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Human genetic variation and the gut microbiome in disease

Key Points

  • Host genetics shape the composition of the gut microbiome in concert with environmental factors such as diet and lifestyle.

  • Certain host genetic variants predispose an individual towards microbiome dysbiosis, which is an important factor in diseases of metabolism and immunity.

  • A subset of species in the gut microbiome are heritable, especially representatives from the phyla Firmicutes and Verrucomicrobia.

  • Variants in single genes (for example, LCT, NOD2 and FUT2) affect the composition of the gut microbiome.

  • Microbiome genome-wide association studies hold promise for the identification of additional host genetic variants that affect disease progression by perturbing the composition of the microbiome.

Abstract

Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

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Figure 1: Major factors influencing the composition of the gut microbiome.
Figure 2: Gut microbiome composition at different body sites in health and disease.
Figure 3: NOD2 and FUT2 — two genes with non-functional variants that influence the composition of the gut microbiome.
Figure 4: Heritable species are partially responsible for the altered microbiome composition in obesity.

References

  1. Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14, e1002533 (2016).

    PubMed  PubMed Central  Google Scholar 

  2. Human Microbiome Project, C. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012). This study represents a comprehensive characterization of the human microbiota in health for multiple body sites.

    Google Scholar 

  3. Donaldson, G. P., Lee, S. M. & Mazmanian, S. K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 14, 20–32 (2016).

    CAS  PubMed  Google Scholar 

  4. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. 105, 15064–15069 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008). This study sequenced the gut microbiota of humans and 59 other mammalian species and showed that herbivores have more diverse microbiota than carnivores.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lehrer, R. I. & Lu, W. α-Defensins in human innate immunity. Immunol. Rev. 245, 84–112 (2012).

    CAS  PubMed  Google Scholar 

  7. Cullen, T. et al. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 347, 170–175 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu, S. et al. The host shapes the gut microbiota via fecal microRNA. Cell Host Microbe 19, 32–43 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Levin, B. J. et al. A prominent glycyl radical enzyme in human gut microbiomes metabolizes trans-4-hydroxy-l-proline. Science 355, eaai8386 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. Ochman, H. et al. Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biol. 8, e1000546 (2010).

    PubMed  PubMed Central  Google Scholar 

  12. Moeller, A. H. et al. Cospeciation of gut microbiota with hominids. Science 353, 380–382 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Seedorf, H. et al. Bacteria from diverse habitats colonize and compete in the mouse gut. Cell 159, 253–266 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Goodrich, J. K. et al. Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe 19, 731–743 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Xie, H. et al. Shotgun metagenomics of 250 adult twins reveals genetic and environmental impacts on the gut microbiome. Cell Syst. 3, 572–584e573 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).

    CAS  PubMed  Google Scholar 

  18. Faith, J. J. et al. The long-term stability of the human gut microbiota. Science 341, 1237439 (2013).

    PubMed  PubMed Central  Google Scholar 

  19. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

    CAS  PubMed  Google Scholar 

  20. Knights, D. et al. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med. 6, 107 (2014). This GWAS of 474 individuals found that Enterobacteriaceae are significantly enriched in IBD.

    PubMed  PubMed Central  Google Scholar 

  21. Spor, A., Koren, O. & Ley, R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat. Rev. Microbiol. 9, 279–290 (2011).

    CAS  PubMed  Google Scholar 

  22. Wang, J. et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat. Genet. 48, 1396–1406 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Turpin, W. et al. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat. Genet. 48, 1413–1417 (2016).

    CAS  PubMed  Google Scholar 

  24. Bonder, M. J. et al. The effect of host genetics on the gut microbiome. Nat. Genet. 48, 1407–1412 (2016).

    CAS  PubMed  Google Scholar 

  25. Blekhman, R. et al. Host genetic variation impacts microbiome composition across human body sites. Genome Biol. 16, 191 (2015).

    PubMed  PubMed Central  Google Scholar 

  26. Davenport, E. R. et al. Genome-wide association studies of the human gut microbiota. PLoS ONE 10, e0140301 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. 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).

    CAS  PubMed  Google Scholar 

  28. Sentausa, E. & Fournier, P. E. Advantages and limitations of genomics in prokaryotic taxonomy. Clin. Microbiol. Infect. 19, 790–795 (2013).

    CAS  PubMed  Google Scholar 

  29. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    CAS  PubMed  Google Scholar 

  30. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hugot, J. P. et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 379, 821–823 (1996).

