The effects of the microbiota on the host immune system

Autoimmunity

Volumn 47, Issue 8, 2014, Pages 494-504

  Karczewski, Jacek ^a   Poniedziałek, Barbara ^a   Adamski, Zygmunt ^a   Rzymski, Piotr ^a  

^a POZNAN UNIVERSITY OF MEDICAL SCIENCES   (Poland)

Author keywords

Autoimmune disease; Dysbiosis; Immune system; Inflammatory disease; Microbiota

Indexed keywords

AUTOIMMUNE DISEASE; B LYMPHOCYTE; CARBOHYDRATE DIET; CD4+ T LYMPHOCYTE; CELL FUNCTION; DYSBIOSIS; GAMMA DELTA T LYMPHOCYTE; HOST PATHOGEN INTERACTION; HUMAN; IMMUNE SYSTEM; IMMUNOLOGICAL TOLERANCE; INFLAMMATORY DISEASE; INNATE IMMUNITY; INTESTINE EPITHELIUM CELL; INTESTINE FLORA; MUCOSAL IMMUNITY; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; SHIGELLA FLEXNERI; TH17 CELL; ANIMAL; GASTROINTESTINAL TRACT; IMMUNOLOGY; INFLAMMATION; MICROBIOLOGY; MICROFLORA; SIGNAL TRANSDUCTION;

ANIMALS; AUTOIMMUNE DISEASES; GASTROINTESTINAL TRACT; HOST-PATHOGEN INTERACTIONS; HUMANS; INFLAMMATION; MICROBIOTA; SIGNAL TRANSDUCTION;

EID: 84912067103     PISSN: 08916934     EISSN: 1607842X     Source Type: Journal    
DOI: 10.3109/08916934.2014.938322     Document Type: Review

References (176)

