106_Hanaway_DIGIN_Gut_Dysfunction_AFMCP_Online2021sept.pdf

DIGIN to Root Causes of Gut Dysfunction PATRICK HANAWAY, MD Applying Functional Medicine in Clinical Practice  Disclosures Patrick Hanaway, MD has no financial relationships to...

DIGIN to Root Causes of Gut Dysfunction PATRICK HANAWAY, MD Applying Functional Medicine in Clinical Practice  Disclosures Patrick Hanaway, MD has no financial relationships to disclose. ©2020 The Institute for Functional Medicine  Evidence Icons: Key Clinical Disclaimers: Study Types: Association, not causation Animal study Lab test (Labs not generally accepted in conventional care) In vitro study Clinical experience (Intervention warranted by historical clinical experience of ©2021 The Institute for Functional Medicine educator and/or functional medicine community of practitioners in the context of evidentiary paucity) n of 1, or single-case study Clinical judgment (Intervention warranted by clinical judgment of educator and/or functional medicine community of practitioners in the context of evidentiary paucity) In silico (Computerized molecular modeling) Conflict of interest  Naturopathic maxim … “Death begins in the colon.” The practical application ©2021 The Institute for Functional Medicine … “When in doubt, treat the gut.” Permission to use the photograph granted by Bernard Jensen International ©2021 The Institute for Functional Medicine  Why Focus On The Gut? The gut is the organ that produces most of the body’s serotonin. The gut is the largest immune organ in the body. Latest estimates suggest that there are at least as many human cells as bacterial cells in the body. ©2021 The Institute for Functional Medicine The gut houses a genome 100-150 times larger than the human genome. The gut’s metabolic functions are comparable in magnitude to the liver. See References: Why Focus on the Gut?  References: Why Focus on the Gut? 1. Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264-276. doi:10.1016/j.cell.2015.02.047. 2. Galland L. The Gut Microbiome and the Brain. Journal of Medicinal Food. 2014;17(12):1261-1272. doi:10.1089/jmf.2014.7000. 3. Chassaing B, Kumar M, Baker MT, Singh V, Vijay-Kumar M. Mammalian Gut Immunity. Biomedical journal. 2014;37(5):246-258. doi:10.4103/2319-4170.130922. 4. Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clinical and Experimental Immunology. 2008;153(Suppl 1):3-6. doi:10.1111/j.1365- 2249.2008.03713.x. 5. Wang H-X, Wang Y-P. Gut Microbiota-brain Axis. Chinese Medical Journal. ©2021 The Institute for Functional Medicine 2016;129(19):2373-2380. doi:10.4103/0366-6999.190667. 6. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007 Jan;132(1):397-414. doi: 10.1053/j.gastro.2006.11.002. PMID: 17241888. 7. Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biol. 2016 Aug 19;14(8):e1002533. doi: 10.1371/journal.pbio.1002533. PMID: 27541692; PMCID: PMC4991899. 8. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65. doi: 10.1038/nature08821.  Why Focus On The Gut? The most effective clinical outcomes across all disease spectrums can result ©2021 The Institute for Functional Medicine from normalization of gut function.  Performance Objectives Following this activity, successful participants will be able to… 1. Identify the key functional roles of the gastro- intestinal tract, and recognize how impairments may lead to dysfunction 2. Identify the role the gastrointestinal tract plays in many ©2021 The Institute for Functional Medicine chronic diseases 3. Use stool analysis as a foundational tool to help evaluate gastrointestinal function  Triggers: nutrient insufficiency (and excess), medications, dysbiosis, parasites, food reactions, trauma, surgery, etc. Disturbance of Localized irritation/ GI flora inflammation Local reaction/localized symptoms Physical disruption of mucosal barrier Increased mucosal permeability ©2021 The Institute for Functional Medicine Bacterial/yeast/protozoa/LPS Food protein translocation /toxin translocation (macromolecules) Portal and Systemic Overload Immunologically mediated reactions (and perpetuation) Distant Signs and Symptoms: Systemic illness (i.e.The Autoimmune Spectrum)  Key Functional Roles of the Gut D Digestion / Absorption I Intestinal Permeability G Gut microbiota / Dysbiosis ©2021 The Institute for Functional Medicine I Immune Modulation/Inflammation N Nervous System (Enteric Division) ©2021 The Institute for Functional Medicine I I D G N Digestion/Absorption ©2021 The Institute for Functional Medicine Body GI Tract Doughnut Hole  Area of Contact With the Outside World GI mucosal surface area: ©2021 The Institute for Functional Medicine 30-40 m 2 Helander H, Fändriks L. Surface area of the digestive tract – revisited. Scandinavian Journal of Gastroenterology. 