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MODELLING GI
DISEASES
Translating Symptoms into
Mechanisms
Stephen Collins
McMaster University
Hamilton, Ontario, Canada
Collins.Exp Biol 2007
GI DISEASE PROCESSES
Acid-peptic disease
(post-H.pylori era)
Gastric acid secretion
Mucosal barrier
Inflammatory Bowel
Disease (Crohns, Colitis)
Immune dysfunction
Barrier dysfunction
GI Infections
Host defense
Ischemic Injury
Mucosal blood flow
Functional GI Disorders
(e.g. IBS)
Altered gut physiology
Collins.Exp Biol 2007
FUNCTIONAL GI DISORDERS
• Chronic abdominal symptom complexes for
which there is no discernible underlying
structural abnormality.
• By far the most common category of GI disease
• They are disorders of function – and reflect
altered physiology
• The symptoms are non specific and mimic those
of organic diseases such as peptic ulcers or
inflammatory bowel disease
Collins.Exp Biol 2007
THE CHALLENGE OF
FUNCTIONAL GI DISORDERS
• These disorders are poorly conceptualized
• There are no diagnostic or other biomarkers
• Few, if any, drugs are highly efficacious
• Socio-economic burden is high (absenteeism, diagnostic
tests, treatments)
• Traditionally, they are diagnosed by excluding “organic
GI disease”
Collins.Exp Biol 2007
THE DIAGNOSIS OF
FUNCTIONAL GI DISORDERS
“ If I can’t see it, it ain’t
there.
Diagram from National
Cancer Institute showing
GI tract and colonoscopy
procedure
Diagram available at
http://www.cancer.gov/Te
mplates/db_alpha.aspx?C
drID=45648
Collins.Exp Biol 2007
It’s all in your head.”
WHAT HAPPENED TO
COGNITIVE
GASTROENTEROLOGY?
SYMPTOMS ARE
IMPORTANT
THEY MAY TELL YOU ABOUT
UNDERLYING MECHANISMS
(not the cause of disease)
THIS WILL INFLUENCE TREATMENT
& DIRECT RESEARCH ENQUIRY
Collins.Exp Biol 2007
The Conceptualization of
Functional GI Disorders
1. Top Down Model:
A “psychosomatic disorder”
Stress & Major affective
disorders.
GI tract: Innocent bystander
Top Down
Model
1
2
Bottom up
Model
2. Bottom up Model:
A peripheral trigger such as
infection or inflammation
Behavioral issues still relevant
ARE THEY MUTUALLY
EXCLUSIVE CONCEPTS ?
Collins.Exp Biol 2007
CONSTRUCTING A MODEL OF
FUNCTIONAL GI DISORDERS
End point: Altered gut physiology in the
absence of overt tissue damage.
The stimulus used to induce gut
dysfunction must be relevant to the
pathogenesis of these conditions
The resulting dysfunction should be
chronic rather than acute.
Collins.Exp Biol 2007
Common Symptoms of Functional
GI Disorders
•
•
•
•
•
•
•
•
Abdominal pain or discomfort
Indigestion
Early post prandial fullness
Bloating
Excessive Gas
Diarrhea
Constipation
Behavioral symptoms
Collins.Exp Biol 2007
Translating Symptoms in
Mechanisms
Qualitative Aspects of Abdominal Pain:
1. Cramping and related to bowel
movements or eating
Abnormal motility: smooth muscle, enteric nerves or
ICCs
2. Non cramping persistent pain
Visceral hyperalgesia or allodynia: sensory nerves
or specific chemical sensitivity (e.g. acid)
Collins.Exp Biol 2007
MECHANISMS OF ABDOMINAL
PAIN
Abnormal
sensory
perception
i.e. Central
Processing
Altered spinal
modulation
Sensitization of
visceral afferent
fibres
Collins.Exp Biol 2007
Spasm of GI
smooth
muscle
CONSTIPATION
• Multiple definitions
• Artificial clinical classifications (Rome criteria
versions I-III)
• Underlying physiology of defecation is usually
forgotten by clinicians
• Mechanistic classification is helpful (if you
plan to actually listen to the patient!)
