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

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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