved in energy balance, ghrelin and leptin. And as H. pylori has disappeared from people's stomachs, there has been an increase in gastroesophageal reflux, and its attendant problems such as Barrett's oesophagus and oesophageal cancer (Blaser, 2011). [email protected] 2/02/15 Ghrelin 228 Mice exposed to chronic social defeat stress (CSDS), increased both conditioned place preference (CPP) and intake of high-fat diet. The stress-induced food-reward behaviour was dependent on signalling by the peptide hormone ghrelin. Engagement of these neurons (dopaminergic) by ghrelin induces a series of changes that minimises what would otherwise be worsened depression-like behaviours (Chuang et al, 2011) [email protected] 2/02/15 Ghrelin and Motilin 229 Ghrelin and motilin are the only two mammalian hormones known to decrease in the postprandial period. Ghrelin and motilin participate in initiating the migrating motor complex in the stomach, and stimulate gastrointestinal motility, accelerate gastric emptying, and induce "gastric hunger". In addition to modulating the release of growth hormone and gut motility, ghrelin plays a crucial role in the secretion and protection of the stomach and colon (Curr Pharm Des. 2012;18,31). [email protected] 2/02/15 Motilin, Gastrin, and Somatostatin 230 A single oral administration of Ninjin-to, at a dose of 6.0 g, caused significant increases in plasma motilin levels at 40 to 90 min and somatostatin levels at 20 to 90 min, compared with a placebo treated group. These results suggest that pharmacological effects of Ninjin-to on gastrointestinal functions closely relate to changes of motilin, gastrin, and somatostatinimmunoreactive substance levels in human plasma (2001, http://dx.doi.org/10.1248/bpb.24.194). Radix Ginseng (3.0 g), Glycyrrhizae Radix (3.0 g), Atractylodis Rhizoma (3.0 g), Rhizoma Zingiberis (3.0 g) [email protected] 2/02/15 Transmitters 231 The effects of four classical TCM formulas for mediating the spleen and stomach on cerebral neuropeptide transmitters. Buzhongyiqi Decoction could markedly reduce the level of Vasoactive intestinal peptide (VIP) and raise the level of Neuropeptide Y (NPY) in the cerebral cortex, Dachengqi Decoction could decrease the levels of somatostatin (SS) and substance P (SP) in the cerebral cortex and the level of VIP in the hippocampus, Guipi Decoction could increase the level of SS in the cerebral cortex, and Wendan Decoction could lower the level of VIP in the hippocampus (He et al, 2003). [email protected] 2/02/15 Transmitters 232 VIP and dorsal vasopressin affect timing of daily biological rhythms in mammals (SCN) (Stopa et al, 1984) and are seen to control mood disorders like anxiety and as well as peristalsis (Freund, 2003). A correlation between NPY and cortisol was found in suicidal patients with depression. Cortisol was high and corticotrophin releasing hormone (CRH) and neuropeptide Y (NPY) appeared to be low (Westrin et al, 1999) [email protected] 2/02/15 Transmitters 233 The substance P receptor (neurokinin-1 receptor) has been implicated in stress responses and anxiety traits and neurokinin-1 receptor antagonism may have antidepressant and anxiolytic effects. This suggests that the function and/ or expression of neurokinin-1 receptor might be affected in subjects with mood disorders including unipolar depression (Burnet & Harrison, 2000). SP has been supposed to be involved in the aetiopathology of affective disorders (Lieb et al, 2002). [email protected] 2/02/15 Transmitters 234 A single oral administration of Sho-hange-ka-bukuryo-to [SHKBT], comprised of Pinelliae Tuber, Zingiberis Rhizoma and Hoelen caused significant increases in plasma somatostatin-, CGRP- and substance P-immunoreactive substance (IS) levels. Transient elevation of gastrin-IS levels in the placebo group was inhibited by the administration of SHKBT, but the medicine showed no effects on plasma motilin- or VIP-IS levels. These results might indicate that the pharmacological action of SHKBT is closely related to changes in gastrin-, somatostatin-, CGRP- and substance P-IS levels in human plasma (Biol Pharm Bull. 2004 Oct;27(10):1674-8.). [email protected] 2/02/15 Shu Wei Decoction 235 A reduction of the Cajal Interstitial Cells (ICC) expression in the gastric antrum is a pathophysiological basis for functional dyspepsia of liver Qi stagnation and spleen deficiency (LQSD); and a reduced expression of serum Substance P (SP) and motilin might be the neurobiological basis. Shuwei Decoction can significantly promote drinking, eating, ICC and MTL expression, serum SP secretion and gastric emptying in FD rats with LQSD. This study revealed possible mechanisms of SWD on LQSD type functional dyspepsia (Wang et al., Journ Acu and Herbs, 2014). [email protected] 2/02/15 Shu Wei Decoction 236 Pericarpium Citri Bulbus Lilii (bai he) Reticulatae Viride (Qing Pi) or Fructus Immaturus Citri Aurantii (Zhi Shi) Roasted Atractylodes tuber (chao bai zhu) Pinellia tuber (ban xia) Radix Coptis (huang lian) Radix Lindera (wu yao) [email protected] Semen Areca (bing lang) Radix Salvia miltiorrhiza (dan shen) Radix Codonopsis pilosula (dang shen) 2/02/15 Pattern Discrimination 237 Those with depressed liver and insufficient spleen were given SWD plus Bupleurum root and Cyperus tuber, those with water retention due to hypo-function of spleen were given SWD plus Poria and magnolia bark ; those with deficiency of stomach-Yin were given SWD minus with Pinellia, plus Dendrobium and Adenophora root ; those with insufficiency of spleen-Yang were given SWD with the dosage of Coptis reduced but plus Astragalus and dried ginger ; those with retention of food were given SWD plus charred medicate leaven and stir-baked Semen Rephani; those with blood stasis were given SWD plus Corydalis yanhusuo and Typha Angustifolia. [email protected] 2/02/15 Pattern Discrimination 238 The genotype–phenotype distinction is drawn in genetics. "Genotype" is an organism's full hereditary information. "Phenotype" is an organism's actual observed properties, such as morphology, development, or behaviour. This distinction is fundamental in the study of inheritance of traits and their evolution. Chinese medicine looks at phenotype. Polymorphism is described as morphs of the phenotype. The term is also used somewhat differently by molecular biologists to describe certain point mutations in the genotype, such as Single Nucleotide Polymorphism (SNP) [email protected] 2/02/15 Pattern Discrimination 239 Omics informally