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The Human Microbiome: Its Impact On Our Lives and Our Health Robert Rountree, M.D. Boulder, Colorado Christine Stubbe, ND Medical Education Specialist - Asheville Dr. Robert Rountree, M.D. Technical Issues & Clinical Questions Please type any technical issue or clinical question into either the “Chat” or “Questions” boxes, making sure to send them to “Organizer” at any time during the webinar. We will be compiling your clinical questions and answering as many as we can the final 15 minutes of the webinar. DISCLAIMER: Please note that any and all emails provided may be used for follow up correspondence and/or for further communication. Need more resources? Ensure you have an account! The Human Microbiome: Its Impact On Our Lives and Our Health Robert Rountree, M.D. Boulder, Colorado Learning Objectives • Review – How DNA sequencing has redefined what it means to be human – How gut microbiomes impact on our digestion, metabolism, neurology & immunology – The impact of our modern lifestyle on our microbiome and its correlation with chronic diseases – How prebiotics and probiotics may help to maintain a healthy microbiome The Normal Microbiota Humans are like mobile warm-blooded coral reefs, home to vast numbers of microbial ecosystems that are rich in biodiversity The Normal Microbiota Composition of microbiota varies with each individual – most fairly stable – some species transient Each individual has a unique microbial “fingerprint” Types of Human Microbiota • Viruses (acellular) • Prokaryotes (no nucleus) – Archaea (strict anaerobes) – Bacteria (aerobes and anaerobes) • Eukaryotes (nucleus + organelles) – Microfungi (yeasts) – Protozoa – Helminths (parasitic worms) Archaea in the Human Microbiome • Initially thought to be extremophiles that only lived in harsh environments, now known to colonize humans • Strict anaerobes – difficult to culture – Identified by PCR of DNA sequences (16S rRNA gene) – or by breath testing • Usually thought to be commensals or mutualists that aid digestion, but now implicated in oral & GI disorders Methanogens in Human Health and Disease Pimentel et al, Am J Gastroenterol Supp, 2012, Vol 1: 28-33 • Evidence has linked overabundance of methanogenic archaea to constipation & IBS • Methane may influence intestinal transit & pH & facilitate development of constipation • Methanogens ensure more complete fermentation of carbohydrates, leading to higher production & absorption of SCFAs, which may lead to obesity Methanobrevibacter smithii • Dominant archaeon in GI tract: – 10% of prokaryotes • Not detected in about 50% of people • Produces methane from H2, CO2, or SCFAs (acetate): – a major source of flatulence in cows (cause of global warming ?) and in humans • Implicated in constipation predominant IBS, SIBO, obesity, T2DM Am J Gastroenterol Suppl 2012 1:28–33 “A positive methane breath test is synonymous to the presence of methanogenic archaea” World J Gastroenterol 2014 Vol 20(43): 16062-16078 The Bacterial Microbiome: By the Numbers • Every bodily surface hosts a myriad of microorganisms: – Skin = 1012 (one trillion) resident bacteria – Mouth = 1010 (ten billion) – Gut (especially distal) = 1014 (100 trillion) with total weight ~ 2-5 lbs. Mostly anaerobes The Bacterial Microbiome: By the Numbers • Current estimates for oral and intestinal microbiota: – up to 500–1000 different species • 30–40 species make up 99% of total population • Biodiversity defined by – Species richness (number of species) – Relative species abundance Dominant Bacterial Phyla in Human Habitats (Mucosal & Cutaneous) • • • • Bacteroidetes Firmicutes Actinobacteria Proteobacteria The Microbiome: Comparative Mass Meet your microbiome – The bacteria that call you home NOSE • • Mass of microbes 10 g Typical resident Streptococcus MOUTH • • Mass of microbes 20 g Typical resident Streptococcus (cheek), Neisseria (teeth) VAGINA • • • • Mass of microbes 1000 g Typical resident Bacteroidetes Mass of microbes 20 g Typical resident Lactobacillus SKIN • • • GUT Mass of microbes 200 g Typical resident Staphylococcus (oily areas), Corynebacteria (moist areas) MICROBIAL CELLS OUTNUMBER YOUR OWN CELLS 10 TO 1 AND HAVE A TOTAL MASS OF > 1.2 kg Humans vs Bacteria • Human somatic & germ cells: – Approximate average = 1013 (10 trillion) • Total microbiota > 100 trillion – Outnumbering human cells by 10:1 • One of the most complex microbial ecosystems on the planet! Acquisition of the Human Microbiome PLoS Biol, 2013, Vol 11(8): e1001631 • Initial inoculum from mother occurs during pregnancy (womb is not sterile) • Vaginal delivery – – microbiome develops species similar to mother’s vagina • Cesarean section – – microbiome develops predominant species similar to skin flora of mother and hospital attendants • Breast feeding provides bacteria from mother’s GI tract (breast milk is not sterile) The microbes we acquire at birth affect our health throughout our lives We are born 99% human but we die 90% microbial Cesarean Section Delivery Increases Child’s Risk PLoS Biol, 2013, Vol 11(8): e1001631 • • • • • Allergic rhinitis Asthma Celiac disease Type I diabetes Inflammatory bowel disease Bacterial Community Variation in Human Body Habitats Across Space & Time Science 2009: Vol. 326 no. 5960 pp. 1694-1697 • Bacterial community composition is primarily determined by microecology