Of genes and microbes: solving the intricacies in host genomes

Abstract

Microbiome research is a quickly developing field in biomedical research, and we have witnessed its potential in understanding the physiology, metabolism and immunology, its critical role in understanding the health and disease of the host, and its vast capacity in disease prediction, intervention and treatment. However, many of the fundamental questions still need to be addressed, including the shaping forces of microbial diversity between individuals and across time. Microbiome research falls into the classical nature vs. nurture scenario, such that host genetics shape part of the microbiome, while environmental influences change the original course of microbiome development. In this review, we focus on the nature, i.e., the genetic part of the equation, and summarize the recent efforts in understanding which parts of the genome, especially the human and mouse genome, play important roles in determining the composition and functions of microbial communities, primarily in the gut but also on the skin. We aim to present an overview of different approaches in studying the intricate relationships between host genetic variations and microbes, its underlying philosophy and methodology, and we aim to highlight a few key discoveries along this exploration, as well as current pitfalls. More evidence and results will surely appear in upcoming studies, and the accumulating knowledge will lead to a deeper understanding of what we could finally term a “hologenome”, that is, the organized, closely interacting genome of the host and the microbiome.

Key words： gut microbiota; host genetics; quantitative genetics; gene-microbiome association

References

1 Barreiro LB, Quintana-Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11:17–30

2 Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L (2008) Natural selection has driven population differentiation in modern humans. Nat Genet 40:340–345

3 Belheouane M, Gupta Y, Kunzel S, Ibrahim S, Baines JF (2017) Improved detection of gene-microbe interactions in the mouse skin microbiota using high-resolution QTL mapping of 16S rRNA transcripts. Microbiome 5:59

4 Bennett GM, McCutcheon JP, MacDonald BR, Romanovicz D, Moran NA (2014) Differential genome evolution between companion symbionts in an insect-bacterial symbiosis. MBio 5: e01697–14

5 Benson AK (2016) The gut microbiome-an emerging complex trait. Nat Genet 48:1301–1302

6 Benson AK, Kelly SA, Legge R, Ma F, Low SJ, Kim J,Zhang M, Oh PL, Nehrenberg D, Hua K (2010) Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors. Proc Natl Acad Sci USA 107:18933–18938

7 Blekhman R, Goodrich JK, Huang K, Sun Q, Bukowski R, Bell JT, Spector TD, Keinan A, Ley RE, Gevers D (2015) Host genetic variation impacts microbiome composition across human body sites. Genome Biol 16:191

8 Bohn E, Bechtold O, Zahir N, Frick JS, Reimann J, Jilge B, Autenrieth IB (2006) Host gene expression in the colon of gnotobiotic interleukin-2-deficient mice colonized with commensal colitogenic or noncolitogenic bacterial strains: common patterns and bacteria strain specific signatures. Inflamm Bowel Dis 12(9):853–862

9 Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, Deelen P, Vatanen T, Schirmer M, Smeekens SP (2016) The effect of host genetics on the gut microbiome. Nat Genet 48:1407–1412

10 Bordenstein SR, Theis KR (2015) Host biology in light of the microbiome: ten principles of holobionts and hologenomes. Plos Biol 13:e1002226

11 Brinkworth JF, Pechenkina K (2013) Primates, pathogens, and evolution. Springer, New York

12 Brucker RM, Bordenstein SR (2013) The hologenomic basis of speciation: gut bacteria cause hybrid lethality in the genus Nasonia. Science 341:667–669

13 Budden KF, Gellatly SL, Wood DL, Cooper MA, Morrison M, Hugenholtz P, Hansbro PM (2017) Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol 15:55–63

14 Chaston JM, Dobson AJ, Newell PD, Douglas AE (2015) Host genetic control of the microbiota mediates the drosophila nutritional phenotype. Appl Environ Microbiol 82:671–679

