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Signals from the gut microbiota to distant organs in physiology and disease

Abstract

The ecosystem of the human gut consists of trillions of bacteria forming a bioreactor that is fueled by dietary macronutrients to produce bioactive compounds. These microbiota-derived metabolites signal to distant organs in the body, which enables the gut bacteria to connect to the immune and hormone system, to the brain (the gut–brain axis) and to host metabolism, as well as other functions of the host. This microbe–host communication is essential to maintain vital functions of the healthy host. Recently, however, the gut microbiota has been associated with a number of diseases, ranging from obesity and inflammatory diseases to behavioral and physiological abnormalities associated with neurodevelopmental disorders. In this Review, we will discuss microbiota–host cross-talk and intestinal microbiome signaling to extraintestinal organs. We will review mechanisms of how this communication might contribute to host physiology and discuss how misconfigured signaling might contribute to different diseases.

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Figure 1: Gut microbiota convert environmental signals and dietary molecules into signaling metabolites to communicate with the host.
Figure 2: The gut microbiota communicates with host adipose tissue.
Figure 3: The gut microbiota is associated with various diseases in humans.
Figure 4: The gut microbiota communicates with the brain through the gut–brain axis.

References

  1. Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Zoetendal, E.G., Akkermans, A.D. & De Vos, W.M. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Appl. Environ. Microbiol. 64, 3854–3859 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Eckburg, P.B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hold, G.L., Pryde, S.E., Russell, V.J., Furrie, E. & Flint, H.J. Assessment of microbial diversity in human colonic samples by 16S rDNA sequence analysis. FEMS Microbiol. Ecol. 39, 33–39 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  7. Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Tamburini, S., Shen, N., Wu, H.C. & Clemente, J.C. The microbiome in early life: implications for health outcomes. Nat. Med. 22, 713–722 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Knights, D. et al. Rethinking “enterotypes”. Cell Host Microbe. 16, 433–437 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 22, 971–982 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Kommineni, S. et al. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526, 719–722 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pédron, T. et al. A crypt-specific core microbiota resides in the mouse colon. MBio 3, e00116–e00112 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kaiko, G.E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Haag, L.-M. & Siegmund, B. Intestinal microbiota and the innate immune system—a crosstalk in Crohn's disease pathogenesis. Front. Immunol. 6, 489 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Honda, K. & Littman, D.R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Thaiss, C.A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Cani, P.D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Hersoug, L.-G., Møller, P. & Loft, S. Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obes. Rev. 17, 297–312 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Ghoshal, S., Witta, J., Zhong, J., de Villiers, W. & Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50, 90–97 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Bäckhed, F., Normark, S., Schweda, E.K.H., Oscarson, S. & Richter-Dahlfors, A. Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications. Microbes Infect. 5, 1057–1063 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Vatanen, T. et al. Variation in microbiome LPS mmunogenicity Contributes to Autoimmunity in Humans. Cell 165, 842–853 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Larsson, E. et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut. 61, 1124–1131 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–1593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kashyap, P.C. et al. Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice. Gastroenterology 144, 967–977 (2013).

    Article  PubMed  Google Scholar 

  29. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bergman, E.N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 70, 567–590 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 101, 15718–15723 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bäckhed, F., Manchester, J.K., Semenkovich, C.F. & Gordon, J.I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. USA 104, 979–984 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Samuel, B.S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. USA 105, 16767–16772 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tolhurst, G. et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364–371 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fava, S. Glucagon-like peptide 1 and the cardiovascular system. Curr. Diabetes Rev. 10, 302–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Nøhr, M.K. et al. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154, 3552–3564 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. De Vadder, F. et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156, 84–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Perry, R.J. et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kimura, I. et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Midtvedt, T. Microbial bile acid transformation. Am. J. Clin. Nutr. 27, 1341–1347 (1974).

    Article  CAS  PubMed  Google Scholar 

  43. Swann, J.R. et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc. Natl. Acad. Sci. USA 108 (Suppl. 1), 4523–4530 (2011).

    Article  PubMed  Google Scholar 

  44. Sayin, S.I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Islam, K.B.M.S. et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 141, 1773–1781 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Kurdi, P., Kawanishi, K., Mizutani, K. & Yokota, A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J. Bacteriol. 188, 1979–1986 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Parséus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut. http://dx.doi.org/10.1136/gutjnl-2015-310283 (2016).

