Intestinal Microbiota in Health and Disease

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1 Intestinal Microbiota in Health and Disease February 27, 2015 Master s Course in Gastroenterology Prof. Kathy McCoy 1

2 Overview Overview of Gut Microbiota Microbiota in Health Microbiota in Disease 2

is a preferred site over 70% of all bacteria are found in the

Longitudinal: bacteria increase in number and composition

(/,(*'+012 34564*.7'8 9,*7'5%4/'7'8 :*)(%-,*7'54,!

5#,5*",'%7, >7"'5 > 1000 different species 3 FIG. 2.

3 Gut Microbiota: Who is there? All mucosal surfaces are colonised with bacteria The intestine is a preferred site over 70% of all bacteria are found in the colon o large organ o rich in over nutrients stine occurs Longitudinal: bacteria increase in number and composition changes from proximal GUT M to distal GI tract e!"#$%&'(')*+,-.(/,(*' *.7'8 9,*7'5%4/'7'8 :*)(%-,*7'54,!5%7'%-,*7'54, ;#('5&487'7'8 <'55.*%64*5%-4, 3.8%-,*7'54, =.5#,5*",'%7, >7"'5 > 1000 different species 3 FIG. 2. Spatial and temporal aspects of intestinal microbiota compo of the gastrointestinal tract. B: longitudinal variations in microbial comp

4 Gut Microbiota: Where are they? Vaishnava et al. Latitudinal: bacterial composition also differs between lumen, mucus, and attached to epithelium Small intestine 103/g 800 Bacteria Mucus thickness (µm) 700 Bacterial products MAMPs Metabolites 600 Bacterial load 1012/g Colon Outer layer Ileum Antrum Corpus Duodenum Jejunum 100 Large intestine Isolated lymphoid follicles (ILF) NIH-PA Author Manuscript Stomach Inner layer 861 GUT MICROBIOTA ILF ILF ILF Peyer s patch Immune system NIH 4

5 Gut Microbiota: Where do they come from? Initial exposure occurs during passage through birth canal During first year of life, heavily influenced by mother and environment 5

6 Gut Microbiota: Where do they come from? Microbial stability is established after 1 year Composition continues to be influenced by environment; antibiotics, diet, genetics, inflammation, hygiene, lifestyle 6

Gut Microbiota in Health - Increases the metabolic

short chain fatty acids Completion of the bile-salt

7 Gut Microbiota in Health - Increases the metabolic capacity of the host. Digestion of otherwise unused food components. Vitamin synthesis (eg Vitamin K) Production of short chain fatty acids Completion of the bile-salt cycle Protect the host from colonization with pathogenic bacteria (Colonization resistance) 7

metabolic by-products. Commensal bacteria Bifidobacterium?

8 Gut Microbiota in Health: Innate immune system Microbiota regulates intestinal immune responses primarily through the production of pathogen-associated molecular patterns (PAMPs) and metabolic by-products. Commensal bacteria Bifidobacterium? Flagellin LPS Sphingolipids SCFA IL-18 RegIIIγ Mucus GPR TLR4 NLR Enterocytes TLR5 DC IL-22 CD1d IL-23 ROR γt + DC Lamina propria ILC inkt 8

Gut Microbiota in Health: Adaptive immune system Microbiota stimulation leads to B cell

bacteria Commensal bacteria Bacteroides fragilis Clostridium (IV, XIVa, XVIII) SFB ATP

Mucus TLR M cell TLR DC APRIL BAFF TGF-β LT α 1 β 2 ROR γt + ILC sltα 3 IgA MHC II SAA?