1. Ley, R. E., D. A. Peterson, and J. I. Gordon. 2006. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124: 837-848
2. Hooper, L. V., T. Midtvedt, and J. I. Gordon. 2002. How hostmicrobial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr. 22: 283-307
3. Bäckhed, F., R. E. Ley, J. L. Sonnenburg, et al. 2005. Host-bacterial mutualism in the human intestine. Science 307: 1915-1920
4. Berg, R. D. 1996. The indigenous gastrointestinal microflora. Trends Microbiol. 4: 430-435
5. Eckburg, P. B., E. M. Bik, C. N. Bernstein, et al. 2005. Diversity of the human intestinal microbial flora. Science 308: 1635-1638
6. Friswell, M. K., H. Gika, I. J. Stratford, et al. 2010. Site and strainspecific variation in gut microbiota profiles and metabolism in experimental mice. PLoS One 5: e8584
7. Qin, J., R. Li, J. Raes, et al. 2010. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464: 59-65
8. Artis, D. 2008. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol. 8: 411-420
9. Bäckhed, F., H. Ding, T. Wang, et al. 2004. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 101: 15718-15723
10. Stappenbeck, T. S., L. V. Hooper, and J. I. Gordon. 2002. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl. Acad. Sci. USA 99: 15451-15455
11. Sekirov, I., N. M. Tam, M. Jogova, et al. 2008. Antibiotic-induced perturbations of the intestinal microbiota alter host susceptibility to enteric infection. Infect. Immun. 76: 4726-4736
12. Cebra, J. J. 1999. Influences of microbiota on intestinal immune system development. Am. J. Clin. Nutr. 69: 1046S-1051S
13. Spor, A., O. Koren, and R. Ley. 2011. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat. Rev. Microbiol. 9: 279-290
14. Hill, D. A., and D. Artis. 2010. Intestinal bacteria and the regulation of immune cell homeostasis. Ann. Rev. Immunol. 28: 623-667
15. Melgar, S., and F. Shanahan. 2010. Inflammatory bowel disease-from mechanisms to treatment strategies. Autoimmunity 43: 463-477
16. Sellitto, M., G. Bai, G. Serena, et al. 2012. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS One 7: e33387
17. Scher, J. U., and S. B. Abramson. 2011. The microbiome and rheumatoid arthritis. Nat. Rev. Rheumatol. 7: 569-578
18. Wen, L., R. E. Ley, P. Y. Volchkov, et al. 2008. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455: 1109-1113
19. Ochoa-Repáraz, J., D. W. Mielcarz, S. Begum-Haque, and L. H. Kasper. 2011. Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann. Neurol. 69: 240-247
20. Hong, P. Y., B. W. Lee, M. Aw, et al. 2009. Comparative analysis of fecal microbiota in infants with and without eczema. PLoS One 98: 1582-1588
21. Turnbaugh, P. J., R. E. Ley, M. A. Mahowald, et al. 2006. An obesity-Associated gut microbiome with increased capacity for energy harvest. Nature 444: 1027-1031
22. Vijay-Kumar, M., J. D. Aitken, F. A. Carvalho, et al. 2010. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328: 228-231
23. Wang, Z., E. Klipfell, B. J. Bennett, et al. 2011. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57-63
24. Moore, W. E., and L. H. Moore. 1995. Intestinal floras of populations that have a high risk of colon cancer. Appl. Environ. Microbiol. 61: 3202-3207
25. Round, J. L., and S. K. Mazmanian. 2009. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9: 313-323
26. Honda, K., and D. R. Littman. 2013. The microbiome in infectious disease and inflammation. Ann. Rev. Immunol. 30: 759-795
27. Macpherson, A. J., and N. L. Harris. 2004. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4: 478-485
28. Abrams, G. D., H. Bauer, and H. Sprinz. 1963. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Investig. 12: 355-364
29. Maier, B. R., and D. J. Hentges. 1972. Experimental Shigella infections in laboratory animals. I. Antagonism by human normal flora components in gnotobiotic mice. Infect. Immun. 6: 168-173
30. Kamada, N., G. Y. Chen, N. Inohara, and G. Núntez. 2013. Control of pathogens and pathobionts by the gut microbiota. Nat. Immunol. 14: 685-690
31. Di Giacinto, C., M. Marinaro, M. Sanchez, et al. 2005. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J. Immunol. 17: 3237-3246
32. Snsonetti, P. J. 2004. War and peace at mucosal surfaces. Nat. Rev. Immunol. 4: 953-964
33. Rakoff-Nahoum, S., J. Paglino, F. Eslami-Varzaneh, et al. 2004. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118: 229-241
34. Peterson, D. A., N. P. McNulty, J. L. Guruge, and J. I. Gordon. 2007. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2: 328-339
35. Medzhitov, R. 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1: 135-145
36. Takeuchi, O., and S. Akira. 2010. Pattern recognition receptors and inflammation. Cell 140: 805-820
37. von Bernuth, H., C. Picard, Z. Jin, et al. 2008. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691-696