    CAS  PubMed  Google Scholar 

  32. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    CAS  PubMed  Google Scholar 

  33. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    CAS  PubMed  Google Scholar 

  34. Cavanaugh, J. et al. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am. J. Hum. Genet. 68, 1165–1171 (2001).

    CAS  PubMed  Google Scholar 

  35. Hampe, J. et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357, 1925–1928 (2001).

    CAS  PubMed  Google Scholar 

  36. Philpott, D. J., Sorbara, M. T., Robertson, S. J., Croitoru, K. & Girardin, S. E. NOD proteins: regulators of inflammation in health and disease. Nat. Rev. Immunol. 14, 9–23 (2014).

    CAS  PubMed  Google Scholar 

  37. Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–5512 (2003).

    CAS  PubMed  Google Scholar 

  38. Girardin, S. E. et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278, 8869–8872 (2003).

    CAS  PubMed  Google Scholar 

  39. Eckmann, L. & Karin, M. NOD2 and Crohn's disease: loss or gain of function? Immunity 22, 661–667 (2005).

    CAS  PubMed  Google Scholar 

  40. Fritz, J. H. et al. Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur. J. Immunol. 35, 2459–2470 (2005).

    CAS  PubMed  Google Scholar 

  41. Cho, J. H. & Abraham, C. Inflammatory bowel disease genetics: Nod2. Annu. Rev. Med. 58, 401–416 (2007).

    CAS  PubMed  Google Scholar 

  42. Petnicki-Ocwieja, T. et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl Acad. Sci. USA 106, 15813–15818 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wlodarska, M., Kostic, A. D. & Xavier, R. J. An integrative view of microbiome-host interactions in inflammatory bowel diseases. Cell Host Microbe 17, 577–591 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wehkamp, J. et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal α-defensin expression. Gut 53, 1658–1664 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).

    CAS  PubMed  Google Scholar 

  47. Knights, D., Lassen, K. G. & Xavier, R. J. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 62, 1505–1510 (2013).

    CAS  PubMed  Google Scholar 

  48. Chassaing, B. et al. Crohn disease—associated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae. J. Clin. Invest. 121, 966–975 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lapaquette, P., Bringer, M. A. & Darfeuille-Michaud, A. Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response. Cell. Microbiol. 14, 791–807 (2012).

    CAS  PubMed  Google Scholar 

  50. Li, D. et al. A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology 151, 724–732 (2016).

    CAS  PubMed  Google Scholar 

  51. Iliev, I. D. et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336, 1314–1317 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sokol, H. et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 145, 591–601e593 (2013).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lewis, J. D. et al. Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn's disease. Cell Host Microbe 18, 489–500 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Boltin, D., Perets, T. T., Vilkin, A. & Niv, Y. Mucin function in inflammatory bowel disease: an update. J. Clin. Gastroenterol. 47, 106–111 (2013).

    CAS  PubMed  Google Scholar 

  56. Smith, A. C. & Podolsky, D. K. Colonic mucin glycoproteins in health and disease. Clin. Gastroenterol. 15, 815–837 (1986).

    CAS  PubMed  Google Scholar 

  57. Li, H. et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun. 6, 8292 (2015).

    CAS  PubMed  Google Scholar 

  58. Macfarlane, G. T., Gibson, G. R. & Cummings, J. H. Comparison of fermentation reactions in different regions of the human colon. J. Appl. Bacteriol. 72, 57–64 (1992).

    CAS  PubMed  Google Scholar 

  59. Macfarlane, S., Woodmansey, E. J. & Macfarlane, G. T. Colonization of mucin by human intestinal bacteria and establishment of biofilm communities in a two-stage continuous culture system. Appl. Environ. Microbiol. 71, 7483–7492 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kashyap, P. C. et al. Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota. Proc. Natl Acad. Sci. USA 110, 17059–17064 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kelly, R. J., Rouquier, S., Giorgi, D., Lennon, G. G. & Lowe, J. B. Sequence and expression of a candidate for the human Secretor blood group alpha(1,2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J. Biol. Chem. 270, 4640–4649 (1995).

    CAS  PubMed  Google Scholar 

  62. Lindesmith, L. et al. Human susceptibility and resistance to Norwalk virus infection. Nat. Med. 9, 548–553 (2003).

    CAS  PubMed  Google Scholar 

  63. Chaudhuri, A. & DasAdhikary, C. R. Possible role of blood-group secretory substances in the aetiology of cholera. Trans. R. Soc. Trop. Med. Hyg. 72, 664–665 (1978).

    CAS  PubMed  Google Scholar 

  64. Ruiz-Palacios, G. M., Cervantes, L. E., Ramos, P., Chavez-Munguia, B. & Newburg, D. S. Campylobacter jejuni binds intestinal H(O) antigen (Fuc alpha 1, 2Gal beta 1, 4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J. Biol. Chem. 278, 14112–14120 (2003).

