The diverse microbial populations constituting the intestinal microbiota promote immune development and differentiation, but because of their complex metabolic requirements and the consequent difficulty culturing them, they remained, until recently, largely uncharacterized and mysterious. In the last decade, deep nucleic acid sequencing platforms, new computational and bioinformatics tools, and full-genome characterization of several hundred commensal bacterial species facilitated studies of the microbiota and revealed that differences in microbiota composition can be associated with inflammatory, metabolic, and infectious diseases, that each human is colonized by a distinct bacterial flora, and that the microbiota can be manipulated to reduce and even cure some diseases. Different bacterial species induce distinct immune cell populations that can play pro- and anti-inflammatory roles, and thus the composition of the microbiota determines, in part, the level of resistance to infection and susceptibility to inflammatory diseases. This review summarizes recent work characterizing commensal microbes that contribute to the antimicrobial defense/inflammation axis.


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Literature Cited

  1. Hejnol A, Martindale MQ. 1.  2008. Acoel development indicates the independent evolution of the bilaterian mouth and anus. Nature 456:382–86 [Google Scholar]
  2. Maxmen A. 2.  2011. Evolution: a can of worms. Nature 470:161–62 [Google Scholar]
  3. Honda K, Littman DR. 3.  2012. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30:759–95 [Google Scholar]
  4. Belkaid Y, Hand TW. 4.  2014. Role of the microbiota in immunity and inflammation. Cell 157:121–41 [Google Scholar]
  5. 5. Hum. Microbiome Proj. Consort 2012. Structure, function and diversity of the healthy human microbiome. Nature 486:207–14 [Google Scholar]
  6. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L. 6.  et al. 2005. Diversity of the human intestinal microbial flora. Science 308:1635–38 [Google Scholar]
  7. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T. 7.  et al. 2011. Enterotypes of the human gut microbiome. Nature 473:174–80 [Google Scholar]
  8. Koren O, Knights D, Gonzalez A, Waldron L, Segata N. 8.  et al. 2013. A guide to enterotypes across the human body: meta-analysis of microbial community structures in human microbiome datasets. PLOS Comput. Biol. 9:e1002863 [Google Scholar]
  9. Ding T, Schloss PD. 9.  2014. Dynamics and associations of microbial community types across the human body. Nature 509:357–60 [Google Scholar]
  10. Lee SM, Donaldson GP, Mikulski Z, Boyajian S, Ley K, Mazmanian SK. 10.  2013. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501:426–29 [Google Scholar]
  11. Pacheco AR, Curtis MM, Ritchie JM, Munera D, Waldor MK. 11.  et al. 2012. Fucose sensing regulates bacterial intestinal colonization. Nature 492:113–17 [Google Scholar]
  12. Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC. 12.  et al. 2013. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502:96–99 [Google Scholar]
  13. Duerkop BA, Clements CV, Rollins D, Rodrigues JL, Hooper LV. 13.  2012. A composite bacteriophage alters colonization by an intestinal commensal bacterium. PNAS 109:17621–26 [Google Scholar]
  14. Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y. 14.  et al. 2011. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469:543–47 [Google Scholar]
  15. Goodman AL, Kallstrom G, Faith JJ, Reyes A, Moore A. 15.  et al. 2011. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. PNAS 108:6252–57 [Google Scholar]
  16. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y. 16.  et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–36 [Google Scholar]
  17. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T. 17.  et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–41 [Google Scholar]
  18. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T. 18.  et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–98 [Google Scholar]
  19. Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM. 19.  et al. 2012. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149:1578–93 [Google Scholar]
  20. Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M. 20.  et al. 2009. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75:7537–41 [Google Scholar]
  21. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD. 21.  et al. 2010. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7:335–36 [Google Scholar]
  22. Lozupone C, Knight R. 22.  2005. UniFrac: a new phylogenetic method for comparing microbial communities. Appl. Environ. Microbiol. 71:8228–35 [Google Scholar]
  23. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L. 23.  et al. 2011. Metagenomic biomarker discovery and explanation. Genome Biol. 12:R60 [Google Scholar]
  24. Segata N, Waldron L, Ballarini A, Narasimhan V, Jousson O, Huttenhower C. 24.  2012. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat. Methods 9:811–14 [Google Scholar]
  25. Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D. 25.  et al. 2013. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat. Biotechnol. 31:814–21 [Google Scholar]
  26. Stein RR, Bucci V, Toussaint NC, Buffie CG, Ratsch G. 26.  et al. 2013. Ecological modeling from time-series inference: insight into dynamics and stability of intestinal microbiota. PLOS Comput. Biol. 9:e1003388 [Google Scholar]