2014;49(6):681-689. doi:10.3109/00365521.2014.898326. ©2021 The Institute for Functional Medicine ©2021 The Institute for Functional Medicine Forsberg G et al. Presence of Bacteria and Innate Immunity of Intestinal Epithelium in Childhood Celiac Disease. The American Journal of Gastroenterology. 2004;99(5):894-904. doi:10.1111/j.1572- 0241.2004.04157.x ©2021 The Institute for Functional Medicine ©2021 The Institute for Functional Medicine ©2020 The Institute for Functional Medicine  Digestion and Absorption Carbohydrates Fiber Starch Sugar Proteins Fats Salivary Amylase Smaller Starches Proteins Portal Vein to liver Polypeptides Long Smaller Starches Chain Sugars Polypeptides ©2021 The Institute for Functional Medicine Pancreatic Lymph Amylase Trypsin Short vessel to Double Sugars and other Chain blood Brush Enzymes Fatty Border Border Brush Amino Acids Single Sugars Acids Fiber Bacterial Enzymes Gas, acids, undigested fiber Feces: Bacteria, Dead Cells, undigested fiber, other undigested food material  Summary: Digestion/Absorption Mechanical breakdown Enzyme hydrolysis of carbohydrates, proteins, lipids and nucleic acids Active and passive absorption ©2021 The Institute for Functional Medicine Regulation from CNS and ENS integrate hormones & paracrines to coordinate digestion  Mastication Impairments in Digestion and Absorption Inadequate mastication HCL Hypochlorhydria Pancreatic insufficiency Bile ©2021 The Institute for Functional Medicine Bile insufficiency Brush Border Injury Brush Border Injury  Digestion/Absorption D I INTESTINAL PERMEABILITY G ©2021 The Institute for Functional Medicine I N  1 2 3 4 ©2021 The Institute for Functional Medicine 7 6 5 Created with BioRender.com 1. Perrier C, Corthésy B. Gut permeability and food allergies. Clinical & Experimental Allergy. 2011; 41: 20–28. doi:10.1111/j.1365-2222.2010.03639.x 2. Johnston LK, Chien KB, Bryce PJ. The immunology of food allergy. J Immunol. 2014;192(6):2529-2534. doi:10.4049/jimmunol.1303026 ©2021 The Institute for Functional Medicine “Please…tell me again about this imaginary fence.”  Intestinal Permeability The importance of intestinal permeability has been documented in the literature for 30 years or more. “Luminal complexing by secretory IgA and an intact epithelial barrier limits uptake of luminal antigen; however, intestinal inflammation enhances mucosal uptake and systemic ©2021 The Institute for Functional Medicine distribution of potentially injurious macromolecules”2 “An essential function of epithelial-lined surfaces is to create the interface between separate body compartments.”1 1. Turner JR. Molecular Basis of Epithelial Barrier Regulation. The American Journal of Pathology. 2006;169(6):1901-1909. doi:10.2353/ajpath.2006.060681. 2. Sartor RB. Importance of intestinal mucosal immunity and luminal bacterial cell wall polymers in the etiology of inflammatory joint diseases. Baillières Clinical Rheumatology. 1989;3(2):223-245. doi:10.1016/s0950-3579(89)80019-6.  Molecular Basis of Epithelial Barrier Regulation The intestinal mucosa faces a difficult challenge. It must provide a protective barrier against the external environment, but also must function in both active and passive transport. For both normal physiological functioning and disease ©2021 The Institute for Functional Medicine prevention, an intact intestinal barrier is essential. Turner JR. Molecular Basis of Epithelial Barrier Regulation. The American Journal of Pathology. 2006;169(6):1901-1909. doi:10.2353/ajpath.2006.060681.  Human Intestinal Barrier Function in Health and Disease A large number of diseases and disorders are associated with a dysfunctional intestinal barrier ©2021 The Institute for Functional Medicine König J, Wells J, Cani PD, et al. Human Intestinal Barrier Function in Health and Disease. Clinical and Translational Gastroenterology. 2016;7(10):e196-. doi:10.1038/ctg.2016.54. ©2021 The Institute for Functional Medicine Villi ©2021 The Institute for Functional Medicine Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci. 2009 May;1165:195-205. doi: 10.1111/j.1749-6632.2009.04037.x.  Microvilli Actomyosin Network Tight Junction ©2021 The Institute for Functional Medicine Reprinted from The American Journal of Pathology, Vol. 169, Turner, J.R., Turner JR. Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application, Pages 1901-1909, Copyright 2006, with permission from American Society for Investigative Pathology.  