refers to a field of study in biology ending in omics, such as genomics, proteomics or metabolomics. The related suffix Ome is used to address the objects of study of such fields, such as the genome, proteome or metabolome respectively. Omics aims at the collective characterisation and quantification of pools of biological molecules that translate into the structure, function, and dynamics of an organism or organisms. Omics-based medicine and systems pathology will realise a new personalised and predictive medicine (2010, http:// dx.doi.org/10.3414/ME9307) [email protected] 2/02/15 Gastrointestinal Peptides 240 The mechanism of spleen deficiency (SD) was studied by the relationship of gastro-intestinal peptides level and ileal electro-mechanical activity of SD rats and cold restrained rats. Spleen deficiency (SD) model was established by feeding Houpou:Zhishi: Dahuang in the ratio of 3:3:2, 3 ml/time, for 42 days. (2) The cold restrain stress model: Animals were restrained on grille and placed in a cool water at 18 degrees for 3 h. (3) Substance P (SP) and vasoactive intestinal peptide (VIP) levels in all layers of initial part of ileum and blood in rats were measured. [email protected] 2/02/15 Gastrointestinal Peptides 241 Changes of Substance P (SP) and vasoactive intestinal peptide (VIP) levels levels in initial part of ileum and blood of SD rats and cool stress rats may be closely related to the gastrointestinal motility disorders presented in SD and cool stress rats. the Chinese herbs (Jia Wei Si Jun Zi Tang) currently used have partially therapeutic effect. SP and VIP partly distributed in the mucosa of gastric antrum, the mucosa of the jejunum, ileum. In the intestine, VIP markedly stimulates intestinal secretion of electrolytes and hence of water. Its other actions include relaxation of intestinal smooth muscle; sphincters; dilation of peripheral blood vessels; and inhibition of gastric acid secretion (World J Gastroenterol 2003 Mar 15;9(3):553-556). [email protected] 2/02/15 Bowel Motility 242 Daikenchuto stimulates gastrointestinal motility though a neural reflex involving presynaptic cholinergic and 5-HT3 receptors. Daikenchuto improves postoperative bowel motility and postoperative ileus. Furthermore, it is reported to cause an increase in gastrointestinal hormones (motilin, vasoactive intestinal peptide, and calcitonin gene-related peptide) and intestinal blood flow. Rikkunshito, a traditional Japanese medicine consisting of eight herbs, is thought to stimulate gastrointestinal motility and ghrelin secretion (2010, doi: 10.1007/ s00595-010-4388-8). [email protected] 2/02/15 Bowel Motility 243 Rikkunshito increased the plasma acylated ghrelin level in healthy volunteers and normal mice. Additionally, this change was maintained for at least 4 weeks after the end of administration. In mice, Rikkunshito increased the ghrelin mRNA expression level in the stomach (2010, doi: 10.1007/ s00535-009-0166-z). Rikkunshito improves upper gastrointestinal symptoms in patients with functional dyspepsia (FD), accompanied by an increase in the levels of ghrelin (2012, doi: 10.5754/ hge11246) and anorectic conditions including cisplatininduced dyspepsia (Curr Pharm Des. 2012;18,31). [email protected] 2/02/15 Formulas 244 Daikenchuto Rikkunshi-to 5.0 g processed Zingiberis Rhizoma Atractylodes Lancea (pao jiang) 3.0 g ginseng (ren shen) 2.0 g Semen Zanthoxyli (jiao mu) (cang zhu) Panax Ginseng (ren shen) Rhizoma Pinellia (ban xia) Sclerotium Poria (fu ling) Fructus Jujubae (da zao) Citrus Unshiu (wu he ju) Glycyrrhiza (gan cao) Zingiberis (sheng jiang) [email protected] 2/02/15 Big 245 [email protected] 2/02/15 Obesity 246 Obesity is not just a matter of balancing energy in with energy out, it is a great deal more complex. The prevalence of obesity has been rising steadily over the last several decades and is currently at unprecedented levels: more than 68% of US adults are considered overweight, and 35% are obese (JAMA 303:235–241, 2010). Data indicates that segments of individuals in the highest weight categories (i.e., BMI > 40 kg/m2) have increased proportionately more than those in lower BMI categories (BMI < 35 kg/m2) (2012, DOI:10.1007/s00261-012-9862-x). [email protected] 2/02/15 Obesity 247 Body weight is regulated by the hypothalamus, and there have been many recent advances in understanding of energy balance that might help understand why some individuals develop obesity, and lead to new treatments. Both genetic and environmental factors contribute to the development of obesity. The recent identification of a single gene defects that cause severe early onset obesity, such as deficiency of the hormone leptin (2001, DOI: 10.1002/pdi. 277). A TOTAL deficiency in or resistance to the protein leptin causes severe obesity (Science 269, 546−549 1995; Nature 377, 530−532 1995) [email protected] 2/02/15 Obesity 248 Massive obesity with marked increase in body weight was observed after about 10 weeks when norepinephrine (NE) was infused chronically into the unilateral ventromedial (VMH), lateral or paraventricular hypothalamic nucleus, but not into other hypothalamic loci. Plasma insulin level went up markedly at the early stage of NE infusion and remained high during the infusion period, but plasma glucose did not change appreciably. Similar, but less pronounced effects were observed with epinephrine infusion into the VMH (Brain Res. 1986 Mar 26;369:1-2). [email protected] 2/02/15 Obesity 249 The control of body weight and composition depends on an axis with three interrelated and self-controlled components: (1) food intake; (2) nutrient turnover and thermogenesis; (3) body fat stores. Complex feedback mechanisms underlie all these components. The major factors involved in obesity seem to be dietary and physical activity habits. These factors are affected by susceptibility genes that in turn may influence energy expenditure, fuel metabolism, muscle fibre function and appetite or food preferences (2000, doi.org/10.1017/S0029665100000380). [email protected] 2/02/15 Microbiome & Obesity 250 Exposure to broad-spectrum antibiotics in children younger than age 2 years was associated with elevated obesity risk between ages 2 and 5 years. Obesity is also been associated with risk factors such as sleep duration and screen time. By age 24 months, 69% of children had received at least one systemic antibiotic course (average 2.3 courses); narrowspectrum antibiotics 62%; (penicillin or amoxicillin) and broad-spectrum antibiotics, 41%. The microbiome may be adversely influenced by broadspectrum antibiotics (2014, doi.org/10.1001/ jamapediatrics.2014.1539) [email protected] 2/02/15 Panaxea Xlim 251 Fructus Corni (shan zhu Attenuates weight gain yu) Rhizoma Dioscorea (shan yao) Fructus Aurantii (zhi shi) Radix Platycodonis (jie geng) 80% Ethanol Extraction (90% total weight) Platycodin D (10%) Regulates Adipogenesis [email protected] through AMPK 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. 