  27. Marino S, Baxter NT, Huffnagle GB, Petrosino JF, Schloss PD. 27.  2014. Mathematical modeling of primary succession of murine intestinal microbiota. PNAS 111:439–44 [Google Scholar]
  28. Balmer ML, Slack E, de Gottardi A, Lawson MA, Hapfelmeier S. 28.  et al. 2014. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl. Med. 6:237ra66 [Google Scholar]
  29. Godl K, Johansson ME, Lidell ME, Morgelin M, Karlsson H. 29.  et al. 2002. The N terminus of the MUC2 mucin forms trimers that are held together within a trypsin-resistant core fragment. J. Biol. Chem. 277:47248–56 [Google Scholar]
  30. Lidell ME, Moncada DM, Chadee K, Hansson GC. 30.  2006. Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel. PNAS 103:9298–303 [Google Scholar]
  31. van der Post S, Subramani DB, Backstrom M, Johansson ME, Vester-Christensen MB. 31.  et al. 2013. Site-specific O-glycosylation on the MUC2 mucin protein inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB). J. Biol. Chem. 288:14636–46 [Google Scholar]
  32. Martens EC, Chiang HC, Gordon JI. 32.  2008. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4:447–57 [Google Scholar]
  33. Martens EC, Roth R, Heuser JE, Gordon JI. 33.  2009. Coordinate regulation of glycan degradation and polysaccharide capsule biosynthesis by a prominent human gut symbiont. J. Biol. Chem. 284:18445–57 [Google Scholar]
  34. Johansson ME, Larsson JM, Hansson GC. 34.  2011. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. PNAS 108:Suppl. 14659–65 [Google Scholar]
  35. Fu J, Wei B, Wen T, Johansson ME, Liu X. 35.  et al. 2011. Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice. J. Clin. Investig. 121:1657–66 [Google Scholar]
  36. Sommer F, Adam N, Johansson ME, Xia L, Hansson GC, Backhed F. 36.  2014. Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture. PLOS ONE 9:e85254 [Google Scholar]
  37. Johansson ME, Gustafsson JK, Sjoberg KE, Petersson J, Holm L. 37.  et al. 2010. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLOS ONE 5:e12238 [Google Scholar]
  38. Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. 38.  2008. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. PNAS 105:15064–9 [Google Scholar]
  39. Hansson GC, Johansson ME. 39.  2010. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Gut Microbes 1:51–54 [Google Scholar]
  40. Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X. 40.  et al. 2011. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334:255–58 [Google Scholar]
  41. Ermund A, Schutte A, Johansson ME, Gustafsson JK, Hansson GC. 41.  2013. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. Am. J. Physiol. Gastrointest. Liver Physiol. 305:G341–47 [Google Scholar]
  42. Holmen Larsson JM, Thomsson KA, Rodriguez-Pineiro AM, Karlsson H, Hansson GC. 42.  2013. Studies of mucus in mouse stomach, small intestine, and colon. III. Gastrointestinal Muc5ac and Muc2 mucin O-glycan patterns reveal a regiospecific distribution. Am. J. Physiol. Gastrointest. Liver Physiol. 305:G357–63 [Google Scholar]
  43. McAuley JL, Linden SK, Png CW, King RM, Pennington HL. 43.  et al. 2007. MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. J. Clin. Investig. 117:2313–24 [Google Scholar]
  44. Linden SK, Sheng YH, Every AL, Miles KM, Skoog EC. 44.  et al. 2009. MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy. PLOS Pathog. 5:e1000617 [Google Scholar]
  45. Zarepour M, Bhullar K, Montero M, Ma C, Huang T. 45.  et al. 2013. The mucin Muc2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar Typhimurium colitis. Infect. Immun. 81:3672–83 [Google Scholar]
  46. Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU. 46.  et al. 2013. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342:447–53 [Google Scholar]
  47. McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V. 47.  et al. 2012. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483:345–49 [Google Scholar]
  48. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL. 48.  2001. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167:1882–85 [Google Scholar]
  49. Frantz AL, Rogier EW, Weber CR, Shen L, Cohen DA. 49.  et al. 2012. Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. Mucosal Immunol. 5:501–12 [Google Scholar]
  50. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA. 50.  et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–57 [Google Scholar]
  51. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N. 51.  et al. 2005. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–34 [Google Scholar]
  52. Zaph C, Troy AE, Taylor BC, Berman-Booty LD, Guild KJ. 52.  et al. 2007. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446:552–56 [Google Scholar]
  53. Olszak T, Neves JF, Dowds CM, Baker K, Glickman J. 53.  et al. 2014. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 509:497–502 [Google Scholar]
  54. Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X. 54.  et al. 2011. γδ intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. PNAS 108:8743–48 [Google Scholar]
  55. Brown SL, Riehl TE, Walker MR, Geske MJ, Doherty JM. 55.  et al. 2007. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Investig. 117:258–69 [Google Scholar]
  56. Varol C, Zigmond E, Jung S. 56.  2010. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nat. Rev. Immunol. 10:415–26 [Google Scholar]
  57. Tussiwand R, Lee WL, Murphy TL, Mashayekhi M, Kc W. 57.  et al. 2012. Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature 490:502–7 [Google Scholar]
  58. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G. 58.  et al. 2001. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2:361–67 [Google Scholar]
  59. Niess JH, Brand S, Gu X, Landsman L, Jung S. 59.  et al. 2005. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–58 [Google Scholar]
  60. Chieppa M, Rescigno M, Huang AY, Germain RN. 60.  2006. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203:2841–52 [Google Scholar]
  61. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM. 61.  et al. 2007. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid–dependent mechanism. J. Exp. Med. 204:1757–64 [Google Scholar]
  62. Farache J, Koren I, Milo I, Gurevich I, Kim KW. 62.  et al. 2013. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38:581–95 [Google Scholar]
  63. Diehl GE, Longman RS, Zhang JX, Breart B, Galan C. 63.  et al. 2013. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494:116–20 [Google Scholar]
  64. Schulz O, Jaensson E, Persson EK, Liu X, Worbs T. 64.  et al. 2009. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 206:3101–14 [Google Scholar]
  65. Zigmond E, Varol C, Farache J, Elmaliah E, Satpathy AT. 65.  et al. 2012. Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37:1076–90 [Google Scholar]
  66. Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N. 66.  et al. 2014. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14:571–78 [Google Scholar]
  67. Samstein M, Schreiber HA, Leiner IM, Susac B, Glickman MS, Pamer EG. 67.  2013. Essential yet limited role for CCR2+ inflammatory monocytes during Mycobacterium tuberculosis–specific T cell priming. eLife 2:e01086 [Google Scholar]
  68. Mazzini E, Massimiliano L, Penna G, Rescigno M. 68.  2014. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 40:248–61 [Google Scholar]
  69. Cerovic V, Houston SA, Scott CL, Aumeunier A, Yrlid U. 69.  et al. 2013. Intestinal CD103 dendritic cells migrate in lymph and prime effector T cells. Mucosal Immunol. 6:104–13 [Google Scholar]
  70. Grainger JR, Wohlfert EA, Fuss IJ, Bouladoux N, Askenase MH. 70.  et al. 2013. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat. Med. 19:713–21 [Google Scholar]
  71. Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP. 71.  et al. 2014. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288 [Google Scholar]
  72. Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P. 72.  et al. 2012. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat. Immunol. 13:449–56 [Google Scholar]
  73. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM. 73.  et al. 2008. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14:282–89 [Google Scholar]
  74. Merad M, Sathe P, Helft J, Miller J, Mortha A. 74.  2013. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31:563–604 [Google Scholar]
  75. Kinnebrew MA, Buffie CG, Diehl GE, Zenewicz LA, Leiner I. 75.  et al. 2012. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36:276–87 [Google Scholar]
  76. Satpathy AT, Briseno CG, Lee JS, Ng D, Manieri NA. 76.  et al. 2013. Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat. Immunol. 14:937–48 [Google Scholar]
  77. Fujimoto K, Karuppuchamy T, Takemura N, Shimohigoshi M, Machida T. 77.  et al. 2011. A new subset of CD103+CD8α+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity. J. Immunol. 186:6287–95 [Google Scholar]
  78. Cerovic V, Bain CC, Mowat AM, Milling SW. 78.  2014. Intestinal macrophages and dendritic cells: What's the difference?. Trends Immunol. 35:270–77 [Google Scholar]
  79. Bekiaris V, Persson EK, Agace WW. 79.  2014. Intestinal dendritic cells in the regulation of mucosal immunity. Immunol. Rev. 260:86–101 [Google Scholar]
  80. Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J. 80.  et al. 2014. Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment. PLOS Biol. 12:e1001793 [Google Scholar]
  81. Yrlid U, Milling SW, Miller JL, Cartland S, Jenkins CD, MacPherson GG. 81.  2006. Regulation of intestinal dendritic cell migration and activation by plasmacytoid dendritic cells, TNF-alpha and type 1 IFNs after feeding a TLR7/8 ligand. J. Immunol. 176:5205–12 [Google Scholar]
  82. Chu H, Mazmanian SK. 82.  2013. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat. Immunol. 14:668–75 [Google Scholar]
  83. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. 83.  2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–18 [Google Scholar]
  84. Round JL, Lee SM, Li J, Tran G, Jabri B. 84.  et al. 2011. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974–77 [Google Scholar]
  85. Shen Y, Giardino Torchia ML, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK. 85.  2012. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12:509–20 [Google Scholar]
  86. Dasgupta S, Erturk-Hasdemir D, Ochoa-Reparaz J, Reinecker HC, Kasper DL. 86.  2014. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 15:413–23 [Google Scholar]
  87. Cash HL, Whitham CV, Behrendt CL, Hooper LV. 87.  2006. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313:1126–30 [Google Scholar]
  88. Brandl K, Plitas G, Schnabl B, DeMatteo RP, Pamer EG. 88.  2007. MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204:1891–900 [Google Scholar]
  89. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. 89.  2008. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. PNAS 105:20858–63 [Google Scholar]
  90. Loonen LM, Stolte EH, Jaklofsky MT, Meijerink M, Dekker J. 90.  et al. 2014. REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol. 7:939–47 [Google Scholar]
  91. Mukherjee S, Zheng H, Derebe MG, Callenberg KM, Partch CL. 91.  et al. 2014. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505:103–7 [Google Scholar]
  92. Miki T, Holst O, Hardt WD. 92.  2012. The bactericidal activity of the C-type lectin RegIIIβ against gram-negative bacteria involves binding to lipid A. J. Biol. Chem. 287:34844–55 [Google Scholar]
  93. Miki T, Hardt WD. 93.  2013. Outer membrane permeabilization is an essential step in the killing of gram-negative bacteria by the lectin RegIIIβ. PLOS ONE 8:e69901 [Google Scholar]
  94. Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y. 94.  et al. 2006. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat. Immunol. 7:868–74 [Google Scholar]
  95. Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ. 95.  et al. 2008. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9:769–76 [Google Scholar]
  96. Kinnebrew MA, Ubeda C, Zenewicz LA, Smith N, Flavell RA, Pamer EG. 96.  2010. Bacterial flagellin stimulates Toll-like receptor 5–dependent defense against vancomycin-resistant Enterococcus infection. J. Infect. Dis. 201:534–43 [Google Scholar]
  97. Jarchum I, Liu M, Lipuma L, Pamer EG. 97.  2011. Toll-like receptor 5 stimulation protects mice from acute Clostridium difficile colitis. Infect. Immun. 79:1498–503 [Google Scholar]
  98. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S. 98.  et al. 2010. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328:228–31 [Google Scholar]
  99. Carvalho FA, Koren O, Goodrich JK, Johansson ME, Nalbantoglu I. 99.  et al. 2012. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12:139–52 [Google Scholar]
  100. Cullender TC, Chassaing B, Janzon A, Kumar K, Muller CE. 100.  et al. 2013. Innate and adaptive immunity interact to quench microbiome flagellar motility in the gut. Cell Host Microbe 14:571–81 [Google Scholar]
  101. Letran SE, Lee SJ, Atif SM, Flores-Langarica A, Uematsu S. 101.  et al. 2011. TLR5-deficient mice lack basal inflammatory and metabolic defects but exhibit impaired CD4 T cell responses to a flagellated pathogen. J. Immunol. 186:5406–12 [Google Scholar]
  102. Hall JA, Bouladoux N, Sun CM, Wohlfert EA, Blank RB. 102.  et al. 2008. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29:637–49 [Google Scholar]
  103. Brandl K, Plitas G, Mihu CN, Ubeda C, Jia T. 103.  et al. 2008. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455:804–7 [Google Scholar]
  104. Ubeda C, Lipuma L, Gobourne A, Viale A, Leiner I. 104.  et al. 2012. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209:1445–56 [Google Scholar]
  105. Jin C, Henao-Mejia J, Flavell RA. 105.  2013. Innate immune receptors: key regulators of metabolic disease progression. Cell Metab. 17:873–82 [Google Scholar]
  106. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ. 106.  et al. 2012. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179–85 [Google Scholar]
  107. Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP. 107.  et al. 2014. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156:1045–59 [Google Scholar]
  108. Ayres JS, Trinidad NJ, Vance RE. 108.  2012. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nat. Med. 18:799–806 [Google Scholar]
  109. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. 109.  2010. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat. Med. 16:228–31 [Google Scholar]
  110. Kim YG, Kamada N, Shaw MH, Warner N, Chen GY. 110.  et al. 2011. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34:769–80 [Google Scholar]
  111. Ganal SC, Sanos SL, Kallfass C, Oberle K, Johner C. 111.  et al. 2012. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37:171–86 [Google Scholar]
  112. Sonnenberg GF, Artis D. 112.  2012. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37:601–10 [Google Scholar]
  113. Kruglov AA, Grivennikov SI, Kuprash DV, Winsauer C, Prepens S. 113.  et al. 2013. Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science 342:1243–46 [Google Scholar]
  114. de Pavert SA, Ferreira M, Domingues RG, Ribeiro H, Molenaar R. 114.  van et al. 2014. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508:123–27 [Google Scholar]
  115. Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA. 115.  et al. 2012. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336:1321–25 [Google Scholar]
  116. Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S. 116.  et al. 2013. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498:113–17 [Google Scholar]
  117. Qiu J, Guo X, Chen ZM, He L, Sonnenberg GF. 117.  et al. 2013. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39:386–99 [Google Scholar]
  118. Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X. 118.  et al. 2013. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504:158–62 [Google Scholar]
  119. Hooper LV, Littman DR, Macpherson AJ. 119.  2012. Interactions between the microbiota and the immune system. Science 336:1268–73 [Google Scholar]
  120. Cahenzli J, Koller Y, Wyss M, Geuking MB, McCoy KD. 120.  2013. Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host Microbe 14:559–70 [Google Scholar]
