Immune responses to the microbiota at the intestinal mucosal surface.

The mammalian intestinal mucosal surface is continuously exposed to a complex and dynamic community of microorganisms. These microbes establish symbiotic relationships with their hosts, making important contributions to metabolism and digestive efficiency. The intestinal epithelial surface is the primary interface between the vast microbiota and internal host tissues. Given the enormous numbers of enteric bacteria and the persistent threat of opportunistic invasion, it is crucial that mammalian hosts monitor and regulate microbial interactions with intestinal epithelial surfaces. Here we discuss recent insights into how the innate and adaptive arms of the immune system collaborate to maintain homeostasis at the luminal surface of the intestinal host-microbial interface. These findings are also yielding a better understanding of how symbiotic host-microbial relationships can break down in inflammatory bowel disease.

[1]  P. Sansonetti.  War and peace at mucosal surfaces , 2004, Nature Reviews Immunology.

[2]  Bettina L. Lee,et al.  Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20 , 2008, The Journal of experimental medicine.

[3]  A. Macpherson,et al.  Induction of Protective IgA by Intestinal Dendritic Cells Carrying Commensal Bacteria , 2004, Science.

[4]  Keiichiro Suzuki,et al.  Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  K. Michelsen,et al.  Host-Microbial Interactions in the Gut 2-Dependent Bacterial Ligands : Implications Broadly Unresponsive to Toll-Like Receptor Human Intestinal Epithelial Cells , 2003 .

[6]  E. Fuchs,et al.  Protection of the intestinal mucosa by intraepithelial γδ T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Judy H. Cho,et al.  [Letters to Nature] , 1975, Nature.

[8]  Y. You,et al.  Ubiquitination of RIP Is Required for Tumor Necrosis Factor α-induced NF-κB Activation* , 2006, Journal of Biological Chemistry.

[9]  A. Krikos,et al.  Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements. , 1992, The Journal of biological chemistry.

[10]  Lynn K. Carmichael,et al.  A Genomic View of the Human-Bacteroides thetaiotaomicron Symbiosis , 2003, Science.

[11]  Lena Holm,et al.  The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria , 2010, Gut microbes.

[12]  L. Hooper,et al.  Alkaline phosphatase: keeping the peace at the gut epithelial surface. , 2007, Cell host & microbe.

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

[14]  C. Larkin,et al.  Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. , 1983, Laboratory animal science.

[15]  R. B. Hespell,et al.  Physiology and genetics of xylan degradation by gastrointestinal tract bacteria. , 1990, Journal of dairy science.

[16]  Sarah L. Brown,et al.  A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells , 2008, Nature.

[17]  Yanping Wang,et al.  Human intestinal bacteria as reservoirs for antibiotic resistance genes. , 2004, Trends in microbiology.

[18]  A. Andoh,et al.  Differential cytokine regulation of complement C3, C4, and factor B synthesis in human intestinal epithelial cell line, Caco-2. , 1993, Journal of immunology.

[19]  J. Gordon,et al.  IgA response to symbiotic bacteria as a mediator of gut homeostasis. , 2007, Cell host & microbe.

[20]  R. Kenworthy.  Intestinal Microbial Flora of the Pig , 1973 .

[21]  M. Weichenthal,et al.  Reduced Paneth cell alpha-defensins in ileal Crohn's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Gordon,et al.  Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. , 2008, Cell host & microbe.

[23]  H. Weiner,et al.  Peripheral deletion of antigen-reactive T cells in oral tolerance , 1995, Nature.

[24]  I. Moura,et al.  Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. , 2005, Immunity.

[25]  P. Turnbaugh,et al.  Microbial ecology: Human gut microbes associated with obesity , 2006, Nature.

[26]  M. Hornef,et al.  Secreted enteric antimicrobial activity localises to the mucus surface layer , 2008, Gut.

[27]  G. Plitas,et al.  MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection , 2007, The Journal of experimental medicine.

[28]  R Balfour Sartor,et al.  Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. , 2008, Cell host & microbe.

[29]  L. Hooper,et al.  Symbiotic Bacteria Direct Expression of an Intestinal Bactericidal Lectin , 2006, Science.

[30]  S. Normark,et al.  Germ-free and Colonized Mice Generate the Same Products from Enteric Prodefensins* , 2000, The Journal of Biological Chemistry.

[31]  P. Godowski,et al.  Cutting Edge: Bacterial Flagellin Activates Basolaterally Expressed TLR5 to Induce Epithelial Proinflammatory Gene Expression1 , 2001, The Journal of Immunology.

[32]  R. Knight,et al.  Evolution of Mammals and Their Gut Microbes , 2008, Science.

[33]  S. Mazmanian,et al.  Regulation of surface architecture by symbiotic bacteria mediates host colonization , 2008, Proceedings of the National Academy of Sciences.

[34]  Somasekar Seshagiri,et al.  De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling , 2004, Nature.

[35]  L. Comstock,et al.  Human Symbionts Use a Host-Like Pathway for Surface Fucosylation , 2005, Science.

[36]  L. Hooper,et al.  Reciprocal Interactions between Commensal Bacteria and γδ Intraepithelial Lymphocytes during Mucosal Injury1 , 2009, The Journal of Immunology.

[37]  R. Knight,et al.  Worlds within worlds: evolution of the vertebrate gut microbiota , 2008, Nature Reviews Microbiology.