    CAS  PubMed  Google Scholar 

  65. Ikehara, Y. et al. Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer Epidemiol. Biomarkers Prev. 10, 971–977 (2001).

    CAS  PubMed  Google Scholar 

  66. Folseraas, T. et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J. Hepatol. 57, 366–375 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Smyth, D. J. et al. FUT2 nonsecretor status links type 1 diabetes susceptibility and resistance to infection. Diabetes 60, 3081–3084 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Parmar, A. S. et al. Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the Finnish population. Tissue Antigens 80, 488–493 (2012).

    CAS  PubMed  Google Scholar 

  69. Tong, M. et al. Reprograming of gut microbiome energy metabolism by the FUT2 Crohn's disease risk polymorphism. ISME J. 8, 2193–2206 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Comstock, L. E. et al. Analysis of a capsular polysaccharide biosynthesis locus of Bacteroides fragilis. Infect. Immun. 67, 3525–3532 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Coyne, M. J., Reinap, B., Lee, M. M. & Comstock, L. E. Human symbionts use a host-like pathway for surface fucosylation. Science 307, 1778–1781 (2005).

    CAS  PubMed  Google Scholar 

  73. Coyne, M. J., Chatzidaki-Livanis, M., Paoletti, L. C. & Comstock, L. E. Role of glycan synthesis in colonization of the mammalian gut by the bacterial symbiont Bacteroides fragilis. Proc. Natl Acad. Sci. USA 105, 13099–13104 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Tailford, L. E., Crost, E. H., Kavanaugh, D. & Juge, N. Mucin glycan foraging in the human gut microbiome. Front. Genet. 6, 81 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. Pacheco, A. R. et al. Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113–117 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tishkoff, S. A. et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat. Genet. 39, 31–40 (2007).

    CAS  PubMed  Google Scholar 

  77. Azcarate-Peril, M. A. et al. Impact of short-chain galactooligosaccharides on the gut microbiome of lactose-intolerant individuals. Proc. Natl Acad. Sci. USA 114, E367–E375 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013). This study reports the transfer of gut microbiota from twins discordant for obesity to germ-free mice. Mice that received gut microbiota from the obese twin accumulated more fat.

    PubMed  Google Scholar 

  79. Beaumont, M. et al. Heritable components of the human fecal microbiome are associated with visceral fat. Genome Biol. 17, 189 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. Million, M. et al. Correlation between body mass index and gut concentrations of Lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. Int. J. Obes. (Lond.) 37, 1460–1466 (2013).

    CAS  Google Scholar 

  81. Lahti, L. et al. Associations between the human intestinal microbiota. Lactobacillus rhamnosus GG and serum lipids indicated by integrated analysis of high-throughput profiling data. PeerJ 1, e32 (2013).

    PubMed  PubMed Central  Google Scholar 

  82. Chen, J., Chen, L., Sanseau, P., Freudenberg, J. M. & Rajpal, D. K. Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice. Physiol. Rep. 4, e12793 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. Juan-Mateu, J. et al. Neuron-enriched RNA-binding proteins regulate pancreatic beta cell function and survival. J. Biol. Chem. 292, 3466–3480 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Speakman, J. R. Functional analysis of seven genes linked to body mass index and adiposity by genome-wide association studies: a review. Hum. Hered. 75, 57–79 (2013).

    CAS  PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Derrien, M., Vaughan, E. E., Plugge, C. M. & de Vos, W. M. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54, 1469–1476 (2004).

    CAS  PubMed  Google Scholar 

  87. Collado, M. C., Derrien, M., Isolauri, E., de Vos, W. M. & Salminen, S. Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl. Environ. Microbiol. 73, 7767–7770 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Derrien, M., Collado, M. C., Ben-Amor, K., Salminen, S. & de Vos, W. M. The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl. Environ. Microbiol. 74, 1646–1648 (2008).

    CAS  PubMed  Google Scholar 

  89. van Passel, M. W. et al. The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes. PLoS ONE 6, e16876 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Walley, A. J. et al. Differential coexpression analysis of obesity-associated networks in human subcutaneous adipose tissue. Int. J. Obes. (Lond.) 36, 137–147 (2012).

    CAS  Google Scholar 

  91. Ng, M. C. et al. Genome-wide association of BMI in African Americans. Obes. (Silver Spring) 20, 622–627 (2012).

    CAS  Google Scholar 

  92. Cassese, A. et al. Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15. PLoS ONE 8, e60555 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Org, E. et al. Genetic and environmental control of host-gut microbiota interactions. Genome Res. 25, 1558–1569 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Greer, R. L. et al. Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism. Nat. Commun. 7, 13329 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Eriksson, N. et al. A genetic variant near olfactory receptor genes influences cilantro preference. Flavour 1, 1–7 (2012).

