Altered gut microbiome in FUT2 loss‐of‐function mutants in support of personalized medicine for inflammatory bowel diseases

Abstract

Background & Aims FUT2 encodes an α-1,2-fucosyltransferase required for the proper production of oligosaccharides and glycoproteins. The FUT2 polymorphism has been hypothesized to mediate a genetic mechanism to impact gut microbiota and consequently contribute to IBD pathogenesis, because of the high prevalence of loss-of-function polymorphisms of FUT2 and their association with IBD in genome-wide association studies. In this study, we investigated the role of the gut microbiota in IBD patients with FUT2 loss-of-function mutation. Method A total of 81 inflammatory bowel disease (IBD) patients were enrolled in 6th Affiliated Hospital of Sun Yat-sen University in Guangzhou, China between March 2016 and July 2018. To determine the genotypes of the patients at rs1047781 (A385T) and rs601338 (G428A) of the FUT2 gene, individuals were asked to provided blood samples. All participants were divided into 3 groups according to their genotypes: SeSe, Sese, and sese groups. For microbiome study, fecal DNA was collected and the V5-V6 region of the 16S rDNA was sequenced with a MiSeq platform. Metabolomics analysis targeting SCFA was performed by gas chromatography. Result The FUT2 genotypes are associated with specific gut microbiome compositions and functions in IBD patients. Differences in alpha-, beta-diversities, bacterial abundances at every taxonomic levels were observed between different FUT2 genotypes. Escherichia was significantly decreased in the gut of the sese patients. On the other hand, CD8+ inducing Alistipe and Phascolarctobacterium and Th17 inducing Erysipelotrichaceae were more abundant in sese patients suggests that these bacteria may explain the higher incidence of IBD among sese individuals. The PICRUSt functional analysis based on the 16S data showed that, several carbohydrate synthesis pathways were enriched in IBD patients with non-functional mutation of FUT2 (P<0.05). Interestingly, SCFA-producing bacteria in sese patient were not decreased although SCFA is protective against colon inflammation. Metabolomics analysis targeting SCFA confirmed this observation. Discussion Data presented here explained the association of non-secretor status with IBD. Our study supports the hypothesis that FUT2 loss-of-function genotype causes altered gut microbiota that is poised to the development of IBD. The identification of the T cell inducing species in this study contributes to the knowledge base for the development of personalized microbial intervention for IBD.