Epithelial tissue adhesion architecture Zonula Adherens Zonula occludins Apical Face (adherens junction) (Tight junctions) ©2021 The Institute for Functional Medicine Apical actomyosin network Septate junctions Created with BioRender.com Basal Face Basal Extracellular Matrix ©2021 The Institute for Functional Medicine ©2021 The Institute for Functional Medicine  Why is This So Important? “The mucosa is directly exposed to the external environment and taxed with antigenic loads consisting of commensal bacteria, dietary antigens, and viruses at far greater quantities on ©2021 The Institute for Functional Medicine a daily basis than the systemic immune system sees in a lifetime.” Mayer L. Mucosal immunity. Pediatrics. 2003 Jun;111(6 Pt 3):1595-600. PMID: 12777598.  PUBMED ARTICLES ON INTESTINAL PERMEABILITY (1954-2020) increased permeability = leaky gut 900 800 700 600 NUMBER OF ARTICLES 500 400 ©2021 The Institute for Functional Medicine 300 200 100 0 1950 1960 1970 1980 1990 2000 2010 2020 2030 YEARS Adapted from PubMed  Intestinal Permeability: History Concept consolidated by Fasano in 2000 15,273 PubMed articles indexed by “intestinal permeability” as of January 2020 PUBMED ARTICLES ON Other related terms: INTESTINAL PERMEABILITY - Leaky Gut (1954-2020 ) ©2021 The Institute for Functional Medicine 1000 NUMBER OF ARTICLES - Auto-intoxication 800 600 400 - Endotoxemia 200 0 1950 1960 1970 1980 1990 2000 2010 2020 2030 YEARS 1. Fasano A. Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin. Ann N Y Acad Sci. 2000;915:214-22. doi: 10.1111/j.1749-6632.2000.tb05244.x. PMID: 11193578. 2. Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum SE. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000 Apr 29;355(9214):1518-9.  Gate-Keeper Function of the Intestinal Epithelium “Increased epithelial permeability for antigens is a crucial primary or secondary event in the pathogenesis of several disorders.” ©2021 The Institute for Functional Medicine Brandtzaeg P. Gate-keeper function of the intestinal epithelium. Benef Microbes. 2013 Mar 1;4(1):67-82. doi: 10.3920/BM2012.0024. https://pubmed.ncbi.nlm.nih.gov/23257015/  Healthy Gut Healthy Villi ©2021 The Institute for Functional Medicine Healthy Cell Junctions  Leaky Gut Damaged Villi ©2021 The Institute for Functional Medicine Damaged Cell junctions  LEAKY GUT Paracellular Transcellular penetration of penetration of Antigens Antigens Inflammation ©2021 The Institute for Functional Medicine ©2021 The Institute for Functional Medicine Fasano A. Surprises from celiac disease. Sci Am. 2009 Aug;301(2):54-61. ©2021 The Institute for Functional Medicine ©2009 Kimberly Moss Fasano A. Surprises from Celiac Disease. Scientific American. 2009;301(2):54-61. doi:10.1038/scientificamerican0809-54.  Genetic Propensity Environmental Triggers Altered Microbiome with Gut Inflammation Increased Intestinal Permeability and translocation of macromolecules (LPS, foods,…) ©2021 The Institute for Functional Medicine Systemic Immune Response Initiation of the Autoimmune Spectrum Valitutti F, Fasano A, Breaking Down Barriers: How Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments. Dig Dis Sci. 2019 Jul;64(7):1748-1758  Because the interaction between genes and ©2021 The Institute for Functional Medicine environmental triggers can drive autoimmunity, restoring healthy function of the intestinal barrier can halt the autoimmune process Derived from Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9):416-22.  Possible causes of impairment of the intestinal barrier Nutritional factors Tight junction downregulation Histone deacetylase (HDAC) inhibitors Enteric nervous system modulators Infections and toxins Viral intestinal infection Environmental toxins (BPA, Glyphosate,…) Toxic foods “Hygiene hypothesis” Sterile environment ©2021 The Institute for Functional Medicine Lack of farming “Lifestyle hypothesis” Impaired function and diversity of the intestinal microbiota Endogenous factors Hypoperfusion of the intestine Chronic inflammation/autoimmunity Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A, Wells JM. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 2014 Nov 18;14:189. doi: 10.1186/s12876-014-0189-7. PMID: 25407511; PMCID: PMC4253991.  What Are The Triggers of Increased IP? Food antigens/other components Increased uptake of food antigens Stress Infections Dysbiosis Immune activation Altered Malabsorption/ Inflammation Intestinal Intestinal inflammation Malnutrition Systemic disease Permeability ©2020 The Institute for Functional Medicine Many diseases Impaired digestion, i.e., low stomach acid, etc. Toxins Increased uptake of Nutritional insufficiencies toxins and Various medications lipopolysaccharides  References: Triggers of Intestinal Permeability 1. Dietary choices: Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress related psychiatric disorders. Frontiers in Cellular Neuroscience. 2015;9:392. doi:10.3389/fncel.2015.00392. 