2/02/15 Panaxea Blueberrin 252 Blueberrin extracted from blueberry leaf Metabolic Syndrome Hyperlipidaemia High blood glucose Diabetes [email protected] 2/02/15 Blueberin 253 Blueberin reduced fasting plasma glucose from 143+/-5,2mg/L to 104+/-5,7 mg/L (p<0,001), whereas there was no statistically significant changes in the Placebo group from 138+/-4,8 mg/L to 126+/-5,1mg/L (p>0,05). The reduction of fasting glucose was correlated with the reduction of serum CRP in the Blueberin group. Furthermore, the Blueberin also significantly reduced the levels of plasma enzymes ALT, AST and GGT, indicating that, in addition to anti-diabetes effects, Blueberin also possess pharmacologically relevant anti-inflammatory properties (Georgian Med News. 2006 Dec; 141). [email protected] 2/02/15 Obesity 254 The prevalence of obesity and related disorders such as metabolic syndrome has vastly increased throughout the world. Recent insights have generated an entirely new perspective suggesting that our microbiota might be involved in the development of these disorders. Studies have demonstrated that obesity and metabolic syndrome may be associated with profound microbiotal changes (Tilg & Kaser, 2011). [email protected] 2/02/15 Obesity & Microbiota 255 Alcock et al., (2014) reviewed several potential mechanisms for microbial control over eating behaviour including microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vagus nerve, the neural axis between the gut and the brain (DOI: 10.1002/bies.201400071). Altered gut microbiota composition and impaired gut barrier function together with interrelated mesenteric adipose tissue inflammation, result in increased release of pro-inflammatory cytokines, bacteria-derived factors, and lipids into the portal circulation, promoting the development of insulin resistance (Physiology (Bethesda). 2014 Sep;29:5). [email protected] 2/02/15 Obesity & Microbiota 256 Acquired tastes may be due to the acquisition of microbes that benefit from those foods. The review by Alcock et al., (2014) suggests that one way to change eating behaviour is by intervening in our microbiota. It is encouraging that the microbiota can be changed by many interventions, hence facilitating translation to the clinic and public health efforts. Microbiota community structure changes drastically within 24 hours of changing diet (Science 2011 334: 105–8; Science 2013 334: 105–8). Faecal transplants have shown efficacy in treating a variety of diseases (BioEssays 2013 35: 508–12). [email protected] 2/02/15 Obesity & Microbiota 257 Obesity results in a pronounced shift in the relative abundance of the two dominant divisions in the mouse gut. Is the increased ratio of Firmicutes/Bacteroidetes in the obese (ob/ob) gut microbiota a cause of, or a compensatory obesity? [email protected] response to, 2/02/15 Microbiota & SCFAs 258 Microbiota regulates host metabolic functions. The microbiota controls host physiology at multiple levels. Microbial metabolic products such as SCFAs bind to GPCRs on intestinal epithelial cells to control energy balance, partly via the gut-derived hormone Pyy, and also to control the inflammatory responsiveness of the host, which in turn regulates appetite, weight gain, and insulin sensitivity through unknown mechanisms (Tilg & Kaser, 2011). [email protected] 2/02/15 Weight Gain 259 In a small number of studies, investigators have observed that some patients gain weight after eradication of Helicobacter pylori. Prevalence rates of overweight and obesity were inversely correlated with the prevalence of H. pylori in the same populations (r = −0.43; P<0.01 and r = −0.29; P<0.05). The inverse correlation remained after adjusting for GDP per capita (2014, http://dx.doi.org/10.1111/apt.12790). Thus, the gradual decrease of the H. pylori colonisation that has been observed in recent decades (or factors associated with decrease of) could be causally related to the obesity endemic observed in the Western world. [email protected] 2/02/15 Insulin Resistance 260 Insulin resistance is often associated with obesity and is a major risk factor for development of type 2 diabetes as well as cardiovascular and hepatic diseases. Insulin resistance may also increase the incidence or the aggressiveness of some cancers. Insulin resistance occurs owing to defects in insulin signalling in target tissues of this hormone. Inflammatory cytokines activate several signalling pathways that impinge on the insulin signalling pathway and (2014, doi: 10.1051/jbio/2014014). [email protected] 2/02/15 Inflammation & Obesity 261 Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. The discrepancy between the environment, in which hunger and the immune system evolved in prehistoric times, is vastly different from the calorie-rich “obesogenic” environment in the modern world (2008, doi: 10.1189/jlb. 0108028). [email protected] 2/02/15 Inflammation & Obesity 262 Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake (Nutrition. 2001 Nov-Dec;17:11-12). [email protected] 2/02/15 Obesity & Breast Feeding 263 Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain (ibid). [email protected] 2/02/15 Berberine 264 Berberine has been shown to have a significant beneficial effect on type 2 diabetes, and may be as effective, or more so, than metformin. Berberine acts through several mechanisms, including mimicking insulin; improving insulin action by activating AMPK; reducing insulin resistance through protein kinase C-dependent upregulation of insulin receptor expression; inducing glycolysis; and on incretins by promoting GLP-1 secretion and modulating its release, and by inhibiting DPP-4 (Lee et al., 2006; Chen et al., 2010). [email protected] 2/02/15 Berberine 265 Recent evidence suggests that the gut microbiota composition is associated with obesity and type 2 diabetes, which are closely associated with a low-grade inflammatory state. The protective effect against diabetes of gut microbiota modulation with probiotics or antibiotics has been confirmed in recent