Collins.Exp Biol 2007
NORMAL COLONIC
FUNCTION
3.5 litres of
fluid per day
arrive at
cecum
>90% EFFICIENCY
FOR
REABSORBTION
OF WATER OVER
~1m
200-300ml of solid
stool/day
Collins.Exp Biol 2007
ROLE OF COLONIC MOTILITY
2. Occasional peristaltic activity to
push solid stool forward
1. Segmenting
non peristaltic
contractions to
slow fecal
stream
3.5 litres of
fluid per day
arrive at
cecum
Collins.Exp Biol 2007
H20
3. Rare mass
movement
(sustained peristaltic
wave) to push formed
stool to rectum
200-300ml of solid
stool/day
ANO-RECTAL PHYSIOLOGY
4. AWARENESS
“DO
SOMETHING!”
S2
S3
S4
1. STOOL DISTENDS THE
RECTUM
2. REFLEX RELAXATION
OF INTERNAL ANAL
SPHINCTER
3. STOOL ENTERS THE
ANAL CANAL
5. YOUR CALL !
Contract the sphincter & postpone
Relax the sphincter & take the
consequences
Collins.Exp Biol 2007
TRANSLATING SYMPTOMS
INTO MECHANISMS
“Doctor, I can go for weeks without
a bowel movement, I never get the
urge…I get progressively more
distended..
SLOW COLONIC
TRANSIT
and/or
POOR INTAKE OF
WATER, FIBRE & CHO
I always feel I
should go; I never
feel emptied
ALTERED
SENSATION &
ACCOMODATION
I go several times a
day, I strain for
hours…
OUTLET DYSFUNCTION
Pelvic Floor
Anal Sphincter
Collins.Exp Biol 2007
MECHANISTIC APPROACH TO
CONSTIPATION
SLOW COLONIC
TRANSIT
Slow Transit
Constipation
POOR INTAKE OF
WATER, FIBRE & CHO
Reduced bulk & altered
fermentation
Collins.Exp Biol 2007
ALTERED
SENSATION &
ACCOMODATION
Normal Transit
Constipation
OUTLET DYSFUNCTION
Pelvic Floor
Anal Sphincter
Pelvic Floor Dyssynergia
Anismus
RELEVANT PATHOPHYSIOLOGY
• Abnormal colonic motility
• Diminished or altered rectal sensory
function
• Abnormal co-ordination between pelvic
floor, recto-sigmoid and anal sphincter
muscles
Collins.Exp Biol 2007
BLOATING & FULLNESS
Early Post Prandial Fullness
Abnormal gastric physiology: antral dysmotility, impaired accommodation
Abdominal Bloating
Increase gas production? Reduced accommodation of gas?
Increased perception of distension ?
Abnormal fermentation by commensal bacteria
Abnormal compliance of gut wall or allodynia
Altered
motility
Collins.Exp Biol 2007
Bacterial
load
Abnormal motility
GUT FLORA
The average human body, consisting of about 1013 cells
The gut contains > 1014microorganisms.
Bacteria make up most of the flora in the colon and 60% of fecal mass.
Gut microbiota reflects > 500 different bacterial species.
Fungi are also part of the gut eco-system
The majority of bacteria are strict anaerobes and cannot be cultured.
Identification is based on DNA analysis.
Collins.Exp Biol 2007
THE DIVERSITY OF HUMAN GUT
MICROBIAL FLORA
• Diversity between individual subjects
• Diversity between fecal and mucosal-associated
samples
• Patchy distribution of bacteria but not uniform
gradient along the length of the colon
• 395 bacterial phylotypes identified; 244 (64%)
were novel and 80% have not been cultured
Eckburg P et al Science 2005
Collins.Exp Biol 2007
THE ROLE OF GUT FLORA
• Provide nutrition to the host, influence caloric
consumption and regulate fat handling
• Regulate epithelial function
• Instruct innate immunity, imprint adaptive immunity and
maintain “physiological inflammation”
• Influence intestinal angiogenesis
• Metabolize drugs and pre-carcinogens
• Maintain normal gut physiology
Collins.Exp Biol 2007
Antibiotic treatment (10 days) increased
CRD responses
Figure of 3 graphs showing AUC vs.
colonic distension for placebo, antibiotic
therapy, and ATB+L.paracasei and 1
graph of MPO on Day 1 vs. Day 10 for
those 3 treatments
Figure from
Verdú EF, et al. Gastroenterology 127 (3): 826-837, 2004
Available at http://www.gastrojournal.org
(under subscription access)
Collins.Exp Biol 2007
DIARRHEA
Mechanisms
• Usually associated with eating;
better on fasting (gastro-colic reflex?)