15 Chen L, Wilson JE, Koenigsknecht MJ, Chou WC, Montgomery SA, Truax AD, Brickey WJ, Packey CD, Maharshak N, Matsushima GK, Plevy SE, Young VB, Sartor RB, Ting JP (2017a) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18(5):541–551. https://doi.org/10.1038/ni.3690

16 Chen L, Wilson JE, Koenigsknecht MJ, Chou WC, Montgomery SA, Truax AD, Brickey WJ, Packey CD, Maharshak N, Matsushima GK, Plevy SE, Young VB, Sartor RB, Ting JP (2017b) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18(5):541–551. https://doi.org/10.1038/ni.3690

17 Davenport ER, Cusanovich DA, Michelini K, Barreiro LB, Ober C, Gilad Y (2015) Genome-wide association studies of the human gut microbiota. PLoS One 10:e0140301

18 David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563

19 de Bruyn M, Vermeire S (2017) NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease. Expert Opin Ther Targets 21(12):1123–1139. https://doi.org/10.1080/14728222.2017.1397627

20 Dewhirst FE, Chen T, Izard J,Paster BJ, Tanner AC, Yu WH, Lakshmanan A, Wade WG (2010) The human oral microbiome. J Bacteriol 192:5002–5017

21 Dickson RP, Huffnagle GB (2015) The lung microbiome: new principles for respiratory bacteriology in health and disease. PLoS Pathog 11:e1004923

22 Dobson AJ, Chaston JM, Newell PD, Donahue L, Hermann SL, Sannino DR, Westmiller S, Wong AC, Clark AG, Lazzaro BP (2015) Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster. Nat Commun 6:6312

23 Dominianni C, Sinha R, Goedert JJ, Pei Z, Yang L, Hayes RB, Ahn J(2015) Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS One 10:e0124599

24 Dudbridge F (2013) Power and predictive accuracy of polygenic risk scores. Plos Genet 9:e1003348

25 Ellis JG (2017) Can plant microbiome studies lead to effective biocontrol of plant diseases? Mol Plant-Microbe Interact 30:190–193

26 Falony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, Kurilshikov A, Bonder MJ, Valles-Colomer M, Vandeputte D (2016) Population-level analysis of gut microbiome variation. Science 352:560–564

27 Foster J, Neufeld KA (2014) Gut-brain axis: How the microbiome influences anxiety and depression. Int J Neuropsychopharmacol 17:27

28 Gampa A, Engen PA, Shobar R,Mutlu EA (2017) Relationships between gastrointestinal microbiota and blood group antigens. Physiol Genom 49:473–483

29 Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M,Van Treuren W, Knight R, Bell JT (2014) Human genetics shape the gut microbiome. Cell 159:789–799

30 Goodrich JK, Davenport ER, Beaumont M, Jackson MA, Knight R, Ober C, Spector TD, Bell JT, Clark AG, Ley RE (2016) Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe 19:731–743

31 Grice EA, Segre JA (2011) The skin microbiome. Nat Rev Microbiol 9:244–253

32 Gupta S (2016) Infectious disease: something in the water. Nature 533:S114–S115

33 Hall AB, Tolonen AC, Xavier RJ (2017) Human genetic variation and the gut microbiome in disease. Nat Rev Genet 18:690

34 Hanauer SB (2006) Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 12(Suppl 1):S3–S9

35 Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108

36 Hooper LV, Littman DR, Macpherson AJ (2012) Interactions between the microbiota and the immune system. Science 336:1268–1273

37 Horton MW, Bodenhausen N, Beilsmith K, Meng DZ, Muegge BD, Subramanian S, Vetter MM, Vilhjalmsson BJ, Nordborg M, Gordon JI (2014) Genome-wide association study of Arabidopsis thaliana leaf microbial community. Nat Commun 5:5320

38 Hov JR, Zhong HZ, Qin BC, Anmarkrud JA, Holm K, Franke A, Lie BA, Karlsen TH (2015) The influence of the autoimmunityassociated ancestral HLA haplotype AH8.1 on the human gut microbiota: a cross-sectional study. Plos One 10:e0133804