observations. Berberine has significant antimicrobial activity against several microbes through inhibiting the assembly function of FtsZ and halting the bacteria cell division (2011, DOI: 10.12659/MSM.881842). Gut microbiota modulation may be one mechanism of the antidiabetic effect of berberine [email protected] 2/02/15 Obesity, Stress & Inflammation 266 Circulating IL-6 stimulates the hypothalamic–pituitary– adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance (Yudkin et al, 2000). A study by Nishitani & Sakakibara (2005) suggests that obese male Japanese workers tend to be in a stressful state from high job demands and low job latitudes in the workplace. Such stressful conditions may affect eating behaviours to eat much and contribute to obesity. [email protected] 2/02/15 Obesity, Stress & Inflammation 267 Environmental, perinatal and genetic factors induce neuroendocrine perturbations followed by abdominal obesity with its associated co-morbidities. The activation of the HPA axis and the sympathetic nervous system have been utilised as objective measurements of stress reactions and elevated cortisol, particularly when combined with secondary inhibition of sex steroids and growth hormone secretions, which causes accumulation of fat in visceral adipose tissues as well as metabolic abnormalities (Björntorp , 2001). [email protected] 2/02/15 Herbs that suppress cellular inflammatory responses 268 Microglia/microphage: Andrographolide (Chan et al, 2010), Paeonol / Cortex Moutan (Hsieh et al, 2006) Wogonin / Scutellaria baicalensis (Kim et al, 2001), Sophora japonica (Lao et al, 2005), Angelica sinensis (Lin et al, 2008), Panax Notoginseng (Son et al, 2009), Apocynin / Picrorhiza kurroa (Hur et al, 2010) Astrocytes Zizyphus jujube (Yoo et al, 2010) [email protected] 2/02/15 Herbs that suppress cellular inflammatory responses 269 Adhesion Molecules Selectins: Polydatin / Resveratrol analogue (Cheng et al, 2008) Integrins: Polydatin (Cheng et al, 2008) Inter-Cellular Adhesion Molecule 1 (ICAM-1): Ferulic acid / açaí palm (Euterpe oleracea) (Cheng et al, 2006), polydatin (Cheng et al, 2008), Panax Notoginseng saponins (He et al, 2005), apocynin (Genovese et al 2011), Paeoniflorin / Paeonia radix (Tang et al, 2010) [email protected] 2/02/15 Herbs and Suppressed Inflammatory Response 270 Low-grade chronic inflammation in overweight subjects is thought to play an important role in disease development. Dietary products; resveratrol, green tea extract, atocopherol, vitamin C, Omega-3, polyunsaturated fatty acids, and tomato extract, selected for their evidence-based antiinflammatory properties, were combined and given as supplements to healthy overweight men with mildly elevated plasma C-reactive protein concentrations in a RCT crossover study with treatment periods of 5 wk (2010, doi: 10.3945/ajcn.2009.28822). [email protected] 2/02/15 Parasites 271 UNWANTED GUESTS? [email protected] 2/02/15 Gastrointestinal Parasites 272 Intestinal parasites include protozoans (organisms having only one cell) and parasitic worms (helminths). Of these, protozoans, including cryptosporidium, microsporidia, and isospora. Each of these parasites can infect the digestive tract, and sometimes two or more can cause infection at the same time. [email protected] 2/02/15 Gastrointestinal Parasites 273 Blastocystis hominis is a microscopic parasite sometimes found in the stools of healthy people as well as in the stools of those who have diarrhoea, abdominal pain or other gastrointestinal problems. Researchers don't yet fully understand the role that blastocystis plays, if any, in causing an infection. Certain subtypes of blastocystis may be more likely to cause symptomatic infection, or may pose a risk only when combined with other types of infection. In some cases, blastocystis simply resides in the digestive tract without causing harm. [email protected] 2/02/15 Gastrointestinal Parasites 274 International travel and getting traveller’s diarrhoea A history of food poisoning and digestion has not been the same since. Trouble falling asleep, or waking multiple times during the night. Skin irritations or unexplained rashes, hives, rosacea or eczema. Grinding of teeth (bruxism) in sleep. Pain or aching in muscles or joints. Fatigue, exhaustion, depression, or frequent feelings of apathy. Never feeling satisfied or full after meals. Iron-deficiency anaemia. [email protected] 2/02/15 Gastrointestinal Parasites 275 Blastocystis hominis Gastrointestinal Enterobius vermicularis parasites Amoebic dysentery Amoebic/bacterial parasites Bacillary dysentery Giardia lamblia Ancylostoma duodenale Necator americanus Entamoeba histolytica [email protected] 2/02/15 Panaxea Gut Bug 276 Sophorae Flavescentis (Ku Sclerotium Poriae (Fu Shen Gen) Corneum Gigeriae Galli (Ji Nei Jin) Sargento Doxae (Hong Ten) Stemonae (Zhi Bai Bu) Arecae Catechu (Bing Lang) Quisqualis (Shi Jun Zi) Glycyrrhizae (Gan Cao) Ling) Pericarpium Citri Reticulatae (Chen Pi) Dioscorea Bulbifera (Huang Yao Zi) Testa Dolichoris (Bian Dou) Atractylodis Macrocephalae (Bai Zhu) Saussureae Lappae (Mu Xiang) [email protected] 2/02/15 Nausea Motion sickness or seasickness Early stages of pregnancy Medication-induced vomiting Intense pain Emotional stress (such as fear) Gallbladder disease Food poisoning Infections ("stomach bug”) Overeating Ulcers [email protected] 277 A reaction to certain smells or odours Heart attack Concussion or brain injury Brain tumour Some forms of cancer Bulimia or other psychological illnesses Gastroparesis or slow stomach emptying (a condition often seen in people with diabetes) Ingestion of toxins or excessive amounts of alcohol 2/02/15 Panaxea Qi-Inversion 278 Pericarpium Citri Reticulatae (Chen Pi) Ginger Fried Caulis Bambusae in Taenia (Zhu Ru) Rhizoma Zingiberis Recens (Sheng Jiang) Radix Ginseng (Ren Shen) Rhizoma Pinelliae (Ban Xia) Herba Agastache (Huo Xiang) Magnolia Flower (Hou Po Hua) Fructus Amomi (Sha Ren) [email protected] 2/02/15 Candida Albicans Overgrowth 279 Chronic diarrhoea, constipation, bloating and flatulence Lethargy and fatigue Reduced or hyperactive immune function: Autoimmune disease such as Hashimoto’s thyroiditis, Rheumatoid arthritis, Ulcerative colitis, Lupus, Psoriasis, Scleroderma or Multiple sclerosis Skin eruptions Skin and nail fungal infections (such as athlete’s foot or toenail fungus) Vaginal infections, urinary tract infections, rectal itching or vaginal itching [email protected] 2/02/15 Candida Albicans Overgrowth 280 Candida