of body habitat (gut, oral cavity, skin region) • For each specific habitat: – High levels of interpersonal variability: • Each individual has a unique microbial fingerprint – Minimal temporal variability within individuals 6–10 BILLION BACTERIA Archaea Protozoa Fungi Viruses Shaping the oral microbiota through intimate kissing Microbiome, 2014, Vol 2:41 • Kissing for 10 seconds transfers an average of 80 million bacteria • Couples who reported they kissed more often ended up having more similar microbiota than lessfrequent kissers • The similarity was most pronounced for the tongue surface The oral microbiome in health and disease Pharmacol Res 2013, Vol 69(1): 137-143 • 40–60% of oral bacteria have not been cultivated or phenotypically characterized • Periodontitis appears to result from an inappropriate inflammatory reaction to the normal microbiota, exacerbated by the presence of some disease-associated bacterial species Continuing on to the GI tract… Total Bacteria in the Human Gut: Approximately 100 TRILLION • Over 98% of the bacteria in the colon are strict anaerobes • Approx. 1010 bacteria/gm • Anaerobes greatly out number aerobes • Closer to the ileocecal valve, the number and variety of organisms increases to 105 – 6 /gm • Anaerobes increase significantly, including: • Clostridium • Bacteroides • Fusobacterium The stomach contains 103 – 5 acid resistant organisms per gram: • Helicobacter • Streptococci • Lactobacilli • Staphylococci There are 1012 – 13 bacteria per gm in stool • The small intestine starts with organisms similar to the stomach, at amounts of 103 – 5 /gm • Anaerobes only slightly outnumber facultative organisms Cell densities in the colon (1011–1012/ml contents) are the highest recorded for any known ecosystem. The Genome Institute at Washington University Small Intestinal Bacterial Overgrowth • Expansion of archaea & coliforms (E coli, Klebsiella) from colon into small intestine (Pimentel hypothesis) • Predisposed by – Loss of antibacterial mechanisms: achlorhydria (PPIs), pancreatic exocrine deficiency, immunodeficiency syndromes – Anatomical abnormalities – Motility disorders Human Distal Gut Microbiome Marchesi, Environ Microbiol (2011) • After the age of 2.5, the distal gut microbiota is stable and colonized predominantly by two phyla: – Firmicutes and Bacteroidetes, which comprise 90% of the species found • Current estimates are that the microbiome encodes from 3–10 million unique genes…the DNA of which is frequently transferred via phage, plasmids, transposons and other mobile genetic elements (MGEs) Humans as Superorganisms • The mammalian microbiome has evolved over millions of years to its current state of symbiosis • The human metagenome results from an amalgamation of microbial and human genes Although there is a staggering diversity of genes in the human microbiome, many perform similar functions in different individuals What are the functions of proteins made by these genes? (The Metagenome) Functions of Gut Microfloral Metagenome • Digestion and energy harvesting • Detoxification / biotransformation (hormones, toxins) • Chemical synthesis: SCFAs, amino acids, neurotransmitters, vitamins • Colonization resistance against pathogens (C.R.A.P.) • Systemic immune modulation Gut Microbiota, Immunity, & Disease Frontiers in Microbiology, 2011, Vol 2: 1-11 • The gut microbiota has a significant impact on the systemic immune response • …these data suggest that gut microbiota influence the development of inflammatory/autoimmune diseases… • Commensal bacteria belonging to the Bifidobacterium, Bacteroides, Clostridium and Lactobacillus genera are associated with inflammatory/autoimmune disease protection Faecalibacterium prausnitzii and human intestinal health Current Opinion in Microbiology 2013, 16:1–7 • The most abundant bacterium in the human intestinal microbiota of healthy adults – 5–15% of the total bacterial population • One of the most abundant butyrate producing bacteria • Anti-inflammatory / mucosal protective properties Faecalibacterium prausnitzii and human intestinal health Current Opinion in Microbiology 2013, 16:1–7 • Extremely sensitive to oxygen & oxidative stress • Relative abundance can serve as an indicator or biomarker of intestinal health in adults • Very low levels could be predictive for Crohn’s Disease Major Influences on Individual Microbiomes • Host genotype • Type of birth (vaginal vs C-section) • Hygiene (excessive) – PLoS One. 2011;6(12):e28284 • Diet – Macronutrients, fiber, phytochemicals, alcohol • Probiotics and prebiotics Major Influences on Individual Microbiomes • Medications: – Antibiotics, nonsteroidal anti-inflammatory drugs, etc. • Stress (social, emotional) • Chronic disease • Aging • Surgery (gastric bypass) • Fecal bacteriotherapy transplants Chowing down on meat, dairy alters gut bacteria a lot, and quickly Diet rapidly and reproducibly alters the human gut microbiome Turnbaugh, et al (Harvard Medical School), Nature 2014 Vol 505: 559–563 9 Volunteers placed on two extreme diets x 5 days: • 1) meat, egg and cheese, then switched to • 2) grains, vegetables and legumes • Within 1–2 days saw major alterations in microbiome measured by 16S rRNA sequencing • Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation Diet rapidly and reproducibly alters the human gut microbiome Nature 2014 Vol 505: 559–563 • Animal diet – Increased abundance & activity of bile-tolerant organisms (eg biophila wadsworthia – linked to colitis in animal studies) – Decreased Firmicutes species that metabolize plant polysaccharides • Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi, and viruses Dysbiosis, Reduced Microbial Diversity and Disease Diversity Association and Relative Abundance Graphics 51 Internal Exposure to Diversity The Human Microbiome • A lack of microbial species richness and phylogenetic diversity are associated with poor health • Excessively sterile environments, diets low in plant fiber, repeated exposure to antibiotics, and aging all decrease microbial diversity • The Hazda (Tanzanian hunter-foragers) have much great microbial diversity than Westerners humanfoodproject.com 52 Martin Blaser is chair of the Department of Medicine, New York University Langone Medical Center, New York, NY “Antibiotic overuse: Stop the killing of beneficial bacteria” Blaser; Nature, 2011, Vol 476: 393-394 • Bacteria have lived in and on animals—constituting their microbiome — since multicellular life evolved about 1 billion years ago • Babies acquire their founding bacterial populations from their mothers while passing through the vagina at birth • So each generation — particularly the 30% or so of infants born via Caesarian — could be beginning life with a smaller endowment of ancient microbes than the last “Antibiotic overuse: Stop the killing of beneficial bacteria” Blaser; Nature, 2011, Vol 476: 393-394 • Evidence is accumulating that beneficial commensals do not recover completely from antibiotics or are replaced in the long term by resistant organisms • Overuse of antibiotics could be fueling the dramatic increase in conditions such as obesity, type 1 diabetes, inflammatory bowel disease, allergies and asthma, which have more than doubled in many populations J Allergy Clin Immunol, 2011, Vol 128: 646-652 Reduced bacterial diversity of the infant’s intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis and peripheral blood eosinophilia… Membership and Behavior of Ultra-LowDiversity Pathogen Communities Present in the Gut of Humans during Prolonged Critical Illness University of Chicago mBio 2014 Vol 5(5): e01361-14 • Prolonged stays in ICU leads to “complete ecological collapse” with the emergence of ultra-low (1–4 taxa) multi-drug resistant pathogenic bacteria communities in 30% of patients; • ~75% of cases C albicans & C glabrata overgrowth • These limited communities keep each other in check until triggered by acute stressful events (opioids) which can lead to life-threatening sepsis Gut Microbiota Disruption Disease Risk Associations • Acne • Allergies & Asthma • Autoimmune Disease – – – – Diabetes Reactive arthritis Rheumatoid arthritis Ankylosing spondylitis) • Autism Gut Microbiota Disruption Disease Risk Associations • • • • • • • Colorectal cancer Cardiovascular Disease Irritable bowel syndrome Inflammatory Bowel Disease Fatty Liver Disease Obesity Aging Fecal Bacteriotherapy Human Probiotic Infusion • Fecal transplants also being successfully used for inflammatory bowel disease • Does transplanting an entire ecosystem impact the core microbiome in ways that prebiotics and probiotics do not? Conclusions • Research into the microbiome using DNA sequencing has redefined what it means to be human • Humans are superorganisms that represent a blend of genetic traits from human & microbial cells • Our microbiomes have a major impact on our digestion, metabolism, neurology & immunology Conclusions • The vast majority of our interactions with bacteria are either neutral or mutually beneficial: maintaining tolerance is essential to health • Alteration of the microbiome by our modern lifestyle (diet, stress, excessive hygiene and antibiotics) may be responsible for many chronic diseases • Dietary changes, prebiotics and probiotics may help to maintain a healthy microbiome QUESTIONS? Additional Education Materials: www.gdx.net Sample Reports, Support Guides, Kit Instructions, FAQs, Payment Options, and much more! Additional Education Materials: www.gdx.net LiveGDX Additional Questions? US Client Services: 800-522-4762 UK Client Services: 020.8336.7750 Please schedule a complimentary appointment with one of our Medical Education Specialists for questions related to: – Diagnostic profiles featured in this webinar, – How Genova’s profiles might support patients in your clinical practice, or – To review a profile that has already been completed on one of your patients We look forward to hearing from you! Upcoming LiveGDX Webinar Topics • March 2015: – Jill Carnahan, M.D. • Autoimmunity and the Gut: Everything you need to know about microbial and infectious triggers Register for upcoming LiveGDX Webinars online at www.gdx.net The views and opinions expressed herein are solely those of the presenter and do not necessarily represent those of Genova Diagnostics. Thus, Genova Diagnostics does not accept liability for consequences of any actions taken on the basis of the information provided. The Human Microbiome: Its Impact On Our Lives and Our Health Robert Rountree, M.D. Boulder, Colorado The views and opinions expressed herein are solely those of the presenter and do not necessarily represent those of Genova Diagnostics. Thus, Genova Diagnostics does not accept liability for consequences of any actions taken on the basis of the information provided.