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Reprograming of gut microbiome energy metabolism by the FUT2 Crohn's disease risk polymorphism.

  • Author(s): Tong, Maomeng;
  • McHardy, Ian;
  • Ruegger, Paul;
  • Goudarzi, Maryam;
  • Kashyap, Purna C;
  • Haritunians, Talin;
  • Li, Xiaoxiao;
  • Graeber, Thomas G;
  • Schwager, Emma;
  • Huttenhower, Curtis;
  • Fornace, Albert J;
  • Sonnenburg, Justin L;
  • McGovern, Dermot PB;
  • Borneman, James;
  • Braun, Jonathan
  • et al.

Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. The H antigen is an oligosaccharide moiety that acts as both an attachment site and carbon source for intestinal bacteria. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease (CD). To characterize the effect of FUT2 polymorphism on the mucosal ecosystem, we profiled the microbiome, meta-proteome and meta-metabolome of 75 endoscopic lavage samples from the cecum and sigmoid of 39 healthy subjects (12 SeSe, 18 Sese and 9 sese). Imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism and glycan biosynthesis and metabolism-related pathways, and the depletion of amino-acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2(-/-) genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. Therefore, the colonic microbiota of non-secretors is altered at both the compositional and functional levels, affecting the host mucosal state and potentially explaining the association of FUT2 genotype and CD susceptibility.

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