albicans is normally a harmless yeast present in the gastrointestinal tract and vaginas of warm-blooded animals. Hormonal imbalances, antibiotics and oral contraceptives, excessive consumption of sugar and simple carbohydrates, food allergies and sensitivities, stress, or exposure to environmental toxicants can all lower immune defences and contribute to Candida's transformation from a benign, round yeast into a filament-shaped fungus with long hyphae or "roots" that penetrate intestinal cells in search of food. [email protected] 2/02/15 Candidiasis 281 Candida expels waste products into the circulatory system, depressing immunity and leading to numerous ailments that may fall within the syndrome called the Candida Related Complex or Candidiasis. Candida albicans also can be spread by direct contact during intercourse and through intravenous feedings, dialysis and surgery. [email protected] 2/02/15 Candidiasis 282 In traditional Chinese medicine, more than 300 herbs have been discovered to have "pesticidal" activities, and some of these have been used as antifungal agents in clinical practice for many years. These include cortex moutan, cortex pseudolaricis, rhizoma alpiniae officinarum, rhizoma coptidis, clove and cinnamon, anemarrhena cortex phellodendri, ramulus cinnamomi, and Chinese gall. The effective anti-Candida principals were identified to be berberine, palmatine, allincin, pseudolaric acid A and B, magnolol, honokiol, and galangin (2011, doi: 10.1177/0022034511399286) [email protected] 2/02/15 Candida Albicans Overgrowth 283 Check blood levels for IgG, IgA, and IgM candida anti- bodies. These can be checked through most any lab. High levels indicate an overgrowth of candida. Comprehensive stool test rather than the standard stool test. Urinary test detects a waste product of Candida yeast overgrowth known as D-Arabinitol. [email protected] 2/02/15 Panaxea Cand)EX 284 Biotin Phellodendron amurense Calcium undecylenate Pau d'arco (Tabebuia avellanedae) bark extract Enlyse enzyme blend (protease, lipase, serrapeptase, hemicellulase, amylase and chitosanase) [email protected] (contains extract berberine sulfate) Polygonum cuspidatum (contains extract transresveratrol) jin qian cao - lysimachiae, herba huo xiang - agastache, herba bai tou weng - pulsatillae, radix ren dong teng - lonicerae, caulis 2/02/15 Lectins 285 Lectins are a class of protein molecules capable of using these sugar moieties to bind to the surface of cells. Lectins provide the way for one molecule to stick to another molecule without any immunity involved. Lectins play a wide role in health, but their ability to influence the inflammatory process indicates they are involved in inflammatory bowel disease, rheumatoid arthritis and even weight gain. Lectins’ potential involvement in many aspects of our health caused DJ Freed, MD to state, “Lectins are causes in search of diseases.” [email protected] 2/02/15 Lectins 286 There is an abundance of literature from the most prestigious journals that lectins initiate allergic reactions in the gut causing the release of IL-4, and histamine from human basophils producing noticeable allergic symptoms. Wheat germ agglutinin (WGA) has been shown to interfere with protein digestion and increase gut permeability. Dietary lectins, by their chemical reactivity with cell surface receptors on the intestinal epithelium, are metabolic signals for the gut and are capable of modulating immune and hormone functions. [email protected] 2/02/15 Lectins 287 After ingestion, most dietary lectins bind to the absorptive microvilli of the small intestine. From there lectins may gain access into the blood and lymph system through a process called endocytosis which carries the intact lectin across the microvilli membranes as a vesicle. Then, the lectins may enter the liver, pancreas and systemic circulation. It is estimated that about 5 per-cent of ingested lectins enter the body systemically, where, lectin binding occurs on other tissues such as nervous and connective tissue and the bladder, which are very sensitive to the agglutinating effects of lectins. [email protected] 2/02/15 Panaxea Lectin Control 288 N-Acetyl Glucosamine Enhance immunity Bladderwrack (contains Relieve GI disorders extract Fucoidan) D-Mannose Mucin Sodium Alginate Pepsin Fight allergies Supports liver function Inhibit blood clotting Fights against free radicals Lowers cholesterol levels Decreases high blood pressure Stabilises blood sugar level [email protected] 2/02/15 Appendix & Abdominal Obstruction 289 [email protected] 2/02/15 Appendix 290 The appendix or caecal appendix is a blind-ended tube connected to the cecum, from which it develops embryologically. The cecum is a pouch-like structure of the colon, located at the junction of the small intestine and the large intestine. While the true function of the appendix is unknown, it is speculated to play a role in mucosal immunity or to act as a storage site for intestinal flora to repopulate the colon if needed [email protected] 2/02/15 Spleen qi Xu 291 The regulation of intestinal flora for spleen deficiency was determined by colonic content and stool specimens containing Enterobacteriaceae, Enterococcus, Bifidobacteria, bacteroides, Lactobacillus. After one course of treatment with Shenlingbaizhu, the quantities commensal bacteria returned to normal, intestine wall skin layer thickness and cup form cell quantity increased, intestinal mucous membrane increased in a fine arranged order, and mitochondria function improved notably (Yang et al, 2009). [email protected] 2/02/15 Shen Ling Bai Zhu 292 Panax ginseng (ren shen) Dolichos lablab (bai bian Atractylodes dou) Coix lacryma-jobi (yi yi ren) Amomum villosum (sha ren) Platycodon grandiflorum (jie geng) Nelumbo nucifera (lian zi xin) macrocephala (bai zhu) Poria cocos (fu ling) Glycyrrhiza uralensis (gan cao) Dioscorea opposita (shan yao) [email protected] 2/02/15 Appendix & Immunity 293 Gut-associated lymphoid tissues are responsible for the generation of IgA-secreting cells. Appendectomised mice show delayed accumulation of IgA(+) cells in the large intestine, but not the small intestine, after colonization. Decreased colonic IgA(+) cells correlate with altered faecal microbiota composition. The caecal patch is a major site for generation of IgAsecreting cells that migrate to the large intestine (doi: 10.1038/ncomms4704). [email protected] 2/02/15 Appendectomy 294 Appendectomy might be a risk factor for recurrence of Clostridium difficile