    Google Scholar 

  96. Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15, 382–392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Weiser, M. et al. Molecular classification of Crohn's disease reveals two clinically relevant subtypes. Gut http://dx.doi.org/10.1136/gutjnl-2016-312518 (2016).

  98. Mahmood, S. S., Levy, D., Vasan, R. S. & Wang, T. J. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet 383, 999–1008 (2014).

    PubMed  Google Scholar 

  99. Group, T. S. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8, 286–298 (2007).

    Google Scholar 

  100. Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518, 187–196 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014). In this study, participants were fed a plant-based or animal-based diet for 5 days; the results revealed that diet is a major influence on the composition of the gut microbiota.

    CAS  PubMed  Google Scholar 

  102. Carmody, R. N. et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17, 72–84 (2015).

    CAS  PubMed  Google Scholar 

  103. Smillie, C. S. et al. Ecology drives a global network of gene exchange connecting the human microbiome. Nature 480, 241–244 (2011).

    CAS  PubMed  Google Scholar 

  104. Segata, N. et al. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat. Methods 9, 811–814 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Abubucker, S. et al. Metabolic reconstruction for metagenomic data and its application to the human microbiome. PLoS Comput. Biol. 8, e1002358 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Yassour, M. et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci. Transl. Med. 8, 343ra381 (2016).

    Google Scholar 

  107. Saraswati, S. & Sitaraman, R. Aging and the human gut microbiota-from correlation to causality. Front. Microbiol. 5, 764 (2014).

    PubMed  Google Scholar 

  108. Rodriguez, J. M. et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb. Ecol. Health Dis. 26, 26050 (2015).

    PubMed  Google Scholar 

  109. Rolhion, N. & Darfeuille-Michaud, A. Adherent-invasive Escherichia coli in inflammatory bowel disease. Inflamm. Bowel Dis. 13, 1277–1283 (2007).

    PubMed  Google Scholar 

  110. Png, C. W. et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am. J. Gastroenterol. 105, 2420–2428 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

A.B.H. is supported by a Helen Hay Whitney Postdoctoral Fellowship. R.J.X. is supported by the Crohn's and Colitis Foundation and NIH grants U54DE023798, R01DK92405 and P30DK43351.

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Correspondence to Andrew Brantley Hall or Ramnik J. Xavier.

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FURTHER INFORMATION

Human Microbiome Project

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Glossary

Microbiome

The totality of microorganisms (for example, bacteria, fungi and viruses) in a defined environment, such as the human gut. The term microbiome can refer either to the microbial organisms that reside in an environmental niche or specifically to their collective genomes.

Bacterial species

Bacterial organisms with 16S rDNA genes that share greater than 97% identity. However, due to horizontal transfer and high variability in their genomes, bacterial species often differ dramatically in functional potential.

Classic twin studies

A study design used to estimate the importance of genetic versus environmental influences on complex trait variation. The estimate of heritability is based on a comparison of resemblance in monozygotic twins (who share all segregating genetic material) and dizygotic twins (who share, on average, half of their segregating genetic material).

Dysbiosis

Individual and context-specific taxonomic and functional changes to the composition of the microbiome that result in a disease state.

Genome-wide association studies

(GWAS). Studies in which statistical associations between genetic variants and a disease or trait of interest are identified by genotyping individuals with disease and healthy controls for a set of SNPs that capture variation across the entire genome.

Metagenomic

A term used to describe techniques that characterize the genomes of whole communities of organisms rather than individual species.

Human Microbiome Project

An interdisciplinary project funded by the US National Institutes of Health with the aim of generating resources that enable the comprehensive characterization of the human microbiome and the analysis of its role in human health and disease.

Effect sizes

The contributions of loci or alleles to phenotypic variance in a trait.

β diversity

A reflection of the variability in microbial communities between different environments. By contrast, α diversity represents the number of taxa within one microbial environment.

Genetic variance

The variance of trait values that can be ascribed to genetic differences among individuals. The total genetic variance in a trait can be separated into additive, dominance and other components; in populations, these components depend on the frequencies of the alleles at loci affecting the trait.

Prebiotic

A non-viable substrate that is selectively utilized by host microorganisms conferring a health benefit

Heritability

The proportion of variance of a trait attributed to host genetics rather than environmental effects. In the context of this Review, heritability predominantly refers to the proportion of variance in the abundance of a microbial taxon attributed to host genetic effects rather than environmental effects.

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Hall, A., Tolonen, A. & Xavier, R. Human genetic variation and the gut microbiome in disease. Nat Rev Genet 18, 690–699 (2017). https://doi.org/10.1038/nrg.2017.63

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