2. Stress: Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin releasing hormone increase intestinal permeability in humans by a mast cell dependent mechanism. Gut. 2014 Aug; 63(8):12939. doi: 10.1136/gutjnl 2013305690. 3. Infection: Kukuruzovic R, Robins, Browne RM, Anstey NM, Brewster DR. Enteric pathogens, intestinal permeability and nitric oxide production in acute gastroenteritis. Pediatr Infect Dis J. 2002 Aug;21(8):730-9. 4. Dysbiosis: Brown K, DeCoffe D, Molcan E, Gibson DL. Diet induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095-1119. doi:10.3390/nu4081095 5. Inflammation: Michielan A, D’Incà R. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. Mediators of Inflammation. 2015;2015:628157. doi:10.1155/2015/628157 6. Systemic Disease: Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006;55(10):1512-1520. doi:10.1136/gut.2005.085373. ©2020 The Institute for Functional Medicine 7. Impaired Digestion: Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, Delle Fave G,Andreoli M, Annibale B. Atrophic body gastritis in patients with autoimmune thyroid disease: an underdiagnosed association. Arch Intern Med. 1999 Aug 9-23;159(15):1726-30. 8. Toxins: Pinton P, Nougayrède JP, Del Rio JC, et al. The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression. Toxicol Appl Pharmacol. 2009 May 15;237(1):41-8. doi: 10.1016/j.taap.2009.03.003. 9. Nutritional Deficiencies: Tran CD, Hawkes J, Graham RD, et al. Zinc-fortified oral rehydration solution improved intestinal permeability and small intestinal mucosal recovery. Clin Pediatr (Phila). 2015 Jun;54(7):676-82.doi: 10.1177/0009922814562665. 10. Medications: Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4554 61. doi: 10.107 3/pnas.1000087107. 11. Food Allergy: Järvinen KM, Konstantinou GN, et al. Intestinal permeability in children with food allergy on specific elimination diets. Pediatr Allergy Immunol. 2013 Sep;24(6):589-95. doi: 10.1111/pai.12106. 12. Malnutrition: Norman K, Pirlich M, Schulzke JD, Smoliner C, Lochs H, Valentini L, Bühner S. Increased intestinal permeability in malnourished patients with liver cirrhosis. Eur J Clin Nutr. 2012 Oct;66(10):1116-9. doi: 10.1038/ejcn.2012.104.  Triggers and Mediators of Intestinal Permeability What are triggers and mediators in Joan’s case? What are the most important in your patient population? How do you describe intestinal ©2021 The Institute for Functional Medicine permeability to your patients? ©2021 The Institute for Functional Medicine Part 2  D Digestion/Absorption I Intestinal Permeability G GUT MICROBIOTA ©2021 The Institute for Functional Medicine I N  50-100 trillion friends bacteria mostly, occ virus/fungi you may not have ©2021 The Institute for Functional Medicine known you have!  How critical is an understanding of the role of the microbiota in health and disease? Emerging infectious disease Metabolic Liver syndrome disease Human ©2020 The Institute for Functional Medicine microbiota Athero- IBD sclerosis Diabetes Obesity mellitus West CE, Renz H, Jenmalm MC, et al. The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies. Journal of Allergy and Clinical Immunology. 2015;135(1):3-13. doi:10.1016/j.jaci.2014.11.012.  The gut microbiota and host health: a new clinical frontier Like the immune system, the microbiome of the gut is unique in each individual, contains components that are heritable, and contains 150 more genes than the host. Without it, virtually all physiological aspects of the host are altered. The gut microbiome is modifiable through diet, antibiotics, stress, chemicals, and ©2021 The Institute for Functional Medicine other environmental factors, each influencing the makeup and diversity of the microbiome and ultimately physiological function. In all of these ways, the gut microbiome functions like another organ in the body. Marchesi JR, Adams DH, Fava F, et al. The gut microbiota and host health: A new clinical frontier. Gut. 2016;65(2):330-339. doi: 10.1136/gutjnl-2015-309990.  The gut microbiota shapes intestinal immune responses during health and disease “By young adulthood, both humans and other mammals support one of the most complex microbial ©2021 The Institute for Functional Medicine ecosystems on the planet.” Round, J., Mazmanian, S. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313–323 (2009). https://doi.org/10.1038/nri2515  The gut microbiota and inflammatory noncommunicable disease: Associations and potential for gut microbiota therapies “With clear effects on physiologic, immunologic, and metabolic processes in human health, aberrations in the gut microbiome and intestinal homeostasis have the capacity for multisystem effects. Changes in microbial composition are implicated in the increasing propensity ©2021 The Institute for Functional Medicine for a broad range of inflammatory diseases, such as allergic disease, asthma, inflammatory bowel disease (IBD), obesity, and associated non-communicable diseases (NCDs).” West, C. E., et al. (2015). The gut microbiota and inflammatory noncommunicable diseases: Associations and potentials for gut microbiota therapies. Journal of Allergy and Clinical Immunology, 135(1), 3- 13. doi:10.1016/j.jaci.2014.11.014  THE EFFECTS OF INTESTINAL MICROBIOTA ON HUMAN PHYSIOLOGY ©2021 The Institute for Functional Medicine Sekirov I, Russell SL, Antunes LCM, Finlay BB. Gut Microbiota in Health and Disease. Physiological Reviews. 2010;90(3):859-904..  Fast Food Fever: Reviewing the Impacts of the Western Diet on Immunity Similar to ecosystems that are harmed when there is a loss of species or invasions by non-native species, even small microbiome changes caused by unhealthy diets can have far- ©2021 The Institute for Functional Medicine reaching impacts on human health. Myles I. Fast food fever: Reviewing the impacts of the western diet on immunity. Nutrition Journal. 2014;13(61). doi: 10.1186/1475-2891-13-61  Who is directing whom? ©2021 The Institute for Functional Medicine While it appears that the mammalian immune system is intended to control microorganisms… in reality, microorganisms control it. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009 May;9(5):313-23. doi: 10.1038/nri2515. Erratum in: Nat Rev Immunol. 2009 Aug;9(8):600.  ‘Does our Microbiome Control Us or Do We Control It?’ ©2021 The Institute for Functional Medicine ‘When Gut Bacteria Change Brain Function’ 1. Maron DF. Does our Microbiome Control Us or Do We Control It? Scientific American. January 2016. 2. Kohn D. When Gut Bacteria Change Brain Function. The Atlantic. June 2015.  “…the composition of microbiota can shape a healthy immune response or predispose to disease.” Host genetics Early colonization Lifestyle Medical practices Mutations in NOD2, Birth in hospitals Diet Antibiotics IL23R, ATG16L and Altered exposure to Stress Hygiene IGRM microbes ©2021 The Institute for Functional Medicine Dysbiosis Disease Health ↑TH1, TH2 and TH17 cells ↑TReg cells Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology. 2009;9(5):313-323. doi:10.1038/nri2515. For additional references, see References: Contributors to Dysbiosis  Dysbiosis Alters Mucosal Integrity Food antigens/other components Increased uptake Stress of food antigens Infections Altered Immune Intestinal inflammation Dysbiosis Intestinal Malabsorption/ activation Permeability Malnutrition Inflammation ©2021 The Institute for Functional Medicine Many diseases Systemic disease Impaired digestion, i.e., low stomach acid, etc. Toxins Increased uptake of Nutritional insufficiencies toxins and Various medications lipopolysaccharides References – see next slide “References: Contributors to Dysbiosis”  References: Contributors to Dysbiosis 1. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology. 2009;9(5):313-323. doi:10.1038/nri2515. 2. Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microbial Ecology in Health and Disease. 2015;26:10.3402/mehd.v26.26191. doi:10.3402/mehd.v26.26191. 3. Al Nabhani Z, Lepage P, Mauny P, et al. Nod2 Deficiency Leads to a Specific and Transmissible Mucosa-associated Microbial Dysbiosis Which Is Independent of the Mucosal Barrier Defect. J ©2021 The Institute for Functional Medicine Crohns Colitis. 2016 Dec;10(12):1428-1436. 4. Arrieta M-C, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The Intestinal Microbiome in Early Life: Health and Disease. Frontiers in Immunology. 2014;5:427. doi:10.3389/fimmu.2014.00427. 5. Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Seminars in Immunopathology. 2015;37:47-55. doi:10.1007/s00281-014-0454-4. ©2021 The Institute for Functional Medicine Birth Prenatal Diversity increases with age through adulthood, then diminishes with aging  Unbalanced vs. Balanced Microbiome Dysbiosis turns on genes that encode inflammation (TNF and IL-8). VS - An inflammatory immune response occurs. ©2021 The Institute for Functional Medicine NF-KB is NF-KB is not Commensal bacteria turn off activated and activated and turns on genes genes that encode genes encoding inflammation. encoding inflammation inflammation are turned off - Inflammatory immune response is blocked. 1. 2. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020 Jun;30(6):492-506. doi: 10.1038/s41422-020-0332-7. Epub 2020 May 20. PMID: 32433595; PMCID: PMC7264227. Belizário JE, Faintuch J, Garay-Malpartida M. Gut Microbiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases. Mediators Inflamm. 