9 Gut Microbiota in Health: Adaptive immune system Microbiota stimulation leads to B cell switch to IgA, regulatory T cell induction, T cell differentiation to Th17 Commensal bacteria Commensal bacteria Bacteroides fragilis Clostridium (IV, XIVa, XVIII) SFB ATP SCFA PSA? Mucus TLR M cell TLR DC APRIL BAFF TGF-β LT α 1 β 2 ROR γt + ILC sltα 3 IgA MHC II SAA? TLR2 TLR2 TGF-β FDC TGF-β ROR γt + GPCR B cell Isotope switch affinity matura on T BCL6 + Th17 IL-1β DC Foxp3 + Treg Lamina propria Peyer s patch Plasma cell TRENDS in Immunology 9

10 . 5. The role of microbiota in inflammatory bowel disease (IBD) pathogenesis. The interplay between the host microbiota and host genetics Gut Microbiota in Disease: IBD Genetic and environmental factors induce impaired barrier function Translocation of bacteria and bacterial products Immune activation and proinflammatory cytokine production Chronic inflammation leads to tissue destruction and complications

11 Gut Microbiota in Disease: GIT malignancies Three categories of microbiota-induced carcinogenesis o Disproportionate pro-inflammatory signaling at the GIT mucosa, leads to increased sloughing and repair of epithelium, which can ultimately lead to neoplasia and malignancy 12

12 Gut Microbiota in Disease: GIT malignancies Three categories of microbiota-induced carcinogenesis o Certain microbial species can have direct or indirect (through host cell activation) cytotoxic effects on cells o Microbial metabolism can produce by-products toxic to epithelium; repair in injury can lead to neoplastic transformations 13

Gut Microbiota in Disease: Obesity and metabolic syndrome Dietary lipids Chylomicrons HFD induced-microbiota alterations Gram- / Gram+ bacteria?

13 Gut Microbiota in Disease: Obesity and metabolic syndrome Dietary lipids Chylomicrons HFD induced-microbiota alterations Gram- / Gram+ bacteria? LPS PGN DNA M cell LPS TLR (PGN) PGN NOD 1/2 Chronic low-grade inflammation is associated with obesity and metabolic dysfunction (insulin resistance) Gut microbiota (and dietinduced changes in microbiota composition) may contribute to lowgrade inflammation LPS Tight Junction ZO-1 LPS DNA PGN Macrophages Bacteria/ antigens Inflammatory mediators (TNFα, IFN, IL6, IL18, MCP1,etc.) inos, COX2 Claudin-1 Occludin DCs MLN Circulation 15

Gut Microbiota in Disease: Allergic Disease Massive increase in prevalence of allergic diseases in Westernized countries (>20% over 10 year period) Allergic disease is attributed to both genetic

14 Gut Microbiota in Disease: Allergic Disease Massive increase in prevalence of allergic diseases in Westernized countries (>20% over 10 year period) Allergic disease is attributed to both genetic predisposition and environmental factors Genetic drift over such a short period of time cannot explain increased incidence of disease Westernized life-style has introduced several environmental risk factors that disturb the homeostatic balance of gut microbiota o Excessive antibiotic use, especially during early life (or even during pregnancy) o Shift towards more formula-fed babies o Shift towards greater numbers of babies born via Caesarean section o Western diet 18

15 Gut Microbiota in Disease: Food Allergy Certain types of bacteria produce SCFAs, which can drive induction of regulatory T cells Certain types of bacteria promote IL-22 production by CD4+ and ILC, which promotes barrier protection 19

16 Summary The gastrointestinal tract is colonised by a large number of commensal bacteria Colonisation occurs early in life and stabilises 1-3 years of age Composition is heavily influenced by environment (diet) Microbiota provides essential signals to ensure health host-microbial homeostasis Changes in microbial composition is called dysbiosis Microbial dysbiosis is found in many different diseases a causal link and mechanistic insight will pave the way to new therapies to treat and prevent disease 26

Innate immune regulation of T-helper (Th) cell homeostasis in the intestine

Innate immune regulation of T-helper (Th) cell homeostasis in the intestine Masayuki Fukata, MD, Ph.D. Research Scientist II Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation,