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* = Presenting author

OP009 Gene-microbiome interactions underlying the onset and the clinical phenotypes of inflammatory bowel disease

F. Imhann*1, A. Vich Vila1, M. J. Bonder2, D. Gevers3, J. Fu2, M. C. Visschedijk1, L.M. Spekhorst1, L. Franke2, H. van Dullemen1, R. W. F. Ter Steege1, C. Huttenhower4, G. Dijkstra1, R. J. Xavier3, C. Wijmenga2, E. A. M. Festen1, A. Zhernakova2, R. K. Weersma1

1University of Groningen and University Medical Centre Groningen, Department of Gastroenterology and Hepatology, Groningen, Netherlands, 2University of Groningen and University Medical Centre Groningen, Department of Genetics, Groningen, Netherlands, 3The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States, 4Harvard School of Public Health, Biostatistics Department, Boston, Massachusetts, United States

Background

Patients with inflammatory bowel disease (IBD) comprising Crohn’s diseases (CD) and ulcerative colitis (UC) display substantial heterogeneity in disease activity, disease location, and other clinical characteristics. We hypothesise that individual differences in the complex interaction of the host genome and the gut microbiome can explain the onset and the heterogeneous presentation of IBD. Therefore, we performed an integrated single-centre case-control analysis of the luminal gut microbiome, the host genome, and the clinical phenotypes of IBD.

Methods

Stool samples, peripheral blood, laboratory markers, serology, and extensive phenotype data were collected from 313 patients with IBD and 582 healthy controls. The microbiome composition of the stool samples was assessed by tag sequencing the 16S rRNA gene. OTUs were picked using UCLUST, and Greengenes 13.8 was used as a reference. Pathways were imputated using PICRUSt/HUMANn. All participants were genotyped using the Illumina ImmunoChip. 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 (eg, NOD2, ATG16L1, etc). The associations between the microbiota composition, the host genetics risk scores, and the clinical phenotypes were analysed using additive general linear models in MaAsLin.

Results

We observed a significant dysbiosis in patients with IBD: 28% of the bacterial taxa, including 16 families, were significantly altered in CD patients, as compared with healthy controls, whereas 12% of the analysed taxa, including 9 families, were significantly altered in patients with UC (FDR < 0.05). Disease activity was associated with an increase of the family Enterobacteriaceae in patients with CD (FDR = 0.036). Disease location was a major determinant of the gut microbiome: The gut microbiome of patients with colonic CD is markedly different from that of ileal CD patients, with a significant decrease in alpha diversity associated with ileal disease (p = 3.28 × 10–13). Strikingly, we observed significant alterations of the gut microbiome of healthy individuals with a large genetic risk of IBD. An increase of the IBD-genetic risk score of healthy controls was significantly associated with a decrease in the genus Roseburia in healthy controls (FDR 0.03).

Conclusion

This large case-control study provides insight in the gut microbiome associated with the various clinical presentations of IBD. We see large differences in the gut microbiome of colonic disease (UC and colonic CD) vs ileal disease. We show for the first time that genetic risk variants associated with IBD influence the gut microbiome in healthy individuals. Roseburia spp are acetate-to-butyrate converters, and a decrease has already been observed in patients with IBD.