  50. Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Broeders, E.P.M. et al. The bile acid chenodeoxycholic acid increases human brown adipose tissue Activity. Cell Metab. 22, 418–426 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Ryan, K.K. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tremaroli, V. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 22, 228–238 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schauer, P.R. et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N. Engl. J. Med. 370, 2002–2013 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. McGavigan, A.K. et al. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut. http://dx.doi.org/10.1136/gutjnl-2015-309871 (2015).

  56. Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159–165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Downes, M. et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol. Cell 11, 1079–1092 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Neuschwander-Tetri, B.A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, Q.A., Tao, C., Gupta, R.K. & Scherer, P.E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Ziętak, M. et al. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 23, 1216–1223 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chevalier, C. et al. Gut microbiota orchestrates energy homeostasis during Cold. Cell 163, 1360–1374 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Suárez-Zamorano, N. et al. Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat. Med. 21, 1497–1501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Collins, S. & Surwit, R.S. The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog. Horm. Res. 56, 309–328 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Sommer, F. et al. The gut microbiota modulates energy metabolism in the hibernating brown bear Ursus arctos. Cell Rep. 14, 1655–1661 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Turnbaugh, P.J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    Article  PubMed  Google Scholar 

  68. Turnbaugh, P.J., Bäckhed, F., Fulton, L. & Gordon, J.I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 3, 213–223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Turnbaugh, P.J. et al. The effect of diet on the human gut microbiome: A metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Blanton, L.V. et al. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science 351, aad3311 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Smith, M.I. et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548–554 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Engfer, M.B., Stahl, B., Finke, B., Sawatzki, G. & Daniel, H. Human milk oligosaccharides are resistant to enzymatic hydrolysis in the upper gastrointestinal tract. Am. J. Clin. Nutr. 71, 1589–1596 (2000).

    CAS  PubMed  Google Scholar 

  73. Charbonneau, M.R. et al. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell 164, 859–871 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schwarzer, M. et al. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science 351, 854–857 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Fleissner, C.K. et al. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br. J. Nutr. 104, 919–929 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Ding, S. et al. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One 5, e12191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sonnenburg, E.D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tremaroli, V. & Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Caesar, R. et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 61, 1701–1707 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Caesar, R., Tremaroli, V., Kovatcheva-Datchary, P., Cani, P.D. & Bäckhed, F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 22, 658–668 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Luche, E. et al. Metabolic endotoxemia directly increases the proliferation of adipocyte precursors at the onset of metabolic diseases through a CD14-dependent mechanism. Mol. Metab. 2, 281–291 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Erridge, C., Attina, T., Spickett, C.M. & Webb, D.J. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am. J. Clin. Nutr. 86, 1286–1292 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Amar, J. et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol. Med. 3, 559–572 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 110, 9066–9071 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bajaj, J.S. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G168–G175 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Makiura, N. et al. Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiol. Immunol. 23, 348–351 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Koeth, R.A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jonsson, A.L. & Bäckhed, F. Drug the bug! Cell 163, 1565–1566 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Luczynski, P. et al. Adult microbiota-deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur. J. Neurosci. http://dx.doi.org/10.1111/ejn.13291 (2016).

  97. Ogbonnaya, E.S. et al. Adult hippocampal neurogenesis is regulated by the microbiome. Biol. Psychiatry 78, e7–e9 (2015).

    Article  PubMed  Google Scholar 

  98. Hoban, A.E. et al. Regulation of prefrontal cortex myelination by the microbiota. Transl. Psychiatry 6, e774 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Braniste, V. et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. (Lond.) 558, 263–275 (2004).

    Article  CAS  Google Scholar 

  102. Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bravo, J.A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. USA 108, 16050–16055 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609.e3 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Clarke, G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Hsiao, E.Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Niehus, R. & Lord, C. Early medical history of children with autism spectrum disorders. J. Dev. Behav. Pediatr. JDBP 27 (Suppl.), S120–S127 (2006).

    Article  PubMed  Google Scholar 

  108. Finegold, S.M. et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16, 444–453 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Wang, L. et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig. Dis. Sci. 57, 2096–2102 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Mayer, E.A., Padua, D. & Tillisch, K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? BioEssays 36, 933–939 (2014).

    Article  PubMed  Google Scholar 

  111. MacFabe, D.F. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav. Brain Res. 176, 149–169 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Buffington, S.A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sullivan, E.L., Nousen, E.K. & Chamlou, K.A. Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol. Behav. 123, 236–242 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Connolly, N. et al. Maternal metabolic risk factors for autism spectrum disorder-An analysis of electronic medical records and linked birth data. Autism Res. 9, 829–837 (2016).