38. Rakoff-Nahoum, S., J. Paglino, F. Eslami-Varzaneh, et al. 2004. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118: 229-241
39. Araki, A., T. Kanai, T. Ishikura, et al. 2005. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J. Gastroenterol. 40: 16-23
40. Cario, E., G. Gerken, and D. K. Podolsky. 2007. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132: 1359-1374
41. Deretic, V., and B. Levine. 2009. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5: 527-549
42. Vijay-Kumar, M., J. D. Aitken, F. A. Carvalho, et al. 2010. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328: 228-231
43. Vijay-Kumar, M., C. J. Sanders, R. T. Taylor, et al. 2007. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Investig. 117: 3909-3921
44. Carvalho, F. A., O. Koren, J. K. Goodrich, et al. 2012. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12: 139-152
45. Kellermayer, R., S. E. Dowd, R. A. Harris, et al. 2011. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice. FASEB J. 25: 1449-1460
46. de Kivit, S., M. C. Tobin, C. B. Forsyth, et al. 2014. Regulation of intestinal immune responses through TLR activation: implications for pro-And prebiotics. Front. Immunol. 5: 60
47. Turner, J. R. 2009. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9: 799-809
48. Clayburgh, D. R., M. W. Musch, M. Leitges, et al. 2006. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. J. Clin. Investig. 116: 2682-2694
49. Anwar, M. A., S. Basith, and S. Choi. 2013. Negative regulatory approaches to the attenuation of Toll-like receptor signaling. Exp. Mol. Med. 45: e11
50. Huang, B., X. D. Yang, A. Lamb, and L. F. Chen. 2010. Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway. Cell Signal. 22: 1282-1290
51. Kawai, T., Akira, S. 2007. TLR signaling. Semin. Immunol. 19: 24-32
52. Harhaj, E. W., and V. M. Dixit. 2011. Deubiquitinases in the regulation of NF-kB signaling. Cell Res. 21: 22-39
53. Wang, Z., C. S. Potter, J. P. Sundberg, and H. Hogenesch. 2012. SHARPIN is a key regulator of immune and inflammatory responses. J. Cell. Mol. Med. 16: 2271-2279
54. Kondo, T., T. Kawai, and S. Akira. 2012. Dissecting negative regulation of Toll-like receptor signaling. Trends Immunol. 33: 449-458
55. Jiang, X., and Z. J. Chen. 2011. The role of ubiquitylation in immune defence and pathogen evasion. Nat. Rev. Immunol. 12: 35-48
56. Ma, A., and B. A. Malynn. 2012. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat. Rev. Immunol. 12: 774-785
57. Turer, E. E., R. M. Tavares, E. Mortier, et al. 2008. Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20. J. Exp. Med. 205: 451-464
58. Nenci, A., C. Becker, A. Wullaert, et al. 2007. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446: 557-561
59. Welz, P. S., A. Wullaert, K. Vlantis, et al. 2011. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477: 330-334
60. Franchi, L., J. H. Park, M. H. Shaw, et al. 2008. Intracellular NOD-like receptors in innate immunity, infection and disease. Cell. Microbiol. 10: 1-8
61. Inohara, N., M. Chamaillard, C. McDonald, and Z. G. Nunte. 2005. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Ann. Rev. Biochem. 74: 355-383
62. Kobayashi, K. S., M. Chamaillard, Y. Ogura, et al. 2005. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307: 731-734
63. Petnicki-Ocwieja, T., T. Hrncir, Y. J. Liu, et al. 2009. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl. Acad. Sci. USA 106: 15813-15818
64. Bouskra, D., C. Brézillon, M. Bérard, et al. 2008. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456: 507-510
65. Ogura, Y., D. K. Bonen, N. Inohara, et al. 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohns disease. Nature 411: 603-606
66. McGovern, D., D. A. Van Heel, T. Ahmad, and D. P. Jewell. 2001. NOD2 (CARD15), the first susceptibility gene for Crohns disease. Gut 49: 752-754
67. Fagarasan, S., M. Muramatsu, K. Suzuki, et al. 2002. Critical roles of activationinduced cytidine deaminase in the homeostasis of gut flora. Science 298: 1424-1427
68. Cerutti, A. 2008. The regulation of IgA class switching. Nat. Rev. Immunol. 8: 421-434
69. Tsuji, M., K. Suzuki, H. Kitamura, et al. 2008. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29: 261-271
70. Hansson, J., Bosco, N., Favre, L., et al. 2011. Influence of gut microbiota on mouse B2 B cell ontogeny and function. Mol. Immunol. 48: 1091-1101
71. Tezuka, H., Y. Abe, M. Iwata, et al. 2007. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448: 929-933
72. Jacobs, J. P., and J. Braun. 2014. Immune and genetic gardening of the intestinal microbiome. FEBS Lett. DOI: 10.1016/j.febslet. 2014.02.052. [Epub ahead of print]
73. Ivanov, I. I., L. Frutos Rde, N. Manel, et al. 2008. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4: 337-349
