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.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Maomeng
M
Tong
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Ian
I
McHardy
Department of Plant Pathology and Microbiology, University of California, Riverside, CA, USA.
Paul
P
Ruegger
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
Maryam
M
Goudarzi
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Purna C
PC
Kashyap
F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Talin
T
Haritunians
F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Xiaoxiao
X
Li
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Thomas G
TG
Graeber
