1932

Abstract

The body's microbiome, composed of microbial cells that number in the trillions, is involved in human health and disease in ways that are just starting to emerge. The microbiome is assembled at birth, develops with its host, and is greatly influenced by environmental factors such as diet and other exposures. Recently, a role for human genetic variation has emerged as also influential in accounting for interpersonal differences in microbiomes. Thus, human genes may influence health directly or by promoting a beneficial microbiome. Studies of the heritability of gut microbiotas reveal a subset of microbes whose abundances are partly genetically determined by the host. However, the use of genome-wide association studies (GWASs) to identify human genetic variants associated with microbiome phenotypes has proven challenging. Studies to date are small by GWAS standards, and cross-study comparisons are hampered by differences in analytical approaches. Nevertheless, associations between microbes or microbial genes and human genes have emerged that are consistent between human populations. Most notably, higher levels of beneficial gut bacteria called Bifidobacteria are associated with the human lactase nonpersister genotype, which typically confers lactose intolerance, in several different human populations. It is time for the microbiome to be incorporated into studies that quantify interactions among genotype, environment, and the microbiome in order to predict human disease susceptibility.

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2017-11-27
2024-10-09
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Literature Cited

  1. An D, Oh SF, Olszak T, Neves JF, Avci FY. 1.  et al. 2014. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156:1–2123–33 [Google Scholar]
  2. Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. 2.  2009. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and methanogens in anorexic patients. PLOS ONE 4:9e7125 [Google Scholar]
  3. Beaumont M, Goodrich JK, Jackson MA, Yet I, Davenport ER. 3.  et al. 2016. Heritable components of the human fecal microbiome are associated with visceral fat. Genome Biol 17:1189 [Google Scholar]
  4. Blekhman R, Goodrich JK, Huang K, Sun Q, Bukowski R. 4.  et al. 2015. Host genetic variation impacts microbiome composition across human body sites. Genome Biol 16:191 [Google Scholar]
  5. Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F. 5.  et al. 2016. The effect of host genetics on the gut microbiome. Nat. Genet. 48:111407–12 [Google Scholar]
  6. Budden KF, Gellatly SL, Wood DLA, Cooper MA, Morrison M. 6.  et al. 2017. Emerging pathogenic links between microbiota and the gut–lung axis. Nat. Rev. Microbiol. 15:155–63 [Google Scholar]
  7. Bush WS, Moore JH. 7.  2012. Chapter 11: Genome-wide association studies. PLOS Comput. Biol. 8:12e1002822 [Google Scholar]
  8. Dambuza IM, Brown GD. 8.  2015. C-type lectins in immunity: recent developments. Curr. Opin. Immunol. 32:21–27 [Google Scholar]
  9. Davenport ER. 9.  2016. Elucidating the role of the host genome in shaping microbiome composition. Gut Microbes 7:178–84 [Google Scholar]
  10. Davenport ER, Cusanovich DA, Michelini K, Barreiro LB, Ober C, Gilad Y. 10.  2015. Genome-wide association studies of the human gut microbiota. PLOS ONE 10:11e0140301 [Google Scholar]
  11. Dickinson RE, Dallol A, Bieche I, Krex D, Morton D. 11.  et al. 2004. Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers. Br. J. Cancer 91:122071–78 [Google Scholar]
  12. Edwards SL, Beesley J, French JD, Dunning AM. 12.  2013. Beyond GWASs: illuminating the dark road from association to function. Am. J. Hum. Genet. 93:5779–97 [Google Scholar]
  13. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I. 13.  2002. Identification of a variant associated with adult-type hypolactasia. Nat. Genet. 30:2233–37 [Google Scholar]
  14. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C. 14.  et al. 2013. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS 110:229066–71 [Google Scholar]
  15. Frank DN, Robertson CE, Hamm CM, Kpadeh Z, Zhang T. 15.  et al. 2011. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm. Bowel Dis. 17:1179–84 [Google Scholar]
  16. Frank DN, St. Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. 16.  2007. Molecular–phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. PNAS 104:3413780–85 [Google Scholar]
  17. Fu J, Bonder MJ, Cenit MC, Tigchelaar EF, Maatman A. 17.  et al. 2015. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ. Res. 117:9817–24 [Google Scholar]
  18. Goodrich JK, Davenport ER, Beaumont M, Jackson MA, Knight R. 18.  et al. 2016a. Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe 19:5731–43 [Google Scholar]
  19. Goodrich JK, Davenport ER, Waters JL, Clark AG, Ley RE. 19.  2016b. Cross-species comparisons of host genetic associations with the microbiome. Science 352:6285532–35 [Google Scholar]
