Striking a Balance with Help from our Little Friends – How the Gut Microbiota Contributes to Immune Homeostasis

The trillions of microbes that inhabit the human gut (the microbiota) together with the host comprise a complex ecosystem, and like any ecosystem, health relies on stability and balance. Some of the most important members of the human microbiota are those that help maintain this balance via modulation of the host immune system. Gut microbes, through both molecular factors (such as capsular components) and by-products of their metabolism (such as Short Chain Fatty Acids (SCFAs)), can influence both innate and adaptive components of the immune system, in ways that can drive both effector, and regulatory responses. Here we review how commensal microbes can specifically promote a dynamic balance of these immune responses in the mammalian gut.

[1]  S. Mazmanian,et al.  Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota , 2010, Proceedings of the National Academy of Sciences.

[2]  S. Peterson,et al.  Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota , 2015, Clinical and experimental immunology.

[3]  B. Batten,et al.  Cutting Edge: Bacterial Modulation of Epithelial Signaling via Changes in Neddylation of Cullin-11 , 2005, The Journal of Immunology.

[4]  W. Garrett,et al.  The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis , 2013, Science.

[5]  S. Mazmanian,et al.  An Immunomodulatory Molecule of Symbiotic Bacteria Directs Maturation of the Host Immune System , 2005, Cell.

[6]  A. De Luca,et al.  Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. , 2013, Immunity.

[7]  Th1/Th2 cells. , 1999, Inflammatory bowel diseases.

[8]  J. Delcour,et al.  Arabinoxylooligosaccharides from wheat bran inhibit Salmonella colonization in broiler chickens. , 2008, Poultry science.

[9]  Boquan Jin,et al.  Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance , 2015, Cellular and Molecular Immunology.

[10]  M. Carabotti,et al.  The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems , 2015, Annals of gastroenterology.

[11]  Gabriel Núñez,et al.  Control of pathogens and pathobionts by the gut microbiota , 2013, Nature Immunology.

[12]  G R Gibson,et al.  Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. , 1995, The Journal of nutrition.

[13]  Jay K Kolls,et al.  The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation , 2022 .

[14]  Jeroen Raes,et al.  How informative is the mouse for human gut microbiota research? , 2015, Disease Models & Mechanisms.

[15]  S. Mazmanian,et al.  The gut microbiota shapes intestinal immune responses during health and disease , 2009, Nature Reviews Immunology.

[16]  E. Rietschel,et al.  Bacterial lipopolysaccharides and innate immunity. , 2001, Journal of endotoxin research.

[17]  R. Ley,et al.  Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine , 2006, Cell.

[18]  S. Mazmanian,et al.  A microbial symbiosis factor prevents intestinal inflammatory disease , 2008, Nature.

[19]  E. Sokal,et al.  Maturation of villus and crypt cell functions in rat small intestine , 1993, Digestive Diseases and Sciences.

[20]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[21]  Jeffrey N. Weiser,et al.  Recognition of Peptidoglycan from the Microbiota by Nod1 Enhances Systemic Innate Immunity , 2010, Nature Medicine.

[22]  S. Pettersson,et al.  Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA , 2004, Nature Immunology.

[23]  T. Kirchner,et al.  Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. , 1992, Gastroenterology.

[24]  E. Hobeika,et al.  Natural Aryl Hydrocarbon Receptor Ligands Control Organogenesis of Intestinal Lymphoid Follicles , 2011, Science.

[25]  Sara Omenetti,et al.  The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome , 2015, Front. Immunol..

[26]  Dan R. Littman,et al.  Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria , 2009, Cell.

[27]  S. Sakaguchi,et al.  Regulatory T cells: how do they suppress immune responses? , 2009, International immunology.

[28]  M. Hattori,et al.  Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells , 2015, Cell.

[29]  T. Hudcovic,et al.  Oral administration of Parabacteroides distasonis antigens attenuates experimental murine colitis through modulation of immunity and microbiota composition , 2011, Clinical and experimental immunology.

[30]  B. Finlay,et al.  Anti-Immunology: Evasion of the Host Immune System by Bacterial and Viral Pathogens , 2006, Cell.

[31]  Jonathan L. Linehan,et al.  Focused Specificity of Intestinal Th17 Cells towards Commensal Bacterial Antigens , 2014, Nature.

[32]  A. Rudensky,et al.  Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation , 2013, Nature.

[33]  H. Kiyono,et al.  Probiotic Bifidobacterium breve Induces IL-10-Producing Tr1 Cells in the Colon , 2012, PLoS pathogens.

[34]  Annaïg Lan,et al.  The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. , 2009, Immunity.

[35]  Lori S C Kreisman,et al.  Glycoantigens Induce Human Peripheral Tr1 Cell Differentiation with Gut-homing Specialization* , 2011, The Journal of Biological Chemistry.

[36]  A. Rudensky,et al.  Extrathymically generated regulatory T cells control mucosal TH2 inflammation , 2012, Nature.

[37]  R. Knight,et al.  The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice , 2009, Science Translational Medicine.

[38]  Y. Belkaid,et al.  Intestinal microbiota: shaping local and systemic immune responses. , 2012, Seminars in immunology.

[39]  A. Velcich,et al.  Importance and regulation of the colonic mucus barrier in a mouse model of colitis. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[40]  C. M. Wood,et al.  Treatment of diversion colitis with short-chain-fatty acid irrigation. , 1989, The New England journal of medicine.

[41]  D. Jarrossay,et al.  Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β , 2012, Nature.

[42]  W. Garrett,et al.  Gut microbiota, metabolites and host immunity , 2016, Nature Reviews Immunology.

[43]  M. Hattori,et al.  Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota , 2013, Nature.

[44]  Lan Xiao,et al.  Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[45]  D. Johnson,et al.  The Influence of the Gut Microbiome on Obesity, Metabolic Syndrome and Gastrointestinal Disease , 2015, Clinical and Translational Gastroenterology.

[46]  M. Tomita,et al.  Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells , 2013, Nature.

[47]  E. Riley,et al.  IL-10: The Master Regulator of Immunity to Infection , 2008, The Journal of Immunology.

[48]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[49]  Sharon K. Ahluwalia,et al.  Peripheral Education of the Immune System by Colonic Commensal Microbiota , 2012 .

[50]  T. Junt,et al.  Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis , 2014, Nature Medicine.

[51]  P. van Endert,et al.  Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota. , 2015, Immunity.

[52]  B. Hall T Cells: Soldiers and Spies--The Surveillance and Control of Effector T Cells by Regulatory T Cells. , 2015, Clinical journal of the American Society of Nephrology : CJASN.

[53]  D. Kasper,et al.  A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39+Foxp3+ T cells and Treg function , 2015, Gut microbes.

[54]  K. Honda,et al.  The microbiota in adaptive immune homeostasis and disease , 2016, Nature.

[55]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[56]  Caixia Ma,et al.  MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium‐induced colitis , 2008, Cellular microbiology.