[38]  U. Gophna,et al.  Differences between Tissue-Associated Intestinal Microfloras of Patients with Crohn's Disease and Ulcerative Colitis , 2006, Journal of Clinical Microbiology.

[39]  Y. Kim,et al.  Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. , 1994, The Journal of biological chemistry.

[40]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[41]  Benjamin P. Westover,et al.  Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont , 2005, Science.

[42]  Jennifer M. Bates,et al.  Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. , 2007, Cell host & microbe.

[43]  R. Zinkernagel,et al.  A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. , 2000, Science.

[44]  H. Flint,et al.  Assessment of microbial diversity in human colonic samples by 16S rDNA sequence analysis. , 2002, FEMS microbiology ecology.

[45]  K. McCoy,et al.  Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria , 2005, Immunology.

[46]  A. Ma,et al.  Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. , 2000, Science.

[47]  R. Munford,et al.  Shield as Signal: Lipopolysaccharides and the Evolution of Immunity to Gram-Negative Bacteria , 2006, PLoS pathogens.

[48]  M. Selsted,et al.  Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. , 2000, Nature immunology.

[49]  P. Brigidi,et al.  Prevention of TNBS‐induced colitis by different Lactobacillus and Bifidobacterium strains is associated with an expansion of &ggr;&dgr;T and regulatory T cells of intestinal intraepithelial lymphocytes , 2009, Inflammatory bowel diseases.

[50]  C. Manichanh,et al.  Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach , 2005, Gut.

[51]  E. Zoetendal,et al.  The Intestinal LABs , 2002, Antonie van Leeuwenhoek.

[52]  L. Hooper,et al.  Multi-layered regulation of intestinal antimicrobial defense , 2008, Cellular and Molecular Life Sciences.

[53]  H. Lochs,et al.  Spatial Organization and Composition of the Mucosal Flora in Patients with Inflammatory Bowel Disease , 2005, Journal of Clinical Microbiology.

[54]  J. Gustafsson,et al.  Enterococcus faecalis from newborn babies regulate endogenous PPARγ activity and IL-10 levels in colonic epithelial cells , 2008, Proceedings of the National Academy of Sciences.

[55]  F. Bäckhed,et al.  Host-Bacterial Mutualism in the Human Intestine , 2005, Science.

[56]  P. Ricciardi-Castagnoli,et al.  Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria , 2001, Nature Immunology.

[57]  L. Eckmann,et al.  Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface , 2008, Proceedings of the National Academy of Sciences.

[58]  K. McCoy,et al.  The immune geography of IgA induction and function , 2008, Mucosal Immunology.

[59]  J. Gordon,et al.  Honor thy symbionts , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[60]  L. Comstock,et al.  Bacteroides thetaiotaomicron: a dynamic, niche-adapted human symbiont. , 2003, Bioessays.

[61]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[62]  J. Gordon,et al.  Molecular analysis of commensal host-microbial relationships in the intestine. , 2001, Science.

[63]  B. Stecher,et al.  Comparison of Salmonellaenterica Serovar Typhimurium Colitis in Germfree Mice and Mice Pretreated with Streptomycin , 2005, Infection and Immunity.

[64]  H. Tilg,et al.  XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease , 2008, Cell.

[65]  Tasuku Honjo,et al.  Intestinal IgA synthesis: regulation of front-line body defences , 2003, Nature Reviews Immunology.

[66]  R. Ley,et al.  Innate immunity and intestinal microbiota in the development of Type 1 diabetes , 2008, Nature.

[67]  J. Berzofsky,et al.  Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. , 2008, Immunity.

[68]  A. Palva,et al.  Surface Display of the Receptor-Binding Region of the Lactobacillusbrevis S-Layer Protein in Lactococcuslactis Provides Nonadhesive Lactococci with the Ability To Adhere to Intestinal Epithelial Cells , 2003, Applied and Environmental Microbiology.

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

[70]  G. Dougan,et al.  Salmonella enterica Serovar Typhimurium Exploits Inflammation to Compete with the Intestinal Microbiota , 2007, PLoS biology.

[71]  V. Ladero,et al.  Isolation and identification of tyramine-producing enterococci from human fecal samples. , 2009, Canadian journal of microbiology.

[72]  M. Abreu,et al.  Decreased Expression of Toll-Like Receptor-4 and MD-2 Correlates with Intestinal Epithelial Cell Protection Against Dysregulated Proinflammatory Gene Expression in Response to Bacterial Lipopolysaccharide1 , 2001, The Journal of Immunology.

[73]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

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

[75]  A. Plebani,et al.  Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. , 2007, Immunity.

[76]  Tao Zhang,et al.  RNA Viral Community in Human Feces: Prevalence of Plant Pathogenic Viruses , 2005, PLoS biology.

[77]  Shu-mei He,et al.  Bacteria‐free solution derived from lactobacillus plantarum inhibits multiple NF‐kappaB pathways and inhibits proteasome function , 2009, Inflammatory bowel diseases.

[78]  Jeffrey I. Gordon,et al.  Angiogenins: a new class of microbicidal proteins involved in innate immunity , 2003, Nature Immunology.

[79]  A. Young,et al.  Prokaryotic Regulation of Epithelial Responses by Inhibition of IκB-α Ubiquitination , 2000 .