74. Weaver, C. T., R. D. Hatton, P. R. Mangan, and L. E. Harrington. 2007. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Ann. Rev. Immunol. 25: 821-852
75. Maloy, K. J., and M. C. Kullberg. 2008. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 1: 339-349
76. Mitsdoerffer, M., Y. Lee, A. Jäger, et al. 2010. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc. Natl. Acad. Sci. USA 107: 14292-14297
77. Klatt, N. R., N. T. Funderburg, and J. M. Brenchley. 2013. Microbial translocation, immune activation, and HIV disease. Trends Microbiol. 21: 6-13
78. Witkowski, J., K. Ksiazek, and A. Jorres. 2004. Interleukin-17: a mediator of inflammatory responses. Cell. Mol. Life Sci. 61: 567-579
79. Abraham, C., and J. Cho. 2009. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm. Bowel Dis. 15: 1090-1100
80. Hueber, W., B. E. Sands, and S. Lewitzky, et al. 2012. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohns disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61: 1693-1700
81. Ivanov, I. I., K. Atarashi, N. Manel, et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139: 485-498
82. Wu, S., K. J. Rhee, E. Albesiano, et al. 2009. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15: 1016-1022
83. Sakaguchi, S., T. Yamaguchi, T. Nomura, and M. Ono. 2008. Regulatory T cells and immune tolerance. Cell 133: 775-787
84. Maynard, C. L., L. E. Harrington, K. M. Janowski, et al. 2007. Regulatory T cells expressing interleukin 10 develop from Foxp3+and Foxp3- precursor cells in the absence of interleukin 10. Nat. Immunol. 8: 931-941
85. Sakaguchi, S., M. Miyara, C. M. Costantino, and D. A. Hafler. 2010. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10: 490-500
86. Atarashi, K., T. Tanoue, T. Shima, et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337-341
87. Coombes, J. L., K. R. Siddiqui, C. V. Arancibia-Cárcamo, 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: 1757-1764
88. Klebanoff, C. A., S. P. Spencer, P. Torabi-Parizi, et al. 2013. Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells. J. Exp. Med. 210: 1961-1976
89. Yen, D., J. Cheung, H. Scheerens, et al. 2006. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116: 1310-1316
90. Kühn, R., J. Löhler, D. Rennick, et al. 1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263-274
91. Sellon, R. K., S. Tonkonogy, M. Schultz, et al. 1998. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66: 5224-5231
92. Di Giacinto, C., M. Marinaro, M. Sanchez, et al. 2005. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J. Immunol. 174: 3237-3246
93. Livingston, M., D. Loach, M. Wilson, et al. 2010. Gut commensal Lactobacillus reuteri 100-23 stimulates an immunoregulatory response. Immunol. Cell Biol. 88: 99-102
94. Lathrop, S. K., S. M. Bloom, S. M. Rao, et al. 2011. Peripheral education of the immune system by colonic commensal microbiota. Nature 478: 250-254
95. Cebula, A., M. Seweryn, G. A. Rempala, et al. 2013. Thymusderived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497: 258-262
96. Piccirillo, C. A., E. dHennezel, E. Sgouroudis, and E. Yurchenko. 2008. CD4+Foxp3+ regulatory T cells in the control of autoimmunity: in vivo veritas. Curr. Opin. Immunol. 20: 655-662
97. Sokol, H., B. Pigneur, L. Watterlot, et al. 2008. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA 105: 16731-16736
98. Mazmanian, S. K., J. L. Round, and D. L. Kasper. 2008. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453: 620-625
99. Round, J. L., S. K. Mazmanian. 2010. Inducible Foxp3+regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl. Acad. Sci. USA 107: 12204-11209
100. Atarashi, K., T. Tanoue, K. Oshima, et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500: 232-236
101. Louis, P., S. H. Duncan, S. I. McCrae, et al. 2004. Restricted distribution of the butyrate kinase pathway among butyrateproducing bacteria from the human colon. J. Bacteriol. 186: 2099-2106
102. Macho Fernandez, E., V. Valenti, C. Rockel, et al. 2011. Antiinflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptid. Gut 60: 1050-1059
103. Cepek, K. L., S. K. Shaw, C. M. Parker, et al. 1994. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372: 190-193
104. van Wijk, F., and H. Cheroutre. 2009. Intestinal T cells: facing the mucosal immune dilemma with synergy and diversity. Semmin. Immunol. 21: 130-138
105. Das, G., M. M. Augustine, J. Das, et al. 2003. An important regulatory role for CD4+CD8 alpha alpha T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc. Natl. Acad. Sci. USA 100: 5324-5329
106. Ismail, A. S., K. M. Severson, S. Vaishnava, et al. 2011. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl. Acad. Sci. USA 108: 8743-8748
107. Martin, B., K. Hirota, D. J. Cua, et al. 2009. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31: 321-330