39 Jin D, Wu S, Zhang YG, Lu R, Xia Y, Dong H, Sun J (2015) Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal microbiome. Clin Ther 37(5):996.e7–1009. e7.https://doi.org/10.1016/j.clinthera.2015.04.004

40 Jones EA, Kananurak A, Bevins CL, Hollox EJ, Bakaletz LO (2014) Copy number variation of the beta defensin gene cluster on chromosome 8p influences the bacterial microbiota within the nasopharynx of otitis-prone children. PLoS One. 9(5):e98269. https://doi.org/10.1371/journal.pone.0098269

41 Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA (2012) Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124

42 Kamada N, Seo SU, Chen GY, Nunez G (2013) Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 13:321–335

43 Kang HM, Zaitlen NA, Wade CM, Kirby A, Heckerman D, Daly MJ, Eskin E (2008) Efficient control of population structure in model organism association mapping. Genetics 178:1709–1723

44 Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI (2011) Human nutrition, the gut microbiome and the immune system. Nature 474:327–336

45 Kieser KJ, Kagan JC (2017) Multi-receptor detection of individual bacterial products by the innate immune system. Nat Rev Immunol 17:376–390

46 Kökten T, Gibot S, Lepage P, D’Alessio S, Hablot J, Ndiaye NC, Busby-Venner H, Monot C, Garnier B, Moulin D, Jouzeau JY, Hansmannel F, Danese S, Guéant JL, Muller S, Peyrin-Biroulet L (2018) TREM-1 inhibition restores impaired autophagy activity and reduces colitis in mice. J Crohns Colitis 12(2):230–244. https://doi.org/10.1093/ecco-jcc/jjx129

47 Kostic AD, Xavier RJ, Gevers D (2014) The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146:1489–1499

48 Kostic AD, Gevers D, Siljander H, Vatanen T,Hyotylainen T, Hamalainen AM, Peet A, Tillmann V, Poho P, Mattila I (2015) The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17:260–273

49 Kozik AJ, Nakatsu CH, Chun H, Jones-Hall YL (2017) Age, sex, and TNF associated differences in the gut microbiota of mice and their impact on acute TNBS colitis. Exp Mol Pathol 103(3):311–319. https://doi.org/10.1016/j.yexmp.2017.11.014

50 Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, Bell R, Ajami NJ, Petrosino JF, Morrison L, Potts WK, Jensen PE, O’Connell RM, Round JL (2015a) MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun. 23(6):8642. https://doi.org/10.1038/ncomms9642

51 Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, Bell R, Ajami NJ, Petrosino JF, Morrison L (2015b) MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat Commun 6:8642

52 Kurilshikov A, Wijmenga C, Fu J, Zhernakova A (2017) Host genetics and gut microbiome: challenges and perspectives. Trends Immunol 38:633–647

53 Lahti L, Salojarvi J, Salonen A, Scheffer M, de Vos WM (2014) Tipping elements in the human intestinal ecosystem. Nat Commun.https://doi.org/10.1038/ncomms5344

54 Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H (2016) CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 22(6):598–605. https://doi.org/10.1038/nm.4102

55 Larsson E, Tremaroli V, Lee YS, Koren O, Nookaew I, Fricker A, Nielsen J, Ley RE, Bäckhed F (2012) 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 (8):1124–1131. https://doi.org/10.1136/gutjnl-2011-301104

56 Leamy LJ, Kelly SA, Nietfeldt J, Legge RM, Ma F, Hua K, Sinha R, Peterson DA, Walter J, Benson AK (2014) Host genetics and diet, but not immunoglobulin A expression, converge to shape compositional features of the gut microbiome in an advanced intercross population of mice. Genome Biol 15:552