  121. Suzuki K, Meek B, Doi Y, Muramatsu M, Chiba T. 121.  et al. 2004. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. PNAS 101:1981–86 [Google Scholar]
  122. Mirpuri J, Raetz M, Sturge CR, Wilhelm CL, Benson A. 122.  et al. 2014. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes 5:28–39 [Google Scholar]
  123. Umesaki Y, Setoyama H, Matsumoto S, Imaoka A, Itoh K. 123.  1999. Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system. Infect. Immun. 67:3504–11 [Google Scholar]
  124. Lecuyer E, Rakotobe S, Lengline-Garnier H, Lebreton C, Picard M. 124.  et al. 2014. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity 40:608–20 [Google Scholar]
  125. Kawamoto S, Tran TH, Maruya M, Suzuki K, Doi Y. 125.  et al. 2012. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336:485–89 [Google Scholar]
  126. Hapfelmeier S, Lawson MA, Slack E, Kirundi JK, Stoel M. 126.  et al. 2010. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328:1705–9 [Google Scholar]
  127. Lindner C, Wahl B, Fohse L, Suerbaum S, Macpherson AJ. 127.  et al. 2012. Age, microbiota, and T cells shape diverse individual IgA repertoires in the intestine. J. Exp. Med. 209:365–77 [Google Scholar]
  128. Fritz JH, Rojas OL, Simard N, McCarthy DD, Hapfelmeier S. 128.  et al. 2012. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481:199–203 [Google Scholar]
  129. Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A. 129.  et al. 2009. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31:677–89 [Google Scholar]
  130. Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF. 130.  et al. 2011. The genome of Th17 cell–inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10:260–72 [Google Scholar]
  131. Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M. 131.  et al. 2014. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510:152–56 [Google Scholar]
  132. Goto Y, Panea C, Nakato G, Cebula A, Lee C. 132.  et al. 2014. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40:594–607 [Google Scholar]
  133. Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagan AJ. 133.  et al. 2012. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science 337:1553–56 [Google Scholar]
  134. Shaw MH, Kamada N, Kim YG, Nunez G. 134.  2012. Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J. Exp. Med. 209:251–58 [Google Scholar]
  135. Yu X, Rollins D, Ruhn KA, Stubblefield JJ, Green CB. 135.  et al. 2013. TH17 cell differentiation is regulated by the circadian clock. Science 342:727–30 [Google Scholar]
  136. Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E. 136.  et al. 2011. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34:794–806 [Google Scholar]
  137. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW. 137.  et al. 2011. Peripheral education of the immune system by colonic commensal microbiota. Nature 478:250–54 [Google Scholar]
  138. Round JL, Mazmanian SK. 138.  2010. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. PNAS 107:12204–9 [Google Scholar]
  139. Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. 139.  2014. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl. Med. 6:220ra11 [Google Scholar]
  140. Narushima S, Sugiura Y, Oshima K, Atarashi K, Hattori M. 140.  et al. 2014. Characterization of the 17 strains of regulatory T cell–inducing human-derived Clostridia. Gut Microbes 5:333–39 [Google Scholar]
  141. Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW. 141.  et al. 2013. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340:1456–59 [Google Scholar]
  142. Obata Y, Furusawa Y, Endo TA, Sharif J, Takahashi D. 142.  et al. 2014. The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nat. Immunol. 15:571–79 [Google Scholar]
  143. Olszak T, An D, Zeissig S, Vera MP, Richter J. 143.  et al. 2012. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336:489–93 [Google Scholar]
  144. Wingender G, Stepniak D, Krebs P, Lin L, McBride S. 144.  et al. 2012. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology 143:418–28 [Google Scholar]
  145. Brown LC, Penaranda C, Kashyap PC, Williams BB, Clardy J. 145.  Wieland et al. 2013. Production of alpha-galactosylceramide by a prominent member of the human gut microbiota. PLOS Biol. 11:e1001610 [Google Scholar]
  146. An D, Oh SF, Olszak T, Neves JF, Avci FY. 146.  et al. 2014. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156:123–33 [Google Scholar]
  147. Le Bourhis L, Dusseaux M, Bohineust A, Bessoles S, Martin E. 147.  et al. 2013. MAIT cells detect and efficiently lyse bacterially-infected epithelial cells. PLOS Pathog. 9:e1003681 [Google Scholar]
  148. Brestoff JR, Artis D. 148.  2013. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol. 14:676–84 [Google Scholar]
  149. Sonnenburg JL, Chen CT, Gordon JI. 149.  2006. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLOS Biol. 4:e413 [Google Scholar]
  150. Sonnenburg ED, Zheng H, Joglekar P, Higginbottom SK, Firbank SJ. 150.  et al. 2010. Specificity of polysaccharide use in intestinal Bacteroides species determines diet-induced microbiota alterations. Cell 141:1241–52 [Google Scholar]
  151. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE. 151.  et al. 2013. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341:1241214 [Google Scholar]
  152. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE. 152.  et al. 2014. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–63 [Google Scholar]
