= Microbiota and the immune response Topics discussed today: + What is the microbiome Colonization and composition of a healthy bacterial gut microbiota * Function of the microbiota Interaction with the immune system * Implications for diseasesReduced microbial diversity is associated with diseases Western countries Immune-mediated Stress diseases Urban environment —,, e.g. allergies, IBD Medication metabolic diseases Mode of delivery (se e.g. obesity Western high fat diet, | microbial Colon cancer diversity Neurological diseases Mosca A et al, Front Microbiol 2016What is the microbiom Microbiota: All microorganisms living in and on our body like bacteria, viruses, fungi, protozoa and archaea Microbiome: All microbial genes, 150-times more genes than the human genome Human microbiome projects, Compositon, diversity and function Turnbaugh PJ et al. Nature 2007Human 1 bacterial mi o s The bacterial microbiota at @:| cii\s h@ oe different body areas @ ; od > Focus on gut bacteria etary. arate Spor A et al. Nat Rev Microbiol 2011 ide ‘i Actinobakterien @.Cyanobakterien C Proteobakterien |Gut microbiota composition in early life Clostridiaceae Bacteroidaceae Bifidobacteriaceae Lachnospiraceae —_Ruminococcaseae . Ruminococcaseae Lachnospiraceae Clostridiaceae Bifidob Enterobacteriaceae Lactobacilleaceae Meo Lactobacileaceae Lactobacilleaceae Lachnospiraceae onell Enterobacteriaceae Enlerobacteriaceae Enterobacteriaceae Birth 4 month 12 months 2-3 years — Mlerobiat aiversity | ‘Modified from: Arrieta MC et al. Front Immunol 2014Gut microbiota composition in early life Clostridiaceae Bacteroidaceae Bifidobacteriaceae Done Ruminococcaseae Clostridiaceae Hemera Lachnospiraceae ifidobacteriaceae Enterobacteriaceae Lactobacilleaceae Lactobacilleaceze Lactobacilleaceae Lachnospiraceae lor i 1 Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae Birth 4 month 42 months 2-3 years == Microbial diversity | Modified from: Arrieta MC et al. Front Immunol 2014 % . > Immune tolerance, > Immune disease, intestinal homeostasis, intestinal disease, healthy metabolism metabolic disease Tanaka M et al. Allergol Int 2017Factors influencing gut microbiota colonisation r frm 4 Weaning — GENE operciparor: Baby toe by Anonymous, tow! of soup by slgentscvon Monozygotic —Dizygotic e » > | 8 @ @ @ cenetic q iW ¢ ® @ influences at |Stable gut microbiota composition of a healthy human adult Average composition of colonic microbiota (% major bacterial phyla) based on 16s rRNA sequencing " Bacteroides Ls Lachnospiraceae a | 2 Ruminococca Fm z Veillonellacea « © others seem fe SL " Actinobacteria \ « Proteobacteria « Verrucomicrobia Froesmapescom gLnaimalg Posi initiates > Dominance of Bacteroidetes and Firmicutes Genome Medicine 2016Resilience of microbiota influences health and disease __ 2s Receyery Stable state A ae 1c 778 Stable state A, vey se Stable state A Stable state D eat, Js py (2:9: dysbiosis) AC Pulsed pertubation (e.g. infections, treatment with antibiotics) Resilience Period of pertubation > stable but detrimental state Dysbiosis ‘Sommer F et al. Nature Rev Microbiol 2017Digestion of food, production of beneficial metabolites n Influence on maturation of the intestinal mucosa & Immune system development Metabolism % of toxic compounds pencigartrg Intestinal pat Moin! Fouhy F et al. Gut Microbes 2016The intestinal barrier and the healthy immune response intestinal mS £F microorganisms Mucus intestinal epithelial cells Intestinal barrier Mucosal immune system Samadi N et al. Ann Allergy Asthma Immunol 2018Innate immunity and the microbiome + Epithelial cells orchestrate the host-microbiota interface: Microbial cell components and metabolites recognition by innate immune receptors > adjust antimicrobial programme and metabolic homeostasis y . + Myeloid cells integrate microbial signals: modulation of local metabolites and mediators > influence on myeloid cell function at all stages of their development + ILCs integrate microbial signals: communication between ILCs and microbiota through cytokines, PRR ligands and antimicrobial peptides; epithelial cells or myeloid cells serve as a relay station RORyt* ILC Thaiss CA et al. Nature 2016Microbiota and the adaptive immune response + Mucosal IgA: Secreted across the epithelium > bind to antigens in the intestinal lumen > affinity matured, microbe-specific IgA is essential for balanced microbiota > Bacterial species degrade IgA Treg cells * Tcell differentiation: mediated by environmental factors, diet (e.g. lipids) and microbiota % e.g. Th17 induction by Segmented filamentous bacteria t e.g. Treg cells promotion by Clostridia strains naive Tells Honda K et al, Nature 2016Microbiota drive regulatory T cell induction”, OOo e ee 8 or oo er Treg cells Macrophages “Seen RORYt ILC 3) Expansion _ of CD103+ 2) Release of Csf2 by ILCs DCs naive T cells Dendritic cells Mortha A et al, Science 2014Individual host immune response shapes the microbiota comp: Pattern recognition receptor repertoir R, NOD 1/2) Secreted epithelial proteins (IL-18, antimicrobial products like defensins, cathelicidin, Regllly; goblet cell derived mucus glycoproteins) ILCs: Primary intestinal IL-22 sSurce > epithelial production of anti- microbials : ‘ .. > Defensin secretion pattern, TLR repertoire > Inflammasome signaling control of microbiota by secretory IgA Rakoff-Nahoum S et al. Cell 2004 Levy Met al. Cell 2015 Kubinak JL et al, Celi Host Microbes 2015Microbiome and immune response influence multifactorial diseases ‘ s imfune Microbiota response < > jet 4 | \ Thais CA et al. Nature 2016Personalized medicine Individual influences on immun: Genetic influences — sos Zg Mode of delivery ENS early feeding, q WY IN SS— penetra: tern by 198) yy microbiota composition