57 Lee SY, Yu J, Ahn KM, Kim KW, Shin YH, Lee KS, Hong SA, Jung YH, Lee E, Yang SI, Seo JH, Kwon JW, Kim BJ, Kim HB, Kim WK, Song DJ, Jang GC, Shim JY, Lee SY, Kwon JY, Choi SJ, Lee KJ, Park HJ, Won HS, Yoo HS, Kang MJ, Kim HY, Hong SJ (2014) Additive effect between IL-13 polymorphism and cesarean section delivery/prenatal antibiotics use on atopic dermatitis: a birth cohort study (COCOA). PLoS One. 9(5):e96603. https://doi.org/10.1371/journal.pone.0096603

58 Ley R, Lozupone CA, Hamady M, Knight R, Gordon JI (2008) Worlds within worlds: evolution of the vertebrate gut microbiota. Nat Rev Microbiol 6(10):776–788. https://doi.org/10.1038/nrmicro1978

59 Li D, Achkar JP, Haritunians T, Jacobs JP, Hui KY, D’Amato M, Brand S, Radford-Smith G, Halfvarson J, Niess JH, Kugathasan S, Büning C, Schumm LP, Klei L, Ananthakrishnan A, Aumais G, Baidoo L, Dubinsky M, Fiocchi C, Glas J, Milgrom R, Proctor DD, Regueiro M, Simms LA, Stempak JM, Targan SR, Törkvist L, Sharma Y, Devlin B, Borneman J, Hakonarson H, Xavier RJ, Daly M, Brant SR, Rioux JD, Silverberg MS, Cho JH, Braun J, McGovern DP, Duerr RH (2016) A pleiotropic missense variant in SLC39A8 is associated with Crohn’s Disease and human gut microbiome composition. Gastroenterology 151(4):724–732. https://doi.org/10.1053/j.gastro.2016.06.051

60 Lo Sasso G, Ryu D, Mouchiroud L, Fernando SC, Anderson CL, Katsyuba E, Piersigilli A, Hottiger MO, Schoonjans K, Auwerx J (2014) Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer. PLoS One. 9(7):e102495. https://doi.org/10.1371/journal.pone. 0102495

61 Lozupone C, Lladser ME, Knights D, Stombaugh J, Knight R (2011) UniFrac: an effective distance metric for microbial community comparison. Isme Journal 5:169–172

62 Lundberg DS, Lebeis SL, Paredes SH, Yourstone S, Gehring J, Malfatti S, Tremblay J, Engelbrektson A, Kunin V, Del Rio TG (2012) Defining the core Arabidopsis thaliana root microbiome. Nature 488:86–90

63 McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9:356–369

64 McGovern DPB, Jones MR, Taylor KD, Marciante K, Yan XF, Dubinsky M, Ippoliti A, Vasiliauskas E, Berel D, Derkowski C (2010) Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum Mol Genet 19:3468–3476

65 McKnite AM, Perez-Munoz ME, Lu L, Williams EG, Brewer S, Andreux PA, Bastiaansen JWM, Wang XS, Kachman SD, Auwerx J (2012) Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits. PLoS ONE 7:e39191

66 Milot E, Pelletier F (2013) Human evolution: new playgrounds for natural selection. Curr Biol 23:R446–R448

67 Moalem S, Prince J (2008) Survival of the sickest: the surprising connections between disease and longevity. Harper, London

68 Moeller AH, Li Y, Mpoudi Ngole E, Ahuka-Mundeke S, Lonsdorf EV, Pusey AE, Peeters M, Hahn BH, Ochman H (2014) Rapid changes in the gut microbiome during human evolution. Proc Natl Acad Sci USA 111:16431–16435

69 Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13:R79

70 Moschen AR, Gerner RR, Wang J, Klepsch V, Adolph TE, Reider SJ, Hackl H, Pfister A, Schilling J, Moser PL, Kempster SL, Swidsinski A, Orth Höller D, Weiss G, Baines JF, Kaser A, Tilg H (2016) Lipocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations. Cell Host Microbe. 19(4):455–469. https://doi.org/10.1016/j.chom.2016.03.007

71 Nakagome S, Chinen H, Iraha A, Hokama A, Takeyama Y, Sakisaka S, Matsui T, Kidd JR, Kidd KK, Said HS, Suda W, Morita H, Hattori M, Hanihara T, Kimura R, Ishida H, Fujita J, Kinjo F, Mano S, Oota H (2017) Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn’s disease in the Ryukyu Islands. Hum Genet. 136(4):387–397. https://doi.org/10.1007/s00439-017-1764-0

72 Neefjes J, Jongsma ML, Paul P, Bakke O (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11:823–836

73 Nester EW (2015) Agrobacterium: nature’s genetic engineer. Front Plant Sci 5:730

74 Nielsen R, Hellmann I, Hubisz M, Bustamante C, Clark AG (2007) Recent and ongoing selection in the human genome. Nat Rev Genet 8:857–868

75 Nishida AH, Ochman H (2017) Rates of gut microbiome divergence in mammals. Mol Ecol

76 Nissilä E, Korpela K, Lokki AI, Paakkanen R, Jokiranta S, de Vos WM, Lokki ML, Kolho KL, Meri S (2017) C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease. Clin Exp Immunol. 190(3):394–405. https://doi.org/10.1111/cei.13040

77 Novembre J, Han EJ (2012) Human population structure and the adaptive response to pathogen-induced selection pressures. Philos Trans R Soc B 367:878–886

78 Ochman H, Worobey M, Kuo CH, Ndjango JB, Peeters M, Hahn BH, Hugenholtz P (2010) Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biol 8:e1000546

79 Org E, Parks BW, Joo JW, Emert B, Schwartzman W, Kang EY, Mehrabian M, Pan C, Knight R, Gunsalus R (2015) Genetic and environmental control of host-gut microbiota interactions. Genome Res 25:1558–1569

80 Peuker K, Muff S, Wang J, Künzel S, Bosse E, Zeissig Y, Luzzi G, Basic M, Strigli A, Ulbricht A, Kaser A, Arlt A, Chavakis T, van den Brink GR, Schafmayer C, Egberts JH, Becker T, Bianchi ME, Bleich A, Röcken C, Hampe J, Schreiber S,Baines JF , Blumberg RS, Zeissig S (2016) Epithelial calcineurin controls microbiotadependent intestinal tumor development. Nat Med. 22(5):506–515. https://doi.org/10.1038/nm.4072

81 Pohjanen VM, Koivurova OP, Niemelä SE, Karttunen RA, Karttunen TJ (2016) Role of Helicobacter pylori and interleukin 6–174 gene polymorphism in dyslipidemia: a case-control study. BMJ Open. 6 (1):e009987. https://doi.org/10.1136/bmjopen-2015-009987

82 Price AL, Zaitlen NA, Reich D, Patterson N (2010) New approaches to population stratification in genome-wide association studies. Nat Rev Genet 11:459–463

83 Prugnolle F, Manica A, Charpentier M, Guegan JF, Guernier V,Balloux F (2005) Pathogen-driven selection and worldwide HLA class I diversity. Curr Biol 15:1022–1027

84 Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:59–65

85 Ramanan VK, Shen L, Moore JH, Saykin AJ (2012) Pathway analysis of genomic data: concepts, methods, and prospects for future development. Trends Genet 28:323–332

86 Rausch P,Rehman A, Künzel S, Häsler R, Ott SJ, Schreiber S, Rosenstiel P, Franke A, Baines JF (2011a) Colonic mucosaassociated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc Natl Acad Sci USA 108(47):19030–19035. https://doi.org/10.1073/pnas.1106408108

87 Rausch P, Rehman A, Kunzel S, Hasler R, Ott SJ, Schreiber S, Rosenstiel P, Franke A, Baines JF (2011b) Colonic mucosaassociated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc Natl Acad Sci USA 108:19030–19035

88 Rausch P, Steck N, Suwandi A, Seidel JA, Künzel S, Bhullar K, Basic M, Bleich A, Johnsen JM, Vallance BA, Baines JF, Grassl GA (2015) Expression of the blood-group-related gene B4galnt2 alters susceptibility to salmonella infection. PLoS Pathog 11(7): e1005008. https://doi.org/10.1371/journal.ppat.1005008