    Article  PubMed  Google Scholar 

  115. Benakis, C. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat. Med. 22, 516–523; advance online publication (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Niess, J.H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Houlden, A. et al. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production. Brain Behav. Immun. http://dx.doi.org/10.1016/j.bbi.2016.04.003 (2016).

  118. Arrieta, M.-C., Stiemsma, L.T., Amenyogbe, N., Brown, E.M. & Finlay, B. The intestinal microbiome in early life: health and disease. Front Immunol. 5, 427 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Russell, S.L. et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 13, 440–447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Arrieta, M.-C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Thorburn, A.N. et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat. Commun. 6, 7320 (2015).

    Article  CAS  PubMed  Google Scholar 

  123. Zeevi, D. et al. Personalized nutrition by prediction of Glycemic Responses. Cell 163, 1079–1094 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916.e7 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Hohmann, E.L., Ananthakrishnan, A.N. & Deshpande, V. Case records of the Massachusetts General Hospital. Case 25-2014. A 37-year-old man with ulcerative colitis and bloody diarrhea. N. Engl. J. Med. 371, 668–675 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Alang, N. & Kelly, C.R. Weight gain after fecal microbiota transplantation. Open Forum Infect. Dis. 2, ofv004 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Abrahamsson, T.R. et al. Low diversity of the gut microbiota in infants with atopic eczema. J. Allergy Clin. Immunol. 129, 434–440.e2 (2012).

    Article  PubMed  Google Scholar 

  128. Song, H., Yoo, Y., Hwang, J., Na, Y.-C. & Kim, H.S. Faecalibacterium prausnitzii subspecies-level dysbiosis in the human gut microbiome underlying atopic dermatitis. J. Allergy Clin. Immunol. 137, 852–860 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Hevia, A. et al. Intestinal dysbiosis associated with systemic lupus erythematosus. MBio 5, e01548–14 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lepage, P. et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141, 227–236 (2011).

    Article  PubMed  Google Scholar 

  131. Takahashi, K. et al. Reduced abundance of butyrate-producing bacteria species in the fecal microbial community in Crohn's disease. Digestion 93, 59–65 (2016).

    Article  CAS  PubMed  Google Scholar 

  132. Kostic, A.D. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe. 17, 260–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Alkanani, A.K. et al. Alterations in intestinal microbiota correlate with susceptibility to type 1 diabetes. Diabetes 64, 3510–3520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen, J. et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci. Rep. 6, 28484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Tims, S. et al. Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J. 7, 707–717 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Goodrich, J.K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Huurre, A. et al. Mode of delivery—effects on gut microbiota and humoral immunity. Neonatology 93, 236–240 (2008).

    Article  PubMed  Google Scholar 

  138. Dominguez-Bello, M.G. et al. 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 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Bäckhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 17, 690–703 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Azad, M.B. et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. BJOG 123, 983–993 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Koleva, P.T., Kim, J.-S., Scott, J.A. & Kozyrskyj, A.L. Microbial programming of health and disease starts during fetal life. Birth Defects Res. C Embryo Today 105, 265–277 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Ley, R.E., Turnbaugh, P.J., Klein, S. & Gordon, J.I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Duncan, S.H. et al. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl. Environ. Microbiol. 73, 1073–1078 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Dethlefsen, L., Huse, S., Sogin, M.L. & Relman, D.A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6, e280 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. David, L.A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. David, L.A. et al. Host lifestyle affects human microbiota on daily timescales. Genome Biol. 15, R89 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hofstra, J.J. et al. Changes in microbiota during experimental human Rhinovirus infection. BMC Infect. Dis. 15, 336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Dethlefsen, L. & Relman, D.A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl. Acad. Sci. USA 108 (Suppl. 1), 4554–4561 (2011).

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank A. Hallén for her assistance with figures and artwork. Work in the authors' laboratory is supported by the Swedish Research Council, the NovoNordisk foundation, Torsten Söderberg's foundation, Swedish Heart Lung Foundation, Göran Gustafsson's foundation, IngaBritt och Arne Lundbergs foundation, Knut and Alice Wallenberg foundation, the FP7-sponsored program METACARDIS, the regional agreement on medical training and clinical research (ALF) between Region Västra Götaland and Sahlgrenska University Hospital. F.B. is a recipient of an ERC Consolidator Grant (European Research Council, Consolidator grant 615362 - METABASE). B.O.S. is a recipient of an FP7 Marie Curie IEF Fellowship (622909 MUCUS AND METABOLISM) from the European Union and a Human Frontier Science Program Long-Term Fellowship (LT000109/2014-l).

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Schroeder, B., Bäckhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 22, 1079–1089 (2016). https://doi.org/10.1038/nm.4185

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