2018 Dec 9;2018:2037838. doi: 10.1155/2018/2037838. PMID: 30622429; PMCID: PMC6304917. ? Created with BioRender.com  Symbiotic Microflora in the Gut Metabolic Activities: Microflora ferments non-digestible dietary residue releasing SCFAs and vitamin K. Trophic Activities: SCFAs produced by microfloral action on prebiotic fiber ©2021 The Institute for Functional Medicine control epithelial cell proliferation and differentiation in the colon (to protect against the development of neoplasia). Protective Activities: The barrier effect: resident bacteria provide resistance to colonization by potentially pathogenic microbes  Microflora Functions in the Gut Metabolic Activities: Microflora ferments non-digestible dietary residue, releasing SCFAs and numerous vitamins; also provides detoxification capacity Trophic Activities: SCFAs produced by microflora control epithelial cell proliferation and differentiation in the colon (to protect against the development of neoplasia) ©2021 The Institute for Functional Medicine Immune Activation: Education of the immune system and development of oral tolerance Protective Activities: The barrier effect – resident bacteria provide resistance to colonization by potentially pathogenic microbes Neural Signaling: BiDirectional interface with insular cortex ©2021 The Institute for Functional Medicine What we eat influences the population and metabolic activity of our microflora.  Gut Dysbiosis, Inflammation, and Altered Gut Barrier Function lipopolysaccrhides Systemic LPS Pro-inflammatory Cytokines Endotoxemia Systemic Inflammation ©2021 The Institute for Functional Medicine Altered Blood-Brain Barrier Function Gut Brain Axis Dysfunction Rutsch A, Kantsjö JB, Ronchi F. The Gut-Brain Axis: How Hippocampus/Cerebellum Microbiota and Host Inflammasome Influence Brain Physiology and Pathology. Front Immunol. 2020 Dec 10;11:604179. doi: Dysfunction 10.3389/fimmu.2020.604179. PMID: 33362788; PMCID: PMC7758428.  “Evidence is accumulating that our welcome residents 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 ©2021 The Institute for Functional Medicine conditions such as obesity, type 1 diabetes, inflammatory bowel disease, allergies and asthma, which have more than doubled in Book cover image used courtesy of Macmillan Publishing Group many populations.” Martin Blaser : Chair of the Department of Medicine, New York University Langone Medical Center, New York, NY  Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances Atopic, inflammatory and autoimmune diseases have been linked to gut microbiota dysbiosis, and, in some cases, significant ©2021 The Institute for Functional Medicine associations have been established between these diseases and the intake of antibiotics during early life. Francino MP. Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances. Frontiers in Microbiology. 2016;6. doi:10.3389/fmicb.2015.01543.  Any anti-anaerobic antibiotic exposure was associated with developing IBD A dose-response effect existed, and this ©2021 The Institute for Functional Medicine relationship remained significant throughout childhood Receiving more than 2 antibiotic treatment courses was more highly associated with IBD development than receiving 1-2 Kronman MP et al. Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study. Pediatrics. 2012;130(4). doi:10.1542/peds.2011-3886.  45% of Medicaid Non-Infection-Related And Non-Visit-Based Antibiotics: Antibiotic Prescribing Is Common Among Medicaid Patients prescribed without a clear rationale Study: Measure the frequency with which all filled antibiotic prescriptions were associated with infections and in-person visits for Medicaid patients in the period 2004-2013. Results: ©2021 The Institute for Functional Medicine 298 million antibiotic fills (62% for children) for 53 million patients, 55% were for clinician visits with an infection-related diagnosis, 17% were for clinician visits without an infection-related diagnosis, and 28% were not associated with a visit. Conclusion: Current ambulatory antibiotic stewardship policies miss about half of antibiotic prescribing. To improve antibiotic use, we need to understand the context in which antibiotics are being prescribed Fischer MA, Mahesri M, Lii J, Linder JA. Non-Infection-Related And Non-Visit-Based Antibiotic Prescribing Is Common Among Medicaid Patients. Health Aff (Millwood). 2020 Feb;39(2):280-288. doi: 10.1377/hlthaff.2019.00545.  