  20. Goodrich JK, Di Rienzi SC, Poole AC, Koren O, Walters WA. 20.  et al. 2014a. Conducting a microbiome study. Cell 158:2250–62 [Google Scholar]
  21. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O. 21.  et al. 2014b. Human genetics shape the gut microbiome. Cell 159:4789–99 [Google Scholar]
  22. Han S, Chiang JYL. 22.  2009. Mechanism of vitamin D receptor inhibition of cholesterol 7α-hydroxylase gene transcription in human hepatocytes. Drug Metab. Dispos. 37:3469–78 [Google Scholar]
  23. Hand TW, Vujkovic-Cvijin I, Ridaura VK, Belkaid Y. 23.  2016. Linking the microbiota, chronic disease, and the immune system. Trends Endocrinol. Metab. 27:12831–43 [Google Scholar]
  24. Hansen CHF, Nielsen DS, Kverka M, Zakostelska Z, Klimesova K. 24.  et al. 2012. Patterns of early gut colonization shape future immune responses of the host. PLOS ONE 7:3e34043 [Google Scholar]
  25. Hansen EE, Lozupone CA, Rey FE, Wu M, Guruge JL. 25.  et al. 2011. Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii, studied in twins. PNAS 108:Suppl. 14599–606 [Google Scholar]
  26. Honda K, Littman DR. 26.  2016. The microbiota in adaptive immune homeostasis and disease. Nature 535:761075–84 [Google Scholar]
  27. Hooper LV. 27.  2004. Bacterial contributions to mammalian gut development. Trends Microbiol 12:3129–34 [Google Scholar]
  28. Hua X, Song L, Yu G, Goedert JJ, Abnet CC. 28.  et al. 2015. MicrobiomeGWAS: a tool for identifying host genetic variants associated with microbiome composition. bioRxiv 031187 https://doi.org/10.1101/031187 [Crossref]
  29. Huse SM, Ye Y, Zhou Y, Fodor AA. 29.  2012. A core human microbiome as viewed through 16S rRNA sequence clusters. PLOS ONE 7:6e34242 [Google Scholar]
  30. Igartua C, Davenport ER, Gilad Y, Nicolae DL, Pinto J, Ober C. 30.  2017. Host genetic variation in mucosal immunity pathways influences the upper airway microbiome. Microbiome 5:116 [Google Scholar]
  31. Imhann F, Vich Vila A, Bonder MJ, Fu J, Gevers D. 31.  et al. 2016. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut Oct. 8. https://doi.org/10.1136/gutjnl-2016-312135 [Crossref] [Google Scholar]
  32. Jankipersadsing SA, Hadizadeh F, Bonder MJ, Tigchelaar EF, Deelen P. 32.  et al. 2017. A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency. Gut 66:756–58 [Google Scholar]
  33. Jones RJ, Megarrity RG. 33.  1986. Successful transfer of DHP-degrading bacteria from Hawaiian goats to Australian ruminants to overcome the toxicity of Leucaena. Aust. Vet. J. 63:8259–62 [Google Scholar]
  34. Khan MT, Browne WR, van Dijl JM, Harmsen HJM. 34.  2012. How can Faecalibacterium prausnitzii employ riboflavin for extracellular electron transfer?. Antioxid. Redox Signal. 17:101433–40 [Google Scholar]
  35. Knights D, Silverberg MS, Weersma RK, Gevers D, Dijkstra G. 35.  et al. 2014. Complex host genetics influence the microbiome in inflammatory bowel disease. Genome Med 6:12107 [Google Scholar]
  36. Kostic AD, Xavier RJ, Gevers D. 36.  2014. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146:61489–99 [Google Scholar]
  37. Larsen N, Vogensen FK, van den Berg FWJ, Nielsen DS, Andreasen AS. 37.  et al. 2010. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLOS ONE 5:2e9085 [Google Scholar]
  38. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F. 38.  et al. 2013. Richness of human gut microbiome correlates with metabolic markers. Nature 500:7464541–46 [Google Scholar]
  39. Ley RE, Peterson DA, Gordon JI. 39.  2006. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:4837–48 [Google Scholar]
  40. Lim MY, You HJ, Yoon HS, Kwon B, Lee JY. 40.  et al. 2017. The effect of heritability and host genetics on the gut microbiota and metabolic syndrome. Gut 66:1031–38 [Google Scholar]
  41. Liu Y-J, Liu X-G, Wang L, Dina C, Yan H. 41.  et al. 2008. Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. Hum. Mol. Genet. 17:121803–13 [Google Scholar]
  42. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH. 42.  et al. 2015. Genetic studies of body mass index yield new insights for obesity biology. Nature 518:7538197–206 [Google Scholar]
  43. Lynch J, Tang K, Sands J, Sands M, Tang E. 43.  et al. 2016. HOMINID: a framework for identifying associations between host genetic variation and microbiome composition. bioRxiv 081323 https://doi.org/10.1101/081323 [Crossref]
  44. Magnúsdóttir S, Heinken A, Kutt L, Ravcheev DA, Bauer E. 44.  et al. 2017. Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota. Nat. Biotechnol. 35:181–89 [Google Scholar]
  45. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H. 45.  et al. 2002. Vitamin D receptor as an intestinal bile acid sensor. Science 296:55711313–16 [Google Scholar]
  46. Million M, Maraninchi M, Henry M, Armougom F, Richet H. 46.  et al. 2012. Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii. Int. J. Obes. 36:6817–25 [Google Scholar]
