Complex host genetics influence the microbiome in inflammatory bowel disease

详细信息    查看全文

• 作者：Dan Knights (1) (2) (3) (4)
  Mark S Silverberg (5)
  Rinse K Weersma (6)
  Dirk Gevers (2)
  Gerard Dijkstra (6)
  Hailiang Huang (7)
  Andrea D Tyler (5)
  Suzanne van Sommeren (6) (8)
  Floris Imhann (6) (8)
  Joanne M Stempak (5)
  Hu Huang (9)
  Pajau Vangay (9)
  Gabriel A Al-Ghalith (9)
  Caitlin Russell (10) (3)
  Jenny Sauk (10)
  Jo Knight (11)
  Mark J Daly (12) (13) (2)
  Curtis Huttenhower (14) (2)
  Ramnik J Xavier (10) (2) (3)
  
  1. Department of Computer Science and Engineering ; University of Minnesota ; Minneapolis ; Minnesota ; 55455 ; USA
  2. Broad Institute of Harvard and MIT ; Cambridge ; Massachusetts ; 02142 ; USA
  3. Center for Computational and Integrative Biology ; Massachusetts General Hospital and Harvard Medical School ; Boston ; Massachusetts ; 02114 ; USA
  4. Biotechnology Institute ; University of Minnesota ; St. Paul ; Minnesota ; 55108 ; USA
  5. Zane Cohen Centre for Digestive Diseases ; Mount Sinai Hospital IBD Group ; University of Toronto ; Toronto ; Ontario ; M5G 1X5 ; Canada
  6. Department of Gastroenterology and Hepatology ; University Medical Center Groningen ; Groningen ; 9700RB ; The Netherlands
  7. Analytic and Translational Genetics Unit ; Massachusetts General Hospital ; Boston ; Massachusetts ; 02114 ; USA
  8. Department of Genetics ; University Medical Center Groningen ; Groningen ; 9700RB ; The Netherlands
  9. Biomedical Informatics and Computational Biology ; University of Minnesota ; Minneapolis ; Minnesota ; 55455 ; USA
  10. Division of Gastroenterology ; Massachusetts General Hospital and Harvard Medical School ; Boston ; Massachusetts ; 02114 ; USA
  11. Department of Psychiatry ; University of Toronto ; Toronto ; Ontario ; M5T 1R8 ; Canada
  12. Department of Medicine ; Analytic and Translational Genetics Unit ; Massachusetts General Hospital and Harvard Medical School ; Boston ; Massachusetts ; 02114 ; USA
  13. Program in Medical and Population Genetics ; Broad Institute of Harvard and MIT ; Cambridge ; Massachusetts ; 02142 ; USA
  14. Biostatistics Department ; Harvard School of Public Health ; Boston ; Massachusetts ; 02115 ; USA
  
• 刊名：Genome Medicine
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：6
• 期：12
• 全文大小：1,533 KB
• 参考文献：1. Jostins, L, Ripke, S, Weersma, RK, Duerr, RH, McGovern, DP, Hui, KY, Lee, JC, Schumm, LP, Sharma, Y, Anderson, CA, Essers, J, Mitrovic, M, Ning, K, Cleynen, I, Theatre, E, Spain, SL, Raychaudhuri, S, Goyette, P, Wei, Z, Abraham, C, Achkar, JP, Ahmad, T, Amininejad, L, Ananthakrishnan, AN, Andersen, V, Andrews, JM, Baidoo, L, Balschun, T, Bampton, PA, Bitton, A (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491: pp. 119-124 CrossRef
  2. Abraham, C, Cho, J (2009) Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 15: pp. 1090-1100 CrossRef
  3. Knights, D, Lassen, KG, Xavier, RJ (2013) Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 62: pp. 1505-1510 12-303954" target="_blank" title="It opens in new window">CrossRef
  4. Morgan, XC, Tickle, TL, Sokol, H, Gevers, D, Devaney, KL, Ward, DV, Reyes, JA, Shah, SA, LeLeiko, N, Snapper, SB, Bousvaros, A, Korzenik, J, Sands, BE, Xavier, RJ, Huttenhower, C (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13: pp. R79 12-13-9-r79" target="_blank" title="It opens in new window">CrossRef
  5. Baumgart, M, Dogan, B, Rishniw, M, Weitzman, G, Bosworth, B, Yantiss, R, Orsi, RH, Wiedmann, M, McDonough, P, Kim, SG, Berg, D, Schukken, Y, Scherl, E, Simpson, KW (2007) Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn鈥檚 disease involving the ileum. ISME J 1: pp. 403-418 CrossRef
  6. Frank, DN, St Amand, AL, Feldman, RA, Boedeker, EC, Harpaz, N, Pace, NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104: pp. 13780-13785 CrossRef
  7. Scanlan, PD, Shanahan, F, O鈥橫ahony, C, Marchesi, JR (2006) Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn鈥檚 disease. J Clin Microbiol 44: pp. 3980-3988 128/JCM.00312-06" target="_blank" title="It opens in new window">CrossRef
  8. Li, E, Hamm, CM, Gulati, AS, Sartor, RB, Chen, H, Wu, X, Zhang, T, Rohlf, FJ, Zhu, W, Gu, C, Robertson, CE, Pace, NR, Boedeker, EC, Harpaz, N, Yuan, J, Weinstock, GM, Sodergren, E, Frank, DN (2012) Inflammatory bowel diseases phenotype, C. difficile and NOD2 genotype are associated with shifts in human ileum associated microbial composition. PLoS One 7: pp. e26284 CrossRef
  9. Dalton, JP, Desmond, A, Shanahan, F, Hall, C (2014) Detection of Mycobacterium avium subspecies paratuberculosis in patients with Crohn鈥檚 disease is unrelated to the presence of single nucleotide polymorphisms rs2241880 (ATG16L1) and rs10045431 (IL12B). Med microbiol and immun 203: pp. 195-205 CrossRef
  10. Ott, SJ, Musfeldt, M, Wenderoth, DF, Hampe, J, Brant, O, F枚lsch, UR, Timmis, KN, Schreiber, S (2004) Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut 53: pp. 685-693 CrossRef
  11. Smeekens, SP, Huttenhower, C, Riza, A, Veerdonk, FL, Zeeuwen, PLJM, Schalkwijk, J, Meer, JWM, Xavier, RJ, Netea, MG, Gevers, D (2013) Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses. J Innate Immun 6: pp. 253-262
  12. Frank, DN, Robertson, CE, Hamm, CM, Kpadeh, Z, Zhang, T, Chen, H, Zhu, W, Sartor, RB, Boedeker, EC, Harpaz, N, Pace, NR, Li, E (2011) Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 17: pp. 179-184 CrossRef
  13. Couturier-Maillard, A, Secher, T, Rehman, A, Normand, S, Arcangelis, A, Haesler, R, Huot, L, Grandjean, T, Bressenot, A, Delanoye-Crespin, A, Gaillot, O, Schreiber, S, Lemoine, Y, Ryffel, B, Hot, D, N霉帽ez, G, Chen, G, Rosenstiel, P, Chamaillard, M (2013) NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 123: pp. 700-711
  14. Rajili膰-Stojanovi膰, M, Smidt, H, Vos, WM (2007) Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol 9: pp. 2125-2136 CrossRef
  15. Hansen, EE, Lozupone, CA, Rey, FE, Wu, M, Guruge, JL, Narra, A, Goodfellow, J, Zaneveld, JR, McDonald, DT, Goodrich, JA, Heath, AC, Knight, R, Gordon, JI (2011) Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii, studied in twins. Proc Natl Acad Sci U S A 108: pp. 4599-4606 CrossRef
  16. Ley, RE, B盲ckhed, F, Turnbaugh, P, Lozupone, CA, Knight, RD, Gordon, JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 102: pp. 11070-11075 CrossRef
  17. Hashimoto, T, Perlot, T, Rehman, A, Trichereau, J, Ishiguro, H, Paolino, M, Sigl, V, Hanada, T, Hanada, R, Lipinski, S, Wild, B, Camargo, SM, Singer, D, Richter, A, Kuba, K, Fukamizu, A, Schreiber, S, Clevers, H, Verrey, F, Rosenstiel, P, Penninger, JM (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487: pp. 477-481 1228" target="_blank" title="It opens in new window">CrossRef
  18. Cortes, A, Brown, MA (2011) Promise and pitfalls of the Immunochip. Arthritis Res Ther 13: pp. 101 CrossRef
  19. Meth茅, BA, Nelson, KE, Pop, M, Creasy, HH, Giglio, MG, Huttenhower, C, Gevers, D, Petrosino, JF, Abubucker, S, Badger, JH, Chinwalla, AT, Earl, AM, FitzGerald, MG, Fulton, RS, Hallsworth-Pepin, K, Lobos, EA, Madupu, R, Magrini, V, Martin, JC, Mitreva, M, Muzny, DM, Sodergren, EJ, Versalovic, J, Wollam, AM, Worley, KC, Wortman, JR, Young, SK, Zeng, Q, Aagaard, KM, Abolude, OO (2012) A framework for human microbiome research. Nature 486: pp. 215-221 1209" target="_blank" title="It opens in new window">CrossRef
  20. Gevers, D, Kugathasan, S, Denson, LA, V谩zquez-Baeza, Y, Treuren, W, Ren, B, Schwager, E, Knights, D, Song, SJ, Yassour, M, Morgan, XC, Kostic, AD, Luo, C, Gonz谩lez, A, McDonald, D, Haberman, Y, Walters, T, Baker, S, Rosh, J, Stephens, M, Heyman, M, Markowitz, J, Baldassano, R, Griffiths, A, Sylvester, F, Mack, D, Kim, S, Crandall, W, Hyams, J, Huttenhower, C (2014) The treatment-naive microbiome in new-onset Crohn鈥檚 disease. Cell Host Microbe 15: pp. 382-392 CrossRef
  21. Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MAR, Bender, D, Maller, J, Sklar, P, Bakker, PIW, Daly, MJ, Sham, PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: pp. 559-575 CrossRef
  22. Caporaso, JG, Kuczynski, J, Stombaugh, J, Bittinger, K, Bushman, FD, Costello, EK, Fierer, N, Pe帽a, AG, Goodrich, JK, Gordon, JI, Huttley, GA, Kelley, ST, Knights, D, Koenig, JE, Ley, RE, Lozupone, CA, McDonald, D, Muegge, BD, Pirrung, M, Reeder, J, Sevinsky, JR, Turnbaugh, PJ, Walters, WA, Widmann, J, Yatsunenko, T, Zaneveld, J, Knight, R (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7: pp. 335-336 CrossRef
  23. McDonald, D, Price, MN, Goodrich, J, Nawrocki, EP, DeSantis, TZ, Probst, A, Andersen, GL, Knight, R, Hugenholtz, P (2012) An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea. ISME J 6: pp. 610-618 CrossRef
  24. Lozupone, C, Lladser, ME, Knights, D, Stombaugh, J, Knight, R (2011) UniFrac: an effective distance metric for microbial community comparison. ISME J 5: pp. 169-172 CrossRef
  25. Meyer PE: infotheo: Information-Theoretic Measures [http://cran.r-project.org/web/packages/infotheo/index.html]
  26. Press WH, Flannery BP, Teukolsky SA, Vetterling WT: Statistical Description of Data. In / Numerical Recipes in C: The Art of Scientific Computing. 3rd edition. New York: Cambridge University Press; 1992:634..
  27. Csardi G, Nepusz T: The igraph software package for complex network research. / InterJournal 2006, Complex Sy:1695.
  28. Knights, D, Parfrey, LW, Zaneveld, J, Lozupone, C, Knight, R (2011) Human-associated microbial signatures: examining their predictive value. Cell Host Microbe 10: pp. 292-296 CrossRef
  29. Rivas, MA, Beaudoin, M, Gardet, A, Stevens, C, Sharma, Y, Zhang, CK, Boucher, G, Ripke, S, Ellinghaus, D, Burtt, N, Fennell, T, Kirby, A, Latiano, A, Goyette, P, Green, T, Halfvarson, J, Haritunians, T, Korn, JM, Kuruvilla, F, Lagac茅, C, Neale, B, Lo, KS, Schumm, P, T枚rkvist, L, Dubinsky, MC, Brant, SR, Silverberg, MS, Duerr, RH, Altshuler, D, Gabriel, S (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43: pp. 1066-1073 CrossRef
  30. Zuberi, K, Franz, M, Rodriguez, H, Montojo, J, Lopes, CT, Bader, GD, Morris, Q (2013) GeneMANIA prediction server 2013 update. Nucleic Acids Res 41: pp. W115-W122 CrossRef
  31. Migone, TS, Zhang, J, Luo, X, Zhuang, L, Chen, C, Hu, B, Hong, JS, Perry, JW, Chen, SF, Zhou, JXH, Cho, YH, Ullrich, S, Kanakaraj, P, Carrell, J, Boyd, E, Olsen, HS, Hu, G, Pukac, L, Liu, D, Ni, J, Kim, S, Gentz, R, Feng, P, Moore, PA, Ruben, SM, Wei, P (2002) TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16: pp. 479-492 CrossRef
  32. Jin, S, Chin, J, Seeber, S, Niewoehner, J, Weiser, B, Beaucamp, N, Woods, J, Murphy, C, Fanning, A, Shanahan, F, Nally, K, Kajekar, R, Salas, A, Planell, N, Lozano, J, Panes, J, Parmar, H, Demartino, J, Narula, S, Thomas-Karyat, DA (2012) TL1A/TNFSF15 directly induces proinflammatory cytokines, including TNF伪, from CD3鈥?鈥塁D161+ T cells to exacerbate gut inflammation. Mucosal Immunol 6: pp. 886-899 12.124" target="_blank" title="It opens in new window">CrossRef
  33. Garrett, WS, Gallini, CA, Yatsunenko, T, Michaud, M, DuBois, A, Delaney, ML, Punit, S, Karlsson, M, Bry, L, Glickman, JN, Gordon, JI, Onderdonk, AB, Glimcher, LH (2010) Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8: pp. 292-300 CrossRef
  34. Mylonaki, M, Rayment, NB, Rampton, DS, Hudspith, BN, Brostoff, J (2005) Molecular characterization of rectal mucosa-associated bacterial flora in inflammatory bowel disease. Inflamm Bowel Dis 11: pp. 481-487 CrossRef
  35. Tyler, AD, Milgrom, R, Stempak, JM, Xu, W, Brumell, JH, Muise, AM, Sehgal, R, Cohen, Z, Koltun, W, Shen, B, Silverberg, MS (2013) The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis. Gut 62: pp. 1433-1439 CrossRef
  36. Sehgal, R, Berg, A, Hegarty, JP, Kelly, AA, Lin, Z, Poritz, LS, Koltun, WA (2010) NOD2/CARD15 mutations correlate with severe pouchitis after ileal pouch-anal anastomosis. Dis Colon Rectum 53: pp. 1487-1494 CrossRef
  37. Ben-Shachar, S, Yanai, H, Baram, L, Elad, H, Meirovithz, E, Ofer, A, Brazowski, E, Tulchinsky, H, Pasmanik-Chor, M, Dotan, I (2013) Gene expression profiles of ileal inflammatory bowel disease correlate with disease phenotype and advance understanding of its immunopathogenesis. Inflamm Bowel Dis 19: pp. 2509-2521 CrossRef
  38. Tyler AD, Milgrom R, Xu W, Stempak JM, Steinhart AH, McLeod RS, Greenberg GR, Cohen Z, Silverberg MS: Antimicrobial antibodies are associated with a Crohn鈥檚 disease-like phenotype after ileal pouch-anal anastomosis. / Clin Gastroenterol Hepatol 2012, 10:507鈥?2.e1.
  39. Wu, GD, Chen, J, Hoffmann, C, Bittinger, K, Chen, Y-Y, Keilbaugh, SA, Bewtra, M, Knights, D, Walters, WA, Knight, R, Sinha, R, Gilroy, E, Gupta, K, Baldassano, R, Nessel, L, Li, H, Bushman, FD, Lewis, JD (2011) Linking long-term dietary patterns with Gut Microbial Enterotypes. Science 334: pp. 105-108 126/science.1208344" target="_blank" title="It opens in new window">CrossRef
  40. David, LA, Maurice, CF, Carmody, RN, Gootenberg, DB, Button, JE, Wolfe, BE, Ling, AV, Devlin, AS, Varma, Y, Fischbach, MA, Biddinger, SB, Dutton, RJ, Turnbaugh, PJ (2013) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505: pp. 559-563 12820" target="_blank" title="It opens in new window">CrossRef
  41. Eklund A: beeswarm: The bee swarm plot, an alternative to stripchart [http://cran.r-project.org/web/packages/beeswarm/index.html]
  42. Bach, J-F (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347: pp. 911-920 CrossRef
  
• 刊物主题：Human Genetics; Proteomics; Bioinformatics; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1756-994X

文摘

Background Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease. Methods We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways. Results We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways. Conclusions These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.