89 Rausch P, Künzel S, Suwandi A, Grassl GA, Rosenstiel P, Baines JF (2017) Multigenerational influences of the Fut2 gene on the dynamics of the gut microbiota in mice. Front Microbiol. 8:991. https://doi.org/10.3389/fmicb.2017.00991

90 Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO (2011) Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA 108:4680–4687

91 Ray K (2017) Alcoholic liver disease: gut-liver axis: PPIs, enterococcus and promotion of alcoholic liver disease. Nat Rev Gastroenterol Hepatol 14:689

92 Rodriguez-Nunez I, Caluag T, Kirby K, Rudick CN, Dziarski R, Gupta D (2017) Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction. Sci Rep. 7(1):548. https://doi.org/10.1038/s41598-017-00484-2

93 Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kébir H,Anandasabapathy N , Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 22(6):586–597. https://doi.org/10.1038/nm.4106 Epub 2016 May 9

94 Ruhlemann MC, Degenhardt F, Thingholm LB, Wang J, Skieceviciene J, Rausch P, Hov JR, Lieb W, Karlsen TH, Laudes M (2017) Application of the distance-based F test in an mGWAS investigating beta diversity of intestinal microbiota identifies variants in SLC9A8 (NHE8) and 3 other loci. Gut Microbes 48:1–8

95 Sadaghian Sadabad M, Regeling A, de Goffau MC, Blokzijl T, Weersma RK, Penders J, Faber KN, Harmsen HJ, Dijkstra G (2015) The ATG16L1-T300A allele impairs clearance of pathosymbionts in the inflamed ileal mucosa of Crohn’s disease patients. Gut. 64(10):1546–1552. https://doi.org/10.1136/gutjnl-2014-307289

96 Santos-Cortez RL, Hutchinson DS, Ajami NJ, Reyes-Quintos MR, Tantoco ML, Labra PJ, Lagrana SM, Pedro M, Llanes EG, Gloria-Cruz TL, Chan AL, Cutiongco-de la Paz EM, Belmont JW, Chonmaitree T, Abes GT, Petrosino JF, Leal SM, Chiong CM (2016) Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene. Infect Dis Poverty 5(1):97

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

98 Sovran B, Loonen LM, Lu P, Hugenholtz F, Belzer C, Stolte EH, Boekschoten MV, van Baarlen P, Kleerebezem M, de Vos P, Dekker J, Renes IB, Wells JM (2015) IL-22-STAT3 pathway plays a key role in the maintenance of ileal homeostasis in mice lacking secreted mucus barrier. Inflamm Bowel Dis. 21(3):531–542. https://doi.org/10.1097/MIB.0000000000000319

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

100 Srinivas G, Moller S, Wang J, Kunzel S, Zillikens D, Baines JF, Ibrahim SM (2013) Genome-wide mapping of gene-microbiota interactions in susceptibility to autoimmune skin blistering. Nat Commun 4:2462

101 Staubach F, Kunzel S, Baines AC, Yee A, McGee BM, Backhed F, Baines JF, Johnsen JM (2012) Expression of the blood-grouprelated glycosyltransferase B4galnt2 influences the intestinal microbiota in mice. ISME J 6:1345–1355

102 Stein JM, Lammert F, Zimmer V, Granzow M, Reichert S, Schulz S, Ocklenburg C, Conrads G (2010) Clinical periodontal and microbiologic parameters in patients with Crohn’s disease with consideration of the CARD15 genotype. J Periodontol. 81(4):535–545

103 Taylor SL, Woodman RJ, Chen AC, Burr LD, Gordon DL, McGuckin MA, Wesselingh S, Rogers GB (2017) FUT2 genotype influences lung function, exacerbation frequency and airway microbiota in non-CF bronchiectasis. Thorax 72(4):304–310. https://doi.org/10.1136/thoraxjnl-2016-208775

104 Thingholm L, Rühlemann M, Wang J, Hübenthal M, Lieb W, Laudes M, Franke A, D’Amato M (2018) Sucrase-isomaltase 15Phe IBS risk variant in relation to dietary carbohydrates and faecal microbiota composition. Gut. https://doi.org/10.1136/gutjnl-2017-315841

105 Tschurtschenthaler M, Wang J, Fricke C, Fritz TM, Niederreiter L, Adolph TE, Sarcevic E, Künzel S, Offner FA, Kalinke U, Baines JF, Tilg H, Kaser A (2014) Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelial regeneration. Gut. 63(12):1921–1931. https://doi.org/10.1136/gutjnl-2013-305863

106 Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, Guttman DS, Griffiths A, Panaccione R, Otley A (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48:1413–1417

107 Vallier M, Abou Chakra M, Hindersin L, Linnenbrink M, Traulsen A, Baines JF (2017) Evaluating the maintenance of disease-associated variation at the blood group-related gene B4galnt2 in house mice. BMC Evol Biol 17:187

108 Walter J, Ley R (2011) The human gut microbiome: ecology and recent evolutionary changes. Ann Rev Microbiol 65(65):411–429

109 Wang J, Kalyan S, Steck N, Turner LM, Harr B, Kunzel S, Vallier M, Hasler R, Franke A, Oberg HH (2015) Analysis of intestinal microbiota in hybrid house mice reveals evolutionary divergence in a vertebrate hologenome. Nat Commun 6:6440

110 Wang J, Thingholm LB, Skieceviciene J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen FA, Ruhlemann MC, Szymczak S (2016) Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 48:1396–1406

111 Ward MA, Pierre JF, Leal RF, Huang Y, Shogan B, Dalal SR, Weber CR, Leone VA, Musch MW, An GC, Rao MC, Rubin DT, Raffals LE, Antonopoulos DA, Sogin ML, Hyman NH, Alverdy JC, Chang EB (2016) Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility. Am J Physiol Gastrointest Liver Physiol. 310(11):G973–G988. https://doi.org/10.1152/ajpgi.00017.2016

112 Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA (2008) Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455:1109–1113

113 Wernegreen JJ (2002) Genome evolution in bacterial endosymbionts of insects. Nat Rev Genet 3:850–861

114 World Health Organization (2016) Global tuberculosis report 2016. WHO, Geneva

115 Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434

116 Xie HL, Guo RJ, Zhong HZ, Feng Q, Lan Z, Qin BC, Ward KJ, Jackson MA, Xia Y, Chen X (2016) Shotgun metagenomics of 250 adult twins reveals genetic and environmental impacts on the gut microbiome. Cell Syst 3:572

117 Yassour M, Vatanen T, Siljander H, Hamalainen AM, Harkonen T, Ryhanen SJ, Franzosa EA, Vlamakis H, Huttenhower C, Gevers D (2016) Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med 8:343ra381

118 Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP (2012) Human gut microbiome viewed across age and geography. Nature 486:222–227

119 Ye Y, Carlsson G, Wondimu B, Fahlén A, Karlsson-Sjöberg J, Andersson M,Engstrand L, Yucel-Lindberg T, Modéer T, Pütsep K (2011) Mutations in the ELANE gene are associated with development of periodontitis in patients with severe congenital neutropenia. J Clin Immunol. 31(6):936–945. https://doi.org/10.1007/s10875-011-9572-0 Epub 2011 Jul 29

120 Zhao L, Wang G,Siegel P, He C, Wang H, Zhao W, Zhai Z, Tian F, Zhao J, Zhang H(2013) Quantitative genetic background of the host influences gut microbiomes in chickens. Sci Rep 3:1163

121 Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira-Silva S (2016) Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352:565–569

122 Zhu B, Wang X, Li L (2010) Human gut microbiome: the second genome of human body. Protein Cell 1:718–725

123 Zilber-Rosenberg I, Rosenberg E (2008) Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution. FEMS Microbiol Rev 32:723–735