  153. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K. 153.  et al. 2012. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150:470–80 [Google Scholar]
  154. Hall JA, Grainger JR, Spencer SP, Belkaid Y. 154.  2011. The role of retinoic acid in tolerance and immunity. Immunity 35:13–22 [Google Scholar]
  155. Hall JA, Cannons JL, Grainger JR, Dos Santos LM, Hand TW. 155.  et al. 2011. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha. Immunity 34:435–47 [Google Scholar]
  156. Spencer SP, Wilhelm C, Yang Q, Hall JA, Bouladoux N. 156.  et al. 2014. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343:432–37 [Google Scholar]
  157. Degnan PH, Barry NA, Mok KC, Taga ME, Goodman AL. 157.  2014. Human gut microbes use multiple transporters to distinguish vitamin B12 analogs and compete in the gut. Cell Host Microbe 15:47–57 [Google Scholar]
  158. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R. 158.  et al. 2014. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:128–39 [Google Scholar]
  159. Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G. 159.  et al. 2013. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–85 [Google Scholar]
  160. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E. 160.  et al. 2013. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19:576–85 [Google Scholar]
  161. Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, Turnbaugh PJ. 161.  2013. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341:295–98 [Google Scholar]
  162. Franzosa EA, Morgan XC, Segata N, Waldron L, Reyes J. 162.  et al. 2014. Relating the metatranscriptome and metagenome of the human gut. PNAS 111:E2329–38 [Google Scholar]
  163. Maurice CF, Haiser HJ, Turnbaugh PJ. 163.  2013. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152:39–50 [Google Scholar]
  164. Ursell LK, Haiser HJ, Van Treuren W, Garg N, Reddivari L. 164.  et al. 2014. The intestinal metabolome: an intersection between microbiota and host. Gastroenterology 146:1470–76 [Google Scholar]
  165. Antunes LC, Han J, Ferreira RB, Lolic P, Borchers CH, Finlay BB. 165.  2011. Effect of antibiotic treatment on the intestinal metabolome. Antimicrob. Agents Chemother. 55:1494–503 [Google Scholar]
  166. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J. 166.  et al. 2012. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488:621–26 [Google Scholar]
  167. Marcobal A, Kashyap PC, Nelson TA, Aronov PA, Donia MS. 167.  et al. 2013. A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice. ISME J. 7:1933–43 [Google Scholar]
  168. Louis P, Flint HJ. 168.  2009. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol. Lett. 294:1–8 [Google Scholar]
  169. Fukuda S, Toh H, Taylor TD, Ohno H, Hattori M. 169.  2012. Acetate-producing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters. Gut Microbes 3:449–54 [Google Scholar]
  170. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F. 170.  et al. 2009. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–86 [Google Scholar]
  171. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA. 171.  et al. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–73 [Google Scholar]
  172. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G. 172.  et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–50 [Google Scholar]
  173. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J. 173.  et al. 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–55 [Google Scholar]
  174. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H. 174.  et al. 2012. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487:104–8 [Google Scholar]
  175. Vrieze A, Out C, Fuentes S, Jonker L, Reuling I. 175.  et al. 2014. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J. Hepatol. 60:824–31 [Google Scholar]
  176. Bergstrom KS, Kissoon-Singh V, Gibson DL, Ma C, Montero M. 176.  et al. 2010. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLOS Pathog. 6:e1000902 [Google Scholar]
  177. Perez-Munoz ME, Bergstrom K, Peng V, Schmaltz R, Jimenez-Cardona R. 177.  et al. 2014. Discordance between changes in the gut microbiota and pathogenicity in a mouse model of spontaneous colitis. Gut Microbes 5:286–95 [Google Scholar]
  178. Johansson ME, Gustafsson JK, Holmen-Larsson J, Jabbar KS, Xia L. 178.  et al. 2014. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63:281–91 [Google Scholar]
  179. Mazmanian SK, Round JL, Kasper DL. 179.  2008. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–25 [Google Scholar]
  180. Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL. 180.  et al. 2007. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2:119–29 [Google Scholar]
  181. Winter SE, Thiennimitr P, Winter MG, Butler BP, Huseby DL. 181.  et al. 2010. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467:426–29 [Google Scholar]
  182. Winter SE, Winter MG, Xavier MN, Thiennimitr P, Poon V. 182.  et al. 2013. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339:708–11 [Google Scholar]
  183. Rooks MG, Veiga P, Wardwell-Scott LH, Tickle T, Segata N. 183.  et al. 2014. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J. 8:1403–17 [Google Scholar]
  184. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W. 184.  et al. 2014. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15:382–92 [Google Scholar]
  185. Zenewicz LA, Yin X, Wang G, Elinav E, Hao L. 185.  et al. 2013. IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J. Immunol. 190:5306–12 [Google Scholar]
  186. Mielke LA, Jones SA, Raverdeau M, Higgs R, Stefanska A. 186.  et al. 2013. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210:1117–24 [Google Scholar]
  187. Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK. 187.  et al. 2007. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131:33–45 [Google Scholar]
  188. Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A. 188.  et al. 2010. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8:292–300 [Google Scholar]
  189. Powell N, Walker AW, Stolarczyk E, Canavan JB, Gokmen MR. 189.  et al. 2012. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37:674–84 [Google Scholar]
  190. Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A. 190.  et al. 2013. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Investig. 123:700–11 [Google Scholar]
  191. Li XD, Chiu YH, Ismail AS, Behrendt CL, Wight-Carter M. 191.  et al. 2011. Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. PNAS 108:17390–95 [Google Scholar]
  192. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P. 192.  et al. 2013. Gender bias in autoimmunity is influenced by microbiota. Immunity 39:400–12 [Google Scholar]
  193. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM. 193.  et al. 2013. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–88 [Google Scholar]
  194. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L. 194.  et al. 2008. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455:1109–13 [Google Scholar]
  195. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C. 195.  et al. 2013. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS 110:9066–71 [Google Scholar]
  196. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C. 196.  et al. 2013. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2:e01202 [Google Scholar]
  197. Karlsson FH, Fak F, Nookaew I, Tremaroli V, Fagerberg B. 197.  et al. 2012. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat. Commun. 3:1245 [Google Scholar]
  198. Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R. 198.  et al. 2012. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209:903–11 [Google Scholar]
  199. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T. 199.  et al. 2010. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–27 [Google Scholar]
  200. Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. 200.  2011. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. PNAS 108:Suppl. 14615–22 [Google Scholar]
  201. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER. 201.  et al. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–63 [Google Scholar]
  202. Rakoff-Nahoum S, Medzhitov R. 202.  2009. Toll-like receptors and cancer. Nat. Rev. Cancer 9:57–63 [Google Scholar]
  203. Sears CL, Garrett WS. 203.  2014. Microbes, microbiota, and colon cancer. Cell Host Microbe 15:317–28 [Google Scholar]
  204. Gagliani N, Hu B, Huber S, Elinav E, Flavell RA. 204.  2014. The fire within: Microbes inflame tumors. Cell 157:776–83 [Google Scholar]
  205. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA. 205.  et al. 2013. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14:207–15 [Google Scholar]
  206. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. 206.  2013. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14:195–206 [Google Scholar]
  207. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X. 207.  et al. 2009. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15:1016–22 [Google Scholar]
  208. Hu B, Elinav E, Huber S, Booth CJ, Strowig T. 208.  et al. 2010. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. PNAS 107:21635–40 [Google Scholar]
  209. Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK. 209.  et al. 2010. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207:1045–56 [Google Scholar]
  210. Wang Y, Wang K, Han GC, Wang RX, Xiao H. 210.  et al. 2014. Neutrophil infiltration favors colitis-associated tumorigenesis by activating the interleukin-1 (IL-1)/IL-6 axis. Mucosal Immunol. 7:1106–15 [Google Scholar]
  211. Arthur JC, Perez-Chanona E, Muhlbauer M, Tomkovich S, Uronis JM. 211.  et al. 2012. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–23 [Google Scholar]
  212. Chen GY, Liu M, Wang F, Bertin J, Nunez G. 212.  2011. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J. Immunol. 186:7187–94 [Google Scholar]
  213. Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T. 213.  et al. 2011. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. PNAS 108:9601–6 [Google Scholar]
  214. Hu B, Elinav E, Huber S, Strowig T, Hao L. 214.  et al. 2013. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. PNAS 110:9862–67 [Google Scholar]
  215. Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B. 215.  et al. 2012. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254–58 [Google Scholar]
  216. Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L. 216.  et al. 2012. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491:259–63 [Google Scholar]
  217. Kirchberger S, Royston DJ, Boulard O, Thornton E, Franchini F. 217.  et al. 2013. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210:917–31 [Google Scholar]
  218. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S. 218.  et al. 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101 [Google Scholar]
  219. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N. 219.  et al. 2013. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:967–70 [Google Scholar]
  220. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R. 220.  et al. 2013. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971–76 [Google Scholar]
  221. Bohnhoff M, Drake BL, Miller CP. 221.  1954. Effect of streptomycin on susceptibility of intestinal tract to experimental Salmonella infection. Proc. Soc. Exp. Biol. Med. 86:132–37 [Google Scholar]
  222. Bohnhoff M, Miller CP. 222.  1962. Enhanced susceptibility to Salmonella infection in streptomycin-treated mice. J. Infect. Dis. 111:117–27 [Google Scholar]
  223. Freter R. 223.  1955. The fatal enteric cholera infection in the guinea pig, achieved by inhibition of normal enteric flora. J. Infect. Dis. 97:57–65 [Google Scholar]
  224. Freter R. 224.  1962. In vivo and in vitro antagonism of intestinal bacteria against Shigella flexneri. II. The inhibitory mechanism. J. Infect. Dis. 110:38–46 [Google Scholar]
  225. Stecher B, Hardt WD. 225.  2011. Mechanisms controlling pathogen colonization of the gut. Curr. Opin. Microbiol. 14:82–91 [Google Scholar]
  226. Kamada N, Chen GY, Inohara N, Nunez G. 226.  2013. Control of pathogens and pathobionts by the gut microbiota. Nat. Immunol. 14:685–90 [Google Scholar]
  227. Buffie CG, Pamer EG. 227.  2013. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13:790–801 [Google Scholar]
  228. Dethlefsen L, Huse S, Sogin ML, Relman DA. 228.  2008. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLOS Biol. 6:e280 [Google Scholar]
  229. Antunes LC, Finlay BB. 229.  2011. A comparative analysis of the effect of antibiotic treatment and enteric infection on intestinal homeostasis. Gut Microbes 2:105–8 [Google Scholar]
  230. Ubeda C, Taur Y, Jenq RR, Equinda MJ, Son T. 230.  et al. 2010. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J. Clin. Investig. 120:4332–41 [Google Scholar]
  231. Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A. 231.  et al. 2012. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile–induced colitis. Infect. Immun. 80:62–73 [Google Scholar]
  232. Bohnhoff M, Miller CP, Martin WR. 232.  1964. Resistance of the mouse's intestinal tract to experimental Salmonella infection. I. Factors which interfere with the initiation of infection by oral inoculation. J. Exp. Med. 120:805–16 [Google Scholar]
  233. Ferreira RB, Gill N, Willing BP, Antunes LC, Russell SL. 233.  et al. 2011. The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization. PLOS ONE 6:e20338 [Google Scholar]
  234. Wlodarska M, Willing B, Keeney KM, Menendez A, Bergstrom KS. 234.  et al. 2011. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium–induced colitis. Infect. Immun. 79:1536–45 [Google Scholar]
  235. Endt K, Stecher B, Chaffron S, Slack E, Tchitchek N. 235.  et al. 2010. The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea. PLOS Pathog. 6:e1001097 [Google Scholar]
  236. Ubeda C, Bucci V, Caballero S, Djukovic A, Toussaint NC. 236.  et al. 2013. Intestinal microbiota containing Barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect. Immun. 81:965–73 [Google Scholar]
  237. Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J. 237.  et al. 2012. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis. 55:905–14 [Google Scholar]
  238. Rupnik M, Wilcox MH, Gerding DN. 238.  2009. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat. Rev. Microbiol. 7:526–36 [Google Scholar]
  239. Lawley TD, Clare S, Walker AW, Goulding D, Stabler RA. 239.  et al. 2009. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 77:3661–69 [Google Scholar]
  240. Jarchum I, Liu M, Shi C, Equinda M, Pamer EG. 240.  2012. Critical role for MyD88-mediated neutrophil recruitment during Clostridium difficile colitis. Infect. Immun. 80:2989–96 [Google Scholar]
  241. Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM. 241.  et al. 2014. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat. Commun. 5:3114 [Google Scholar]
  242. Theriot CM, Young VB. 242.  2014. Microbial and metabolic interactions between the gastrointestinal tract and Clostridium difficile infection. Gut Microbes 5:86–95 [Google Scholar]
  243. Schubert AM, Rogers MA, Ring C, Mogle J, Petrosino JP. 243.  et al. 2014. Microbiome data distinguish patients with Clostridium difficile infection and non-C. difficile-associated diarrhea from healthy controls. MBio 5:e01021–14 [Google Scholar]
  244. van Nood E, Dijkgraaf MG, Keller JJ. 244.  2013. Duodenal infusion of feces for recurrent Clostridium difficile. N. Engl. J. Med. 368:2145 [Google Scholar]
  245. Pamer EG. 245.  2014. Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns. Mucosal Immunol. 7:210–14 [Google Scholar]
  246. Tvede M, Rask-Madsen J. 246.  1989. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1:1156–60 [Google Scholar]
  247. Emanuelsson F, Claesson BE, Ljungstrom L, Tvede M, Ung KA. 247.  2013. Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand. J. Infect. Dis. 46:89–97 [Google Scholar]
  248. Lawley TD, Clare S, Walker AW, Stares MD, Connor TR. 248.  et al. 2012. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLOS Pathog. 8:e1002995 [Google Scholar]

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