Journal
ISME JOURNAL
Volume 8, Issue 11, Pages 2193-2206Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ismej.2014.64
Keywords
glycan foraging; intestinal microbiome; microbial ecology; multi'omic analysis
Categories
Funding
- NIH [DK046763, DK08569, AI078885, DK062413]
- NCRR
- NCATS [UL1TR000124]
- Crohn's and Colitis Foundation of America [3153]
- Burroughs Wellcome Fund Inter-school Program in Metabolic Diseases Fellowship
- Cedars-Sinai F. Widjaja Family Foundation Inflammatory Bowel
- Immunobiology Research Institute Research Funds
- Helmsley Foundation
- NIH/NCI [P30-CA051008]
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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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