infection (Im et al., 2011). Researchers identified 396 patients with C. difficile infection, of whom 244 had undergone abdominal computed tomography (CT) scans, allowing determination of appendectomy. In multivariate analysis, appendectomy was independently associated with an increased risk for recurrent C. difficile infection, as was age >60. The recurrence rate was 18% in patients with an appendix versus 45% in those without. [email protected] 2/02/15 Acute Abdominal Obstruction 295 The cessation of peristalsis in either the small or large bowel leads to obstruction. This may me due to adhesions or incarceration of a hernial sac. Also impacted faeces, strictures due inflammatory diseases/infections, gallstones, haematomas amongst others. Vomiting, ‘crampy’ pain and distension are common symptoms. TCM diagnosis is Internal, Full and Hot; Stagnation of qi and Blood Stasis and in the elderly, emptiness of righteous qi. [email protected] 2/02/15 Stage 1: Ileus, increased upper intestinal motility, accumulation Of qi & Fluid. Distension of Intestine Qi Congestion in Intestines Qi Congestion becomes Blood Stasis Stage 2: Upper abdominal distension, Mucosa, vilii and microvessels compressed & obstructed. Cell death Accumulation & Congestion of Blood Changes into Heat damage to the Blood and mucosa Stage 3: Intestinal vasoconstriction, necrosis, and perforation. Fluid, bacterial translocation and peritonitis. Septic shock Necrosis © DR.D.Weber 2012 296 2/02/15 Formulas 297 Emptiness of Righteous qi Blood Stasis Angelicae Sinensis (dang Pruni Persicae (tao ren) gui) Pruni Persicae (tao ren) Viridis Citri Reticulatae (qing pi) Linderae Strychnifolii (wu yao) Rubrus Paeoniae [email protected] Lactiflorae (chi shao) Carthami Tinctorii (hong hua) Angelicae Sinensis (dang gui) MagnoliaeOfficinalis (hou po) Rhei (da huang) 2/02/15 Formulas 298 Heat Accumulation Damp & Heat Magnoliae Officinalis (hou Euphorbiae Kansui (gan sui) po) Raphani Sativa (lai fu zi) Pruni Persicae (tao ren) Rubrus Paeoniae Lactiflorae (chi shao) Rhei (da huang) Mirabilitum (mang xiao) Pruni Persicae (tao ren) Note: Oral and enema [email protected] Rubrus Paeoniae Lactiflorae (chi shao) Achyranthis Bidentatae (niu xi) Magnoliae Officinalis (hou po) Rhei (da huang) Auklandiae (mu xiang) (From: Marcus, Blue Poppy Press 1991) 2/02/15 Formulas for Appendicitis 299 Qi Stagnation, Blood Stasis Qi Stagnation, Blood Stasis & Heat Sargentodoxae (hong Sargentodoxae (hong teng) Violae Yedoensis (zi huang di ding) MeliaeToosendanis (chuan lian zi) teng) Berberis Sargentianae or brachypoda (san ke zhen) Rhei (da huang) Mirabilitum (mang xiao) [email protected] (From: Marcus, 1991) 2/02/15 Coeliac Disease 300 AND GLUTEN SENSITIVITY [email protected] 2/02/15 Coeliac Disease 301 Coeliac disease is a digestive disorder that damages the small intestine and interferes with the absorption of nutrients from food. It is the prototype of an immune mediated response dominated by the activation of the adaptive immune system and in particular of CD4+ HLA class II restricted T cells. Patients with this condition have an intolerance to the protein in gluten which damages their intestinal lining and makes it difficult to absorb nutrients. Coeliac disease is four times more common now than it was in the 1950's and People who have CD appear to have a higher rate of Crohn's disease than the general population. [email protected] 2/02/15 Coeliac Disease 302 Individuals with CD are at significantly increased risk for developing thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis (Journal of Clinical Endocrinology and Metabolism, 2008). As many as three to four percent of patients who have osteoporosis have the bone disease as a consequence of having CD, which makes them unable to absorb normal amounts of calcium and Vitamin D. Frequent rotavirus infections predicted a higher risk of CD autoimmunity. The rate ratio for CD autoimmunity was 1.94 for one rotavirus infection and 3.76 for two or more rotavirus infections compared with zero rotavirus infections (American Journal of Gastroenterology, 2006). [email protected] 2/02/15 Coeliac Patients are at greater risk for: 303 Anaemia Non-Hodgkin lymphoma Addison's Disease (doi: 10.1111/j. 1365-2036.2011.04972.x) Lupus Sjogren's syndrome Scleroderma Crohn's Disease Thyroid Disease Fibromyalgia Chronic active hepatitis Alopecia Areata Graves Disease Diabetes Myasthenia gravis [email protected] 2/02/15 Non-Coeliac Gluten Sensitivity 304 Non-coeliac gluten sensitivity, is characterised by gastrointestinal or extra-intestinal symptoms that respond to gluten withdrawal without evidence of underlying coeliac disease. Its symptoms overlap considerably with those of irritable bowel syndrome and the number of individuals embracing a gluten-free diet is rapidly growing. Its pathogenesis remains obscure but may be related to non-gliadin molecules in grains that stimulate the innate immune system of the intestine (Ned Tijdschr Geneeskd. 2013;157(21):A6168). [email protected] 2/02/15 Non-Coeliac Gluten Sensitivity 305 No underlying cause for gluten intolerance has yet been discovered. Moreover, there are a host of triggers for gastrointestinal distress. Generally, non-coeliac gluten sensitivity is assumed to be the culprit when coeliac disease is ruled out. Symptoms display significant overlap with the irritable bowel syndrome. Many important factors regarding this relatively novel condition remain to be elucidated; no discriminative markers to support a diagnosis of gluten sensitivity have been identified yet and its pathogenesis remains obscure (Biesiekierski et al., 2013). [email protected] 2/02/15 Non-Coeliac Gluten Sensitivity 306 Gibson (2013) found that each treatment diet, whether it included gluten or not, prompted subjects to report a worsening of gastrointestinal symptoms to similar degrees. Reported pain, bloating, nausea, and gas all increased over the baseline low-FODMAP diet. Even in the second experiment, when the placebo diet was identical to the baseline diet, subjects reported a worsening of symptoms. Gluten wasn't the culprit; the cause was likely psychological. Participants expected the diets to make them sick, and so they did. FODMAPS are a far more likely cause of the gastrointestinal problems attributed to gluten intolerance (doi: 10.1007/s11882-013-0386-4). [email protected] 2/02/15 Non-Coeliac Gluten Sensitivity 307 A double-blinded, randomised, placebo-controlled rechallenge trial was recently reported in patients in whom coeliac disease had been excluded by either normal duodenal histology on a gluten containing diet. Participants were randomly assigned to receive either 16 g/day carbohydrate-free gluten or placebo for six weeks. Change between baseline and final weeks were greater for patients receiving gluten in overall symptom severity compared with those receiving placebo. and were worse with gluten within one week for pain, bloating, satisfaction with stool consistency, and tiredness (2011, doi: 10.1111/j. 1440-1746.2011.06653.x.). [email protected] 2/02/15 Gut Inflammation 308 IgA-class anti-reticulin or anti-gliadin antibody-positive patients with normal small-bowel mucosal morphology frequently have immunohistochemical markers of coeliac disease latency. Together with our follow-up data this implies that they may be gluten-sensitive (Scand J Gastroenterol. 