Gut microbiota and immunity

1. Gut microbiota and immunity 答辩人：本硕二班二组

2. CONTENTS Modulate immune cell differentiation immunity→microorganism Tweak the production of immune mediators Induce the development of lymphoid structure Background

3. Role Function Challenge Background

4. Background Role In adult intestine, a total of about 1014 bacterial cells are present, which is ten times the number of human cells in the body. In fact, the metabolic capacity of gut microbiota equals that of the liver, and the gut microbiota can therefore be considered as an additional organ. Function 1.Facilitate the metabolism of otherwise indigestible polysaccharides and produce essential vitamins. 2.They are required for the development and differentiation of host’s intestinal epithelium and immune system . 3.They confer protection against invasion by opportunistic pathogens. ect

5. Background Challenge The dynamic fluctuations in the microbiota and their close proximity to epithelial tissue represent a massive challenge to immune system as microbial growth has to be restricted to a beneficial homeostasis. Furthermore, activation of the host immune system has to be controlled to circumvent the detrimental effects of chronic inflammation.

6. Self or non-self Mucosal immune system → Requirements Immunity~microbiota

7. Immunity~microbiota Self 1.The realization that we live in a microbially dominated world and in fact benefit greatly from our microbiota has led to a paradigm shift in immunology. 2.Thus the definition of self in the superorganism theory has been extended to incorporate the constituents of both our own body and our microbiota. 3.Tolerance rather than responsiveness Requirements 1.Mucosal immune system has to be tolerant towards the huge number of mutualistic microorganisms. 2. It has to assure a beneficial microbiota composition by keeping pathobionts in check, restricting microbial overgrowth and reacting to penetrating microorganisms.

8. Gut-associated lymphoid tissue → microbiota~lymphoid structure

9. Inclusion Peyer's patches，（PP） Mesenteric lymph nodes Isolated lymphoid follicles，(ILFs) Vermiform appendix，（VA）...... GALT

10. Process Forma tion GALT is initiated pre-natally in the sterile environment of the fetus through induction by lymphoid tissue inducer (LTi) cells. Maturation Maturation of these tissues, including an increase in tissue size and the development of germinal centres, depends on postnatal microbial colonization

11. Process Mesenchymal cells Induced by retinoic acid to produce CXC chemokine ligand 13(CXCL13) 1 LTi precursor cells 5 2 GALT formation CXCL13 recruit and cluster the LTi precursor cells and their maturation into LTi cells Stromal organizer cells LTi cells 4 3 Express several cytokines and adhesion molecules that attract further immune cells Induce the differentiation of stromal organizer cells

12. Example PRR-NOD1 TLRs Gram-negative bacteria surface peptidoglycan Stromal, Epithelial cells CCR6 on LTi cells Express CC-chemokine ligand 20 and β-defensin 3 Activate ILF formation

13. IgA AMPs microbiota~immune mediators

14. SIg A dendritic cells flagellin TLR5 B cells IgA-producing plasma cells IgA PD1-deficient mice harbour an altered IgA altered IgA repertoire then shifts the normal gut microbiota composition

15. AMPs production 1.They are produced by IECs as a consequence of their tight contact with a dense and highly diverse microbial community. 2.It not only help to sustain host–microorganism segregation, but also affect the microbiota composition. classification 1.defensins C-type lectins (such as REG3β and REG3γ) 2.ribonucleases (for example, angiopoietin 4 (ANG4)) 3.S100 proteins (for example, psoriasin (also known as S100A7))

16. RORγt+Nkp46-LTi-like cell iNKT cells → specific T cell microbiota~immune cell differentiation

17. RORγt+Nkp46-LTi-like cell ↓ RORγt+Nkp46+NK-like cell ↓ IL-22 IL-23 and intestinal microbiota 1.Promote intestinal barrier function by modulating mucosal homeostasis

18. IL-22 1. Promote the integrity of the intestinal barrier 2. Reduce bacterial infiltration by inducing epithelial repair （1）STAT3 （2）Produce antimicrobial proteins

19. 2.Promote homeostasis by decrease iNKT cells iNKT cell：a unique T cell subset that expressan invariant T cell receptor α-chain Function：promote inflammation.Secret pro-inflammatory Th1and Th2 type chemokines and cytokines.Such as IFN-r，IL and TNF.

20. T cells are important “legislators” of intestinal homeostasis . pro-inflammatory immune response:Th1、Th2、Th17. T cells anti-inflammatory immune response:CD4+CD25+FOXP3+ Treg cell. The balance between pro- and anti-inflammatory T cells determines the overall equilibrium.

21. 3.Several gut microbiota drive specific T cell response. (1)Bacteroides fragilis（脆弱拟杆菌） (2)Clostridia（梭状芽孢杆菌） (3)Segmented filamentous bacteria/SFB （分节丝状菌）

22. Bacteroides fragilis Gram-negative bacterium Elicit an anti-inflammatory response by inducing the differentiation of CD4+ T cell into Treg cell. Treg cells produce IL-10 and supress the pro-inflammatory Th17 response, which mediated by polysaccharide A（PSA）. CD4+T cell → signalling cascade involving MYD88→Treg cell TLR2

23. Clostridia Gram-positive class Induce the expansion of Treg cells in the mucosal lamina propria Increase levels of the immunosuppressive cytokine IL-10. IL-10: inhibit the release of inflammatory mediators of mononuclear macrophage, furthermore, enhance the release of anti-inflammatory cytokines.

24. SFB Elicit a pro-inflammatory immune response by promoting the differention of Th17 cell and, to a lesser extent,Th1 cell SFB reside are in contact with epithelial cells to invade those cells Local actin poymerization in the epithelium Initiate a signalling events that activate the differentiation of Th17 cell . Scanning electron microscopy of intestine in mice colonized with SFB

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