Imbalances in Gut Flora: Dysbiosis Dysbiosis (also called dysbacteriosis) is the condition of having microbial imbalances on or within the body. Dysbiosis is most prominent in the digestive tract but can also occur on any exposed surface or mucous membrane such as the skin, vagina, lungs, nose, ©2021 The Institute for Functional Medicine sinuses, ears, nails, or eyes. Gut Dysbiosis Beneficial microbes Symbionts Pathogenic microbes Pathobionts ©2021 The Institute for Functional Medicine Dysbiosis: History  Dysbiosis: History Concept consolidated by Metchnikoff in 1908 9,755 PubMed articles indexed by “dysbiosis” as of March 2021 Other related terms: Dysbacteriosis Autointoxication ©2021 The Institute for Functional Medicine Dermatitis-arthritis syndrome Small intestinal bacterial overgrowth (SIBO) Mucosal colonization Subclinical infection  Dysbiosis is not so much about the microbe as it is about the effect of that microbe on a susceptible host; i.e., it is about the relationship between ©2021 The Institute for Functional Medicine host and microbe.  Dysbiosis We are not looking for classic “infection” Dysbiosis in one patient may present with dermatitis; the same microbial imbalance in another patient can present as peripheral neuropathy or inflammatory arthritis. ©2021 The Institute for Functional Medicine Often what we find when working with autoimmune/ inflammatory patients is that they are having a pathogenic inflammatory response to a nonpathogenic microbe.  Oral Tolerance, NF-κB, IL-10, IL-17 Obesity BioFilm & Nutrition & Metabolism Permeability Defense and Repair Assimilation Structural Integrity Gastrointestinal n-Butyrate Energy Communication Ecosystem SCFA Production ©2021 The Institute for Functional Medicine Mast Cell Degranulation Transport Detoxification & Biotransformation GI Motility Entero-Hepatic Phase III Detoxification Recirculation  Microbial Wildlife Managers ©2021 The Institute for Functional Medicine Photo of Julie Segre courtesy of National Institutes of Health Intramural Research Program.  Digestion/Absorption D I Intestinal Permeability G Gut Microbiota IMMUNE MODULATION ©2021 The Institute for Functional Medicine I AND INFLAMMATION N  Understanding the Puzzle of Complex Diseases ? Complex diseases ? arise from the smoking combined action of viruses ©2021 The Institute for Functional Medicine many genes and genes environmental diet factors pollution  Where is the ‘Front Line’ where most of this combined ©2021 The Institute for Functional Medicine action occurs?  Intranasal: NALT Upper and lower respiratory, Salivary glands Mucosal gastric and genital tracts Sublingual: Intranasal Cervical lymph nodes Upper and lower respiratory and Tonsils Sublingual Immune gastrointestinal tracts Adenoids Oral: Oral Gastrointestinal tract, salivary System glands and mammary glands Rectal: Rectal and genital tracts Intravaginal: Axillary Genital tract Lymph BALT Nodes Critical ©2021 The Institute for Functional Medicine ‘Line of Defense’ Mesenteric Lymph nodes GALT Isolated lymphoid follicles Peyer’s patches Genital Tract- Inguinal Associated lymph nodes GALT 1. Lycke N. Recent progress in mucosal vaccine development: potential and lymphoid Para-aortic lymph limitations. Nat Rev Immunol. 2012 Jul 25;12(8):592-605. doi: 10.1038/nri3251. tissue 2. Iweala OI, Nagler CR. The Microbiome and Food Allergy. Annu Rev Immunol. 2019 nodes Apr 26;37:377-403. doi: 10.1146/annurev-immunol-042718-041621. PMID: 31026410. 3. Paray BA, Albeshr MF, Jan AT, Rather IA. Leaky Gut and Autoimmunity: An Intricate Balance in Individuals Health and the Diseased State. Int J Mol Sci. 2020 Dec 21;21(24):9770. doi: 10.3390/ijms21249770. PMID: 33371435; PMCID: PMC7767453.  Gut Associated Lymphoid Tissue (GALT) Immunological defense Largest lymph organ in the body: 50-70% of the immune system and immunoglobulin producing cells are located within the GI tract ©2021 The Institute for Functional Medicine Populated by T cells, B cells, plasma cells, activated TH cells and macrophages in loose clusters Tokuhara D, Kurashima Y, Kamioka M, Nakayama T, Ernst P, Kiyono H. A comprehensive understanding of the gut mucosal immune system in allergic inflammation. Allergol Int. 2019 Jan;68(1):17-25. doi: 10.1016/j.alit.2018.09.004. Epub 2018 Oct 23. PMID: 30366757.  Gut Associated Lymphoid Tissue (GALT) The first line of defense to the majority of antigen exposure including dietary molecules and infectious agents The primary focus of GALT is two-fold: - Determination of ‘Friend or Foe’ ©2021 The Institute for Functional Medicine - Initiating and sustaining an appropriate immune response Mucosal Immunology, Third Edition, Elsevier Academic Press, 2005  What Are The Components of GALT That Are Designed To Protect Us? Dendritic cells Commensal bacteria Macrophages Pattern recognition receptors Neutrophils Toll-Like Receptors ©2021 The Institute for Functional Medicine Regulatory T-cells (Th0) Immunoglobulins Goblet Cells Intra epithelial lymphocytes Interleukins Cytokines ©2021 The Institute for Functional Medicine Response to a friend  Used with Permission. Nature Reviews Immunology 2003;3:338. ©2021 The Institute for Functional Medicine Figure 4a -Model of the role of the intestinal microenvironment in polarizing immune functions Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003;3(4):331-341. doi:10.1038/nri1057 ©2021 The Institute for Functional Medicine Response to a foe ©2021 The Institute for Functional Medicine Adapted from “H. Pylori Pathogenesis”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates 1. Bethune MT, Khosla C. Parallels between pathogens and gluten peptides in celiac sprue. PLoS Pathog. 