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. 2018 Jan;67(1):108-119.
doi: 10.1136/gutjnl-2016-312135. Epub 2016 Oct 8.

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease

Floris Imhann  1   2 , Arnau Vich Vila  1   2 , Marc Jan Bonder  2 , Jingyuan Fu  3 , Dirk Gevers  4 , Marijn C Visschedijk  1   2 , Lieke M Spekhorst  1   2 , Rudi Alberts  1   2 , Lude Franke  2 , Hendrik M van Dullemen  1 , Rinze W F Ter Steege  1 , Curtis Huttenhower  4   5 , Gerard Dijkstra  1 , Ramnik J Xavier  4   6 , Eleonora A M Festen  1   2 , Cisca Wijmenga  2 , Alexandra Zhernakova  2 , Rinse K Weersma  1
Affiliations

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease

Floris Imhann et al. Gut. 2018 Jan.

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.

Keywords: BACTERIAL INTERACTIONS; GENETICS; INFLAMMATORY BOWEL DISEASE; INTESTINAL BACTERIA.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Alpha diversity (Shannon Index) of the gut microbiota of healthy controls, Ulcerative Colitis (UC) patients, colonic Crohn’s Disease (CD) patients, ileocolonic CD patients and ileal CD patients. Alpha diversity is not decreased in colonic disease (UC and colonic CD) compared to healthy controls. In contrast, in ileal and ileocolonic CD patients, the alpha diversity is statistically significantly decreased (ileal CD patients vs. healthy controls P = 3.28 × 10−13 and ileocolonic CD patients vs. healthy controls P = 3.11 × 10−11, Wilcoxon test).
Figure 2
Figure 2
Principal Coordinate Analysis (PCoA) of stool samples of 313 IBD patients and 582 healthy controls. (A) The gut microbiota of IBD patients is different from the gut microbiota of healthy controls, with only partial overlap. (B) The first component is related to the Shannon Index. (C, D) There is more overlap between colonic disease (Ulcerative Colitis and colonic Crohn’s Disease combined) and healthy controls than between ileal disease (ileal Crohn’s Disease and ileocolonic Crohn’s Disease combined) and healthy controls. The first component is related to disease location (PCoA1 rho=0.63, P = 7.39 × 10−91, Spearman correlation) and colonic CD patients differ from ileal CD patients (P = 5.42 × 10−9).
Figure 3
Figure 3
Increased risk score of 11 IBD related genetic variants in gut bacterial handling genes (NOD2, CARD9, IRGM, ATG16L1 and FUT2) is statistically significantly associated to decreased abundance of Roseburia spp. in healthy controls (FDR = 0.017).
Figure 4
Figure 4
Fold change of increased and decreased bacterial families in UC and CD patients versus healthy controls (FDR
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