  47. Morotomi M, Nagai F, Watanabe Y. 47.  2012. Description of Christensenella minuta gen. nov., sp. nov., isolated from human faeces, which forms a distinct branch in the order Clostridiales, and proposal of Christensenellaceae fam. nov. Int. J. Syst. Evol. Microbiol. 62:1144–49 [Google Scholar]
  48. Mosca A, Leclerc M, Hugot JP. 48.  2016. Gut microbiota diversity and human diseases: Should we reintroduce key predators in our ecosystem?. Front. Microbiol. 7:455 [Google Scholar]
  49. Mueller UG, Sachs JL. 49.  2015. Engineering microbiomes to improve plant and animal health. Trends Microbiol 23:10606–17 [Google Scholar]
  50. Ng MCY, Hester JM, Wing MR, Li J, Xu J. 50.  et al. 2012. Genome-wide association of BMI in African Americans. Obesity 20:3622–27 [Google Scholar]
  51. Oki K, Toyama M, Banno T, Chonan O, Benno Y, Watanabe K. 51.  2016. Comprehensive analysis of the fecal microbiota of healthy Japanese adults reveals a new bacterial lineage associated with a phenotype characterized by a high frequency of bowel movements and a lean body type. BMC Microbiol 16:1284 [Google Scholar]
  52. Olszak T, An D, Zeissig S, Vera MP, Richter J. 52.  et al. 2012. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336:6080489–93 [Google Scholar]
  53. Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A. 53.  et al. 2015. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat. Genet. 47:7702–9 [Google Scholar]
  54. Ranciaro A, Campbell MC, Hirbo JB, Ko W-Y, Froment A. 54.  et al. 2014. Genetic origins of lactase persistence and the spread of pastoralism in Africa. Am. J. Hum. Genet. 94:4496–510 [Google Scholar]
  55. Roager HM, Hansen LBS, Bahl MI, Frandsen HL, Carvalho V. 55.  et al. 2016. Colonic transit time is related to bacterial metabolism and mucosal turnover in the gut. Nat. Microbiol. 1:916093 [Google Scholar]
  56. Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA. 56.  et al. 2010. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18:1190–95 [Google Scholar]
  57. Smith K, McCoy KD, Macpherson AJ. 57.  2007. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19:259–69 [Google Scholar]
  58. Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I. 58.  et al. 2009. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15:81183–89 [Google Scholar]
  59. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. 59.  1997. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J. Immunol. 159:41739–45 [Google Scholar]
  60. Tanno T, Fujiwara A, Sakaguchi K, Tanaka K, Takenaka S, Tsuyama S. 60.  2007. Slit3 regulates cell motility through RAC/CDC42 activation in lipopolysaccharide-stimulated macrophages. FEBS Lett 581:51022–26 [Google Scholar]
  61. Thakur K, Tomar SK, De S. 61.  2016. Lactic acid bacteria as a cell factory for riboflavin production. Microb. Biotechnol. 9:4441–51 [Google Scholar]
  62. Tigchelaar EF, Bonder MJ, Jankipersadsing SA, Fu J, Wijmenga C, Zhernakova A. 62.  2016. Gut microbiota composition associated with stool consistency. Gut 65:3540–42 [Google Scholar]
  63. Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC. 63.  et al. 2007. Convergent adaptation of human lactase persistence in Africa and Europe. Nat. Genet. 39:131–40 [Google Scholar]
  64. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A. 64.  et al. 2009. A core gut microbiome in obese and lean twins. Nature 457:7228480–84 [Google Scholar]
  65. Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D. 65.  et al. 2016. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat. Genet. 48:111413–17 [Google Scholar]
  66. Upadhyaya B, McCormack L, Fardin-Kia AR, Juenemann R, Nichenametla S. 66.  et al. 2016. Impact of dietary resistant starch type 4 on human gut microbiota and immunometabolic functions. Sci. Rep. 6:28797 [Google Scholar]
  67. Vandeputte D, Falony G, Vieira-Silva S, Tito RY, Joossens M, Raes J. 67.  2016. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut 65:157–62 [Google Scholar]
  68. Wang J, Thingholm LB, Skiecevičienė J, Rausch P, Kummen M. 68.  et al. 2016. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat. Genet. 48:111396–406 [Google Scholar]
  69. Xie H, Guo R, Zhong H, Feng Q, Lan Z. 69.  et al. 2016. Shotgun metagenomics of 250 adult twins reveals genetic and environmental impacts on the gut microbiome. Cell Syst 3:6572–84.e3 [Google Scholar]
  70. Xu L, Paterson AD, Turpin W, Xu W. 70.  2015. Assessment and selection of competing models for zero-inflated microbiome data. PLOS ONE 10:7e0129606 [Google Scholar]
  71. Yamamoto M, Matsumoto S. 71.  2016. Gut microbiota and colorectal cancer. Genes Environ 38:11 [Google Scholar]
  72. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG. 72.  et al. 2012. Human gut microbiome viewed across age and geography. Nature 486:7402222–27 [Google Scholar]
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