- Motility (rapid
transit)
• Typically low-volume diarrhea
(not dominant secretory)
- Secretory (minor)
• Stool consistency is variable
(not dominant secretory)
- Rectal sensory
dysfunction
(pseudo-diarrhea)
• No weight loss
(no clinical malabsorption
or maldigestion)
- Normal pancreatic
and absorptive
function
Collins.Exp Biol 2007
EPITHELIUM IN FUNCTIONAL GI
DISORDERS
• Some evidence that CHO absorption may be
abnormal in some patients with diarrhea
• Bile acid reabsorption is abnormal in some
patients with diarrhea
• Permeability of small intestine to lactulosemannitol is abnormal in some patients with IBS
(post-infective IBS)
Collins.Exp Biol 2007
INSIGHTS IN THE
PATHOGENESIS OF
FUNCTIONAL GI DISORDERS
POST-INFECTIVE IBS
Collins.Exp Biol 2007
INFLAMMATION & INFECTION IN
IBS
• Low grade inflammation is evident in a subset of
IBS patients
• The analogy is made with asthma: i.e. low grade
inflammation causes tissue dysfunction without
significant structural damage.
• There is an established relationship between
acute bacterial gastroenteritis and the
development of IBS. Infection is a trigger for IBS
Collins.Exp Biol 2007
MAY 2000
Walkerton, Ontario
CONTAMINATION OF TOWNS WATER SUPPLY
BY OVERFLOW FROM FARMS
65 HOSPITALIZATIONS
(27 HUS)
Collins.Exp Biol 2007
6 FATALITIES
Walkerton: May 2000
• 1346 reported cases* of acute Gastroenteritis
• 799 were residents of Walkerton
• 1304 had “primary” exposure (to municipal
water)
• E.Coli and C.jejuni were main pathogens
A substantial number of patients remain
symptomatic almost 7 years later
Collins.Exp Biol 2007
BGOS Health Unit Investigative Report
ALTERED GI PHYSIOLOGY IN
PI-IBS
• Rapid gut transit
(Gwee et al. Gut 1999;44:400-406)
• Bile acid malabsorbtion
(Niaz et al. J R Coll Physicians Lond. 1997 Jan-Feb;31(1):53-6)
• Reduced rectal compliance
(Bergin et al. Eur J Gastroenterol Hepatol 1993 5: 617-620)
• Visceral hypersensitivity
(Bergin et al. Eur J Gastroenterol Hepatol 1993 5: 617-620)
• Increased numbers of entero-endocrine cells
(Spiller Gut 2000;47:804-811)
Collins.Exp Biol 2007
INCREASED INTESTINAL
PERMEABILITY IN PI-IBS
Figure showing Lactulose/Mannitol Ratio in
control and PI-IBS treatment at 12 weeks
Figure from R C Spiller et al., Gut 2000;47:804-811
Under access control at
http://gut.bmj.com/cgi/content/abstract/47/6/804
Also see J. Marshall et al., Aliment Pharmacol Ther. 2004
Dec;20(11-12):1317-22
Under access control at
http://www.blackwell-synergy.com/toc/apt/20/11-12
Collins.Exp Biol 2007
INFLAMMATORY CHANGES IN
PI-IBS
• Increased cellularity of lamina propria but normal
mucosal architecture.
• Increased numbers of IELs and CD3 cells
• Increased IL1bmRNA expression
• Increased numbers of mast cell-nerve clusters
(Gwee et al 1999 & 2003; Spiller et al 2000; Barbara et al 2004; Wang et al
2004)
Collins.Exp Biol 2007
CONCEPTUAL MODEL OF
GUT DYSFUNCTION IN PI-IBS
Bacterial & Other
Antigens
INCREASED
PERMEABILITY
LYMPHOCYTIC &
MAST CELL
ACTIVATION
ALTERED SENSORY-MOTOR
FUNCTION
Collins.Exp Biol 2007
IMMUNE ACTIVATION
IMPLICATIONS FOR TEACHING
• Clinically relevant changes occur in the following
GI systems:
Motility apparatus
Sensory circuits
Epithelial biology
• There a clinically relevant interfaces of these
systems with:
The Central Nervous System
The mucosal immune system
Pathogenic and commensal bacteria
Collins.Exp Biol 2007