2008 Feb;4(2):e34. doi: 10.1371/journal.ppat.0040034. PMID: 18425213; PMCID: PMC2323203. 2. Cardoso-Silva D, Delbue D, Itzlinger A, Moerkens R, Withoff S, Branchi F, Schumann M. Intestinal Barrier Function in Gluten-Related Disorders. Nutrients. 2019 Oct 1;11(10):2325. doi: 10.3390/nu11102325. PMID: 31581491; PMCID: PMC6835310. ©2021 The Institute for Functional Medicine https://www.youtube.com/watch?v=gnZEge78_78 ©2021 The Institute for Functional Medicine Used with permission from Tom O’Bryan, MD  Microbes, immunoregulation, and the gut ©2021 The Institute for Functional Medicine “Contact with ‘old friends’ is greatly diminished in rich countries but increased on farms, in cowsheds, and through contact with pets.” Rook GAW. Microbes, immunoregulation, and the gut. Gut. 2005;54(3):317-320. doi:10.1136/gut.2004.053785.  Inducing Tolerance “We found a lower prevalence of reported allergy in children aged 7 to 8 years from families who use hand dishwashing instead of machine dishwashing. This effect was further potentiated if they also ate fermented food or bought food directly from farms. ©2021 The Institute for Functional Medicine We speculate that these lifestyle factors reduce allergy development via increased or more diverse microbial exposure stimulating the immune system to develop in a more tolerant direction.” Hesselmar B, Hicke-Roberts A, Wennergren G. Allergy in Children in Hand Versus Machine Dishwashing. PEDIATRICS. 2015;135(3):e590-e597. doi:10.1542/peds.2014-2968.  Inflammasomes: too big to miss “Immune cells encountering [a foreign antigen]…become activated and release an array of factors leading to the well-known clinical signs ©2021 The Institute for Functional Medicine of inflammation: rubor, calor, dolor, and tumor.” Stutz A, Golenbock D, Latz E. Inflammasomes: too big to miss. Journal of Clinical Investigation. 2009;119(12):3502-3511. doi:10.1172/jci40599.  Inflamm-Aging The over-expression of inflammation genes, immune-response genes and genes ©2021 The Institute for Functional Medicine associated with the lysosomal system Salminen A, Kaarniranta K. NF-κB Signaling in the Aging Process. Journal of Clinical Immunology. 2009;29(4):397-405. doi:10.1007/s10875-009-9296-6.  Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation and IL-17 production in the absence of SIV infection. “The strongest predictor of disease progression is the extent of chronic, systemic ©2021 The Institute for Functional Medicine immune activation.” Klatt N, Harris L, Vinton C et al. Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection. Mucosal Immunology. 2010;3(4):387-398. doi:10.1038/mi.2010.14.  D Digestion/Absorption I Intestinal Permeability G Gut Microbiota ©2021 The Institute for Functional Medicine I Immune Modulation and Inflammation N NERVOUS SYSTEM  Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell dependent mechanism. “An acute psychological stressor increases small intestinal permeability in a subset of healthy humans with endocrinological signs of stress axis activation…“ ©2021 The Institute for Functional Medicine Vanuytsel T, van Wanrooy S, Vanheel H et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2013;63(8):1293-1299. doi:10.1136/gutjnl-2013-305690.  Nervous System Effect On GI Function Alterations in gastrointestinal motility Increase in visceral perception Changes in gastrointestinal secretion Increase in intestinal permeability Negative effects on regenerative capacity of gastrointestinal ©2021 The Institute for Functional Medicine mucosa Negative effects on intestinal microbiota Portal of entry of pathogens into the CNS 1. Konturek P, Brzozowksi T, Konturek S. Stress and the Gut: Pathophysiology, Clinical Consequences, Diagnostic Approach and Treatment Options. Journal of Physiology and Pharmacology. 2011;62(6):591-599. 2. Forsyth C, Shannon K, Kordower J et al. Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease. PLoS ONE. 2011;6(12):e28032. doi:10.1371/journal.pone.0028032.  A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome In recent years, the interface between