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Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease
  1. Floris Imhann1,2,
  2. Arnau Vich Vila1,2,
  3. Marc Jan Bonder2,
  4. Jingyuan Fu3,
  5. Dirk Gevers4,
  6. Marijn C Visschedijk1,2,
  7. Lieke M Spekhorst1,2,
  8. Rudi Alberts1,2,
  9. Lude Franke2,
  10. Hendrik M van Dullemen1,
  11. Rinze W F Ter Steege1,
  12. Curtis Huttenhower4,6,
  13. Gerard Dijkstra1,
  14. Ramnik J Xavier4,5,
  15. Eleonora A M Festen1,2,
  16. Cisca Wijmenga2,
  17. Alexandra Zhernakova2,
  18. Rinse K Weersma1
  1. 1Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  2. 2Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  3. 3Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  4. 4Broad Institute of Harvard and MIT, Boston, Massachusetts, USA
  5. 5Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6Biostatistics Department, Harvard School of Public Health, Boston, Massachusetts, USA
  1. Correspondence to Dr Rinse K Weersma, Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, Groningen 9700RB, The Netherlands; r.k.weersma{at}umcg.nl

Abstract

Objective Patients with IBD display substantial heterogeneity in clinical characteristics. We hypothesise that individual differences in the complex interaction of the host genome and the gut microbiota can explain the onset and the heterogeneous presentation of IBD. Therefore, we performed a case–control analysis of the gut microbiota, the host genome and the clinical phenotypes of IBD.

Design Stool samples, peripheral blood and extensive phenotype data were collected from 313 patients with IBD and 582 truly healthy controls, selected from a population cohort. The gut microbiota composition was assessed by tag-sequencing the 16S rRNA gene. All participants were genotyped. We composed genetic risk scores from 11 functional genetic variants proven to be associated with IBD in genes that are directly involved in the bacterial handling in the gut: NOD2, CARD9, ATG16L1, IRGM and FUT2.

Results Strikingly, we observed significant alterations of the gut microbiota of healthy individuals with a high genetic risk for IBD: the IBD genetic risk score was significantly associated with a decrease in the genus Roseburia in healthy controls (false discovery rate 0.017). Moreover, disease location was a major determinant of the gut microbiota: the gut microbiota of patients with colonic Crohn's disease (CD) is different from that of patients with ileal CD, with a decrease in alpha diversity associated to ileal disease (p=3.28×10−13).

Conclusions We show for the first time that genetic risk variants associated with IBD influence the gut microbiota in healthy individuals. Roseburia spp are acetate-to-butyrate converters, and a decrease has already been observed in patients with IBD.

  • INFLAMMATORY BOWEL DISEASE
  • GENETICS
  • BACTERIAL INTERACTIONS
  • INTESTINAL BACTERIA

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Footnotes

  • FI and AVV are shared first authors.

  • AZ and RKW are shared last authors.

  • Contributors RKW, DG, AZ, GD, CH and RJX designed the study. FI, MCV, LMS, HMvD, RWFTS, GD and RKW collected the data. FI, AVV, MJB, RA and JF analysed the data. FI, AVV, EAMF and RKW drafted the manuscript. CW, JF, EAMF, LF, DG, AZ, GD, CH, RJX and RKW critically reviewed the manuscript.

  • Funding RKW, JF and LF are supported by VIDI grants (016.136.308, 864.13.013 and 917.14.374) from the Netherlands Organization for Scientific Research (NWO). EAMF is funded by a career development grant from the Dutch Digestive Foundation (MLDS) (No. CDG-014). Sequencing of the LifeLines deep cohort was funded by a Top Institute Food and Nutrition grant GH001 to CW. CW is further supported by an ERC advanced grant (ERC-671274). AZ holds a Rosalind Franklin fellowship (University of Groningen) and a CardioVasculair Onderzoek Nederland grant (CVON 2012-03).

  • Competing interests None declared.

  • Ethics approval Institutional Review Board of the University Medical Center Groningen.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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