108. Sutton, C. E., S. J. Lalor, C. M. Sweeney, et al. 2009. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31: 331-341
109. Petermann, F., V. Rothhammer, M. C. Claussen, et al. 2010. gd T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity 33: 351-363
110. Spits, H., and J. P. Di Santo. 2011. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12: 21-27
111. Spits, H., D. Artis, M. Colonna, et al. 2013. Innate lymphoid cells-A proposal for uniform nomenclature. Nat. Rev. Immunol. 13: 145-149
112. Macia, L., A. N. Thorburn, L. C. Binge, et al. 2012. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245: 164-176
113. Kosiewicz, M. M., A. L. Zirnheld, and P. Alard. 2011. Gut microbiota, immunity and disease: a complex relationship. Front. Microbiol. 2: 180
114. Myasoedova, E., C. S. Crowson, H. M. Kremers, et al. 2010. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 62: 1576-1582
115. Koch-Henriksen, N., and P. S. Sørensen. 2010. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 9: 520-532
116. Noverr, M C., and G. B. Huffnagle. 2004. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 12: 562-568
117. Maslowski, K. M., and C. R. Mackay. 2011. Diet, gut microbiota and immune responses. Nature Immunol. 12: 5-9
118. Oh, D. Y., S. Talukdar, E. J. Bae, et al. 2010. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142: 687-698
119. Turnbaugh, P. J., V. K. Ridaura, J. J. Faith, et al. 2009. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Translat. Med. 1: 6-14
120. Wu, G. D., J. Chen, C. Hoffmann, et al. 2011. Linking long-Term dietary patterns with gut microbial enterotypes. Science 334: 105-108
121. De Filippo, C., D. Cavalieri, M. Di Paola, et al. 2010. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl. Acad. Sci. U. S. A. 107: 14691-14696
122. Cummings, J. H., E. W. Pomare, W. J. Branch, et al. 1987. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28: 1221-1227
123. Arpaia, N., C. Campbell, X. Fan, et al. 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504: 451-455
124. Furusawa, Y., Y. Obata, S. Fukuda, et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504: 446-450
125. Davie, J. 2003. Inhibition of histone deacetylase activity by butyrate. J. Nutr. 133: 2485S-2493S
126. Maslowski, K. M., A. T. Vieira, A. Ng, et al. 2009. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282-1286
127. Huda-Faujan, N., A. S. Abdulamir, A. B. Fatimah, et al. 2010. The impact of the level of the intestinal short chain Fatty acids in inflammatory bowel disease patients versus healthy subjects. Open Biochem. J. 4: 53-58
128. Frank, D. N., A. L. St Amand, R. A. Feldman, et al. 2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. USA 104: 13780-13785
129. Venkatraman, A., B. S. Ramakrishna, A. B. Pulimood, et al. 2000. Increased permeability in dextran sulphate colitis in rats: time course of development and effect of butyrate. Scand. J. Gastroenterol. 35: 1053-1059
130. Fung, I., J. P. Garrett, A. Shahane, and M. Kwan. 2012. Do bugs control our fate? The influence of the microbiome on autoimmunity. Curr. Aller. Asthma Rep. 12: 511-519
131. Pérez-Cobas, A. E., M. J. Gosalbes, A. Friedrichs, et al. 2013. Gut microbiota disturbance during antibiotic therapy: a multiomic approach. Gut 62: 1591-1601
132. Blaser, M. 2011. Antibiotic overuse: stop the killing of beneficial bacteria. Nature 476: 393-394
133. De La Cochetière, M. F., T. Durand, P. Lepage, et al. 2005. Resilience of the dominant human fecal microbiota upon shortcourse antibiotic challenge. J. Clin. Microbiol. 43: 5588-5592
134. Ichinohe, T., I. K. Pang, Y. Kumamoto, et al. 2011. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl. Acad. Sci. USA 108: 5354-5359
135. Abt, M. C., L. C. Osborne, L. A. Monticelli, et al. 2012. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37: 158-170
136. Hwang, J. S., C. R. Im, and S. H. Im. 2012. Immune disorders and its correlation with gut microbiome. Immune Netw. 12: 129-138
137. Romagnani, S 2004. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 112: 352-363
138. Belkaid, Y., and S. Naik. 2013. Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 14: 646-653
139. Dominguez-Bello, M. G., E. K. Costello, M. Contreras, et al. 2010. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl. Acad. Sci. USA 107: 11971-11975
140. Bager, P., J. Wohlfahrt, and T. Westergaard. 2008. Caesarean delivery and risk of atopy and allergic disease: meta-Analyses. Clin. Exp. Allergy 38: 634-642
141. Spor, A., O. Koren, R. and Ley. 2011. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat. Rev. Microbiol. 9: 279-290
142. Dicksved, J., J. Halfvarson, M. Rosenquist, et al. 2008. Molecular analysis of the gut microbiota of identical twins with Crohns disease. ISME J. 2: 716-727
143. Gophna, U., K. Sommerfeld, S. Gophna, et al. 2006. Differences between tissue-Associated intestinal microfloras of patients with Crohs disease and ulcerative colitis. J. Clin. Microbiol. 44: 4136-4141
144. Giongo, A., K. A. Gano, D. B. Crabb, et al. 2011. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5: 82-91
145. Murri, M., I. Leiva, J. M. Gomez-Zumaquero, et al. 2013. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 11: 46
146. Qin, J., Y. Li, Z. Cai, et al. 2012. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490: 55-60
147. Karlsson, F. H., V. Tremaroli, I. Nookaew, et al. 2013. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498: 99-103
148. Ley, R. E., F. Bäckhed, P. Turnbaugh, et al. 2005. Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. USA 102: 11070-11075
149. Pflughoeft, K. J., and J. Versalovic. 2012. Human microbiome in health and disease. Ann. Rev. Pathol. 7: 99-122
150. Turnbaugh, P. J., M. Hamady, T. Yatsunenko, et al. 2009. A core gut microbiome in obese and lean twins. Nature 457: 480-484
151. Armougom, F., M. Henry, B. Vialettes, et al. 2009. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLoS One 4: e7125
152. Nadal, I., E. Donat, C. Ribes-Koninckx, et al. 2007. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J. Med. Microbiol. 56: 1669-1674
153. Collado, M. C., M. Calabuig, and Y. Sanz. 2007. Differences between the fecal microbiota of coeliac infants and healthy controls. Curr. Issues Intest. Microbiol. 8: 9-14
154. Wroblewski, L. E., R. M. Peek, and K. T. Wilson. 2010. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin. Microbiol. Rev. 23: 713-739
155. Kostic, A. D., D. Gevers, C. S. Pedamallu, et al. 2012. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22: 292-298
156. Koziel, J., P. Mydel, and J. Potempa. 2014. The link between periodontal disease and rheumatoid arthritis: an updated review. Curr. Rheumatol. Rep. 16: 408
157. Vaahtovuo, J., E. Munukka, M. Korkeamäki, et al. 2008. Fecal microbiota in early rheumatoid arthritis. J. Rheumatol. 35: 1500-1505
158. Sekirov, I., S. L. Russell, L. C. Antunes, and B. B. Finlay. 2010. Gut microbiota in health and disease. Physiol. Rev. 90: 859-904
159. Kang, D. W., J. G. Park, Z. E. Ilhan, et al. 2013. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 8: e68322
160. Finegold, S. M., S. E. Dowd, V. Gontcharova, et al. 2010. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16: 444-453
161. Hörmannsperger, G., T. Clavel, and D. Haller. 2012. Gut matters: microbe-host interactions in allergic diseases. J. Aller. Clin. Immunol. 129: 1452-1459
162. Lu, Y. C., W. C. Yeh, and P. S. Ohashi. 2008. LPS/TLR4 signal transduction pathway. Cytokine 42: 145-151
163. Kamdar, K., V. Nguyen, and R. W. DePaolo. 2013. Toll-like receptor signaling and regulation of intestinal immunity. Virulence 4: 207-212
164. González-Navajas, J. M., S. Fine, J. Law, et al. 2010. TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice. J. Clin. Invest. 120: 570-581
165. Round, J. L., S. M. Lee, J. Li, et al. 2011. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332: 974-977
166. Gewirtz, A. T., T. A. Navas, S. Lyons, et al. 2001. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167: 1882-1885
167. Crellin, N. K., R. V. Garcia, O. Hadisfar, et al. 2005. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J. Immunol. 175: 8051-8059
168. Hisamatsu, T., Suzuki, M., Reinecker, H.C., et al. 2003. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology 124: 993-1000
169. Vignal, C., E Singer, L. Peyrin-Biroulet, et al. 2007. How NOD2 mutations predispose to Crohns disease? Microbes Infect. 9: 658-663
170. Hedl, M., and C. Abraham. 2011. Distinct roles for Nod2 protein and autocrine interleukin-1beta in muramyl dipeptideinduced mitogen-Activated protein kinase activation and cytokine secretion in human macrophages. J. Biol. Chem. 286: 26440-26449
171. Singh, N., A. Gurav, S. Sivaprakasam, et al. 2014. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40: 128-139
172. Hamer, H. M., D. Jonkers, K. Venema, et al. 2008. Review pages: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27: 104-119
173. Konstantinov, S. R., H. Smidt, W. M. de Vos, et al. 2008. S layer protein A of Lactobacillus acidophilus NCFM regulates immature dendritic cell and T cell functions. Proc. Natl. Acad. Sci. USA 105: 19474-19479
174. den Dunnen, J., S. I. Gringhuis, and T. B. Geijtenbeek. 2009. Innate signaling by the C-Type lectin DC-SIGN dictates immune responses. Cancer Immunol. Immunother. 58: 1149-1157
175. Zarek, P. E., C. T. Huang, E. R. Lutz, et al. 2008. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111: 251-259
176. Wilson, J. M., C. C. Kurtz, S. G. Black, et al. 2011. The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6. J. Immunol. 186: 6746-6752