1998 Sep;33:9). Gliadin antibody (AGA)-positivity is often persistent. Overt coeliac disease is seldom found behind persistent AGApositivity, but this characteristic is associated with mucosal inflammation and gastrointestinal symptoms at least in Human Leukocyte Antigen (HLA)-positive individuals (2011, doi: 10.1016/j.dld.2011.04.025). [email protected] 2/02/15 Colonic Pouches 309 DIVERTICULOSIS, DIVERTICULA AND DIVERTICULITIS [email protected] 2/02/15 Diverticula & Diverticulitis 310 This is a problem of the large bowel which is very common in the over 50’s. Symptoms include pain and discomfort usually in the lower belly on the left hand side. It can cause loose stools, ‘crampy’ pain, change in your normal bowel habit and sometimes even bleeding. [email protected] 2/02/15 Si Mo Decoction 311 Simo Decoction (SMD), a traditional Chinese medicine, has been used to improve gastrointestinal dysmotility in clinical practice for a long history in China. SMD dose-dependently evoked hypercontractility of antral circular strips, and the maximal contractile effect of circular smooth muscle induced by SMD was significantly higher than that induced by acetylcholine (10(-3)M). SMD promotes contractions of antral circular strips in rats mainly via activation of muscarinic M3 receptor, but partly via activation of muscarinic M2 receptor, Ca(2+) channel and nicotinic receptor, inhibition of adrenergic receptor and releasing of NO (2012, doi: 10.1016/j.jep.2012.09.008). [email protected] 2/02/15 Si Mo Decoction 312 Fructus aurantii (zhi shi) Radix aucklandiae (mu xiang) Semen Arecae (bing lang) Radix Linderae (wu yao) [email protected] Si Mo Decoction and Clostridium butyricum were given to infants to treat neonatal asphyxia after feeding. SMD promoted gastrointestinal maturation, improved feeding tolerance and reduced vomiting (Zhou W-J, 2012). 2/02/15 Panaxea Cool Blue 313 Cyperus rotundus (xiang Corydalis turtuchanivnovii fu) Citrus reticulata (chen pi) Citrus aurantium (zhi ke) Amomum villosum (sha ren) Alpinia katsumadai (cao kou) Magnolia officinalis (hou po) Aquilaria agallocha (chen xiang) [email protected] (yan hu suo) Melia azederach (chuan lian zi) Aucklandia (mu xiang) Paeonia lactiflora (bai shao) Bupleurum chinensis (chai hu) Poria cocos (fu ling) Silybum marianum - 80% Silymarin 2/02/15 Cool Blue 314 The results showed that Shugan Pill could enhance pain threshold and markedly inhibit gastric ulcer, created by reserpine and absolute ethyl alcohol. It significantly inhibit the secretion of gastric acid and pepsin and promote the secretion of gastric mucus, markedly delay gastric emptying in normal mice and when gastric emptying and small intestinal propulsion was stimulated by neostigmine. These effects might be the pharmacological mechanisms of Shugan Pill on gastric pain (Zhong Cheng Yao. 2004; 26(2): 124-128). [email protected] 2/02/15 Bai Tou Weng Decoction 315 Radix Pulsatillae Chinensis (bai tou weng) Cortex Phellodendri (huang bai) Rhizoma Coptidis Recens (huang lian) Cortex Fraxini (qin pi) Additions: Rhizoma Curcumae E Zhu Radix et Rhizoma Rhei (da huang) Pericarpium Citrus aurantium (zhi shi) [email protected] Clears ‘Heat and Toxicity’ ‘Cools Blood’, and stops diarrhoea. Antibacterial, and aids with diverticulitis 2/02/15 Diverticulitis 316 11 heat-clearing Chinese herbs including Scutellaria baicalensis (huang qin), Coptis chinensis (huang Lian), Flos Lonicerae (jin yin hua), Forsythia suspensa (lian qiao), Isatidis Folium (da qin ye), Radix Isatidis (ban lan gen), Viola yedoensis (zi hua di din), Pulsatilla Radix (bai tou wen), Andrographis paniculata (chuan xin lian), Houttuynia cordata (yu xing cao), and Patrinia Herba (bai jian cao) have anti-inflammatory and antimicrobial effects. Their ability to affect multiple target signalling pathways and their potential mechanisms of action contributing to their anti-inflammatory and antimicrobial activity may be related to their action of removing ‘Heat and counteracting Toxicity’. (2014,doi: 10.4103/2225-4110.126635). [email protected] 2/02/15 Cholecystitis 317 GALL BLADDER DISORDER [email protected] 2/02/15 Cholecystitis 318 Cholecystitis is inflammation of the gallbladder, which occurs most commonly due to obstruction of the cystic duct with gallstones (cholelithiasis). Blockage of the cystic duct with gallstones causes accumulation of bile in the gallbladder and increased pressure within the gallbladder. Concentrated bile, pressure, and sometimes bacterial infection irritate and damage the gallbladder wall, causing inflammation and swelling of the gallbladder. Females are twice as likely to develop cholecystitis as males. Uncomplicated cholecystitis has an excellent prognosis; however, more than 25% of patients require surgery or develop complications [email protected] 2/02/15 Cholecystitis 319 For symptomatic cholecystitis, antibiotics and antispasmodic treatment are conventional therapy while cholecystectomy or laparoscopic cholecystectomy are also appropriate modalities of treatment (Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005440). However gallstone disease of this type may recur within several months. Gallstones may also recur in the biliary tract after cholecystectomy Traditional Chinese medicines (TCM) has a long history of use for treating cholecystitis and has developed an integrated system of medical examination and treatment. [email protected] 2/02/15 Cholecystitis 320 Cholecystitis is considered by TCM to be caused mainly by unrestrained food and drink, exogenous heat and moisture, chronic illness and/or injury (China Press of Traditional Chinese Medicine; 2003. pp. 270–302). Patients with gallstone always have Gan-qi stagnation that affects the functions of Pi-Wei, or even the passage among the triple energisers. Most patients in this study showed signs of Gan-qi stagnation. Shitong Mixture No. 1 was formulated for dissolving Gan-qi stagnancy, normalising the function of gallbladder and removing stones, expelling stagnation and relieving pain, and enlivening the Pi and regulating Wei (Chin J Integr Med 2007 Mar;13:1) [email protected] 2/02/15 Cholecystectomy 321 The symptoms of digestive disturbance would present themselves in patients after laparoscopic cholecystectomy (LC), such as abdominal dissention, poor appetite, belches, nausea and vomiting, corpulent tongue (teeth-imprinted tongue), white sticky tongue after LC, and belong to syndrome of qi-deficiency with dampness stagnation in TCM. For this reason, modified Liujunzi Decoction is chosen for drying up dampness to help digestion, regulating qi and the middle energizer to promote blood circulation (ibid). [email protected] 2/02/15 Shitong Mixture No. 1 322 Radix Bupleuri (chai hu) Fructus Aurantii (zhi shi) 12g Herba Lysimachiae (jin qian cao) 30g Radix Aucklandiae (mu xiang) 18g Radix Curcumae (e zhu) 12g Rhizoma Cyperi (xiang fu) 12g Fructus Hordei germinatus (mai ya) 30g 12g Rhizoma Atractylodis macrocephalae (bai zhu) 30g Pericarpium Citri reticulatae (chen pi) 20g Endothelium Corneum Gigeriae galli (ji nei jin) 20g [email protected] 2/02/15 Liujunzi Variation Decoction 323 Radix Codonopsis pilosulae Fructus Citri sarcodactylis (dang shen) 15g Rhizoma Atractylodis macrocephalae (bai zhu) 15g Poria (fu ling) 20 g Rhizoma Dioscoreae (shan yao) 20g Radix Glycyrrhizae (gan cao) 3g Pericarpium Citri reticulatae (chen pi) 15g Rhizoma Corydalis (yan hu suo) 15g [email protected] (fo shou)10g Rhizoma Pinelliae (ban xia) 6g Fructus Crataegi (shan zha) 20g Radix Salviae miltiorrhizae (dan shen) 30g Radix Aucklandiae (mu xiang) 15g Radix Bupleuri (chai hu) 15g Fructus Amomi (sha ren) 6g 2/02/15 Meta-System or yin/yang: Organism and its Relationships System: Kidney, Liver, Heart Blood, qi etc. i.e. Psycho-Neuro-ImmunoEndocrine-Somatic (Organ) Chronic Degenerative Diseases: Cancer, CVD, etc. Premature Ageing Dementia, Weak Libido, Obesity, etc. Sub-System / Element: Kidney yang / HP Axis Disease Manifestation: i.e. Loss of Integrity of System HPA Axis Dysregulation / Relationships Kidney yang Xu / Hypothalamic Disorder A "meta-system" is a system about other systems, such as describing, generalising, modelling, or analysing the other system(s). A system is a set of interacting or interdependent components forming an integrated whole and is a set of elements and relationships, which are different from relationships of the set or its elements to other elements or sets. © DR.D.Weber 2012 324 2/02/15 Brain/Gut Diseases; The Future 325 Conventional medical treatment for neurologic disorders such as epilepsy, migraine, and autism focuses on the brain, however some individuals respond poorly or not at all to regular medicine. Evidence is accumulating in the medical literature that the enteric nervous system (ENS)-that part of the nervous system associated with the alimentary canal-also plays a role in these disorders. Neurologic diseases with systemic features (particularly with significant GI symptoms) may be approached from a complementary medicine model that recognises the role of the abdominal nervous system with regard to aetiology and treatment (THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE. Volume 5, Number 6, 1999). [email protected] 2/02/15 Cancer References 326 Dong LM, Kristal AR, Peters U, Schenk JM, et al. Dietary supplement use and risk of neoplastic progression in esophageal adenocarcinoma: a prospective study. Nutr Cancer. 2008;60(1):39-48. doi: 10.1080/01635580701586762. Efferth T, Sauerbrey A, Steinbach D, et al. Analysis of single nucleotide polymorphism C3435T of the multidrug resistance gene MDR1 in acute lymphoblastic leukemia. Int J Oncol. 2003 Aug;23(2):509-17. Fan Y, Zhang S, Yao & Li. 2008 CHINESE JOURNAL OF PATHOPHYSIOLOGY Year 2006, Issue 4, Page 748-751 Fu Js. Treating 40 cases of esophageal cancer of middle and late stage with Shen Zhu Fu Zheng Fang in combination with radiotherapy and chemotherapy. Zhong Guo Zhong Yi Yao Xian Dan Yuan Cheng Jiao Yu. 2008, 6(10): 1212) Gao Jl, Shen Zh. Treating 30 cases of esophageal cancer of middle and late stage with the method of clearing phlegm and removing stagnant Blood. Zhe Jiang Zhong Yi Yao Da Xue Xue Bao. 2007, 31(2): 176-177 ) Li J, Sun GZ, Lin HS, et al. Int Immunopharmacol. 2008 Sep;8(9):1196-206. doi: 10.1016/j.intimp.2008.04.007. Lin Zg. Answering clinic questions: how to treat esophageal cancer according to syndrome differentiation. Zhong Yi Za Zhi. 2004, 41(12): 755) Liu Jh, Zhang Z. Treating 25 cases of esophageal cancer of advanced stage with self-formulated Fu Zheng Xiao Ai Tang. Si Chuan Zhong Yi. 2008, 26(1): 82) Ma JW, Song YC, Zhang Y, et al. (2013). Effects of Shenqi Fuzheng injection on the invasiveness of cells and expression of Tenascin-C in human gastric cancer MGC- 803 cells. Journal of Modern Oncology, 21(2), 263-266. Liu YX, Jiang SH, Kuang TH, Yao YW, Yang JW, Wang YQ. (2008). Clinical Observation on 28 Cases of the Metabasis of Stomach Cancer after Operation Treated by Yiqi Bushen Oral Liquid: and Chemotherapy. Zhong Yi Za Zhi, 49(2): 128-130. 2012, Pages 240–252 [email protected] 2/02/15 Cancer References 327 Wu L, & Yang Y. (2007). A clinical study of treating advanced gastric cancer with the combination of Kangai injection and chemotherapy. Proceeding of Clinical Medicine, 18(7), 1671-8631. Xu HX, Huang XE, Li Y, Li CG, Tang JH. A clinical study on safety and efficacy of Aidi injection combined with chemotherapy. Asian Pac J Cancer Prev. 2011;12(9):2233-6. Xu Lx, Zhong Jh. Treating 80 cases of esophageal cancer with Ding Xiang Tou Ge Tang. Ji Lin Zhong Yi Yao. 2006, 26(12): 36-37) Yin LL, & Jiang CY. (2013). Observation on the influence of Shenqi-Fuzheng injection on T-lymphocyte subsets, NKcell and the leukocyte of the patients with advanced gastric cancer. International Journal of Traditional Chinese Medicine, 35(1), 22-24. Zhong LLD, Chen H-Y, Cho WCS, et al. The efficacy of Chinese herbal medicine as an adjunctive therapy for colorectal cancer: A systematic review and meta-analysis. Complementary Therapies in Medicine. Volume 20, Issue 4, August [email protected] 2/02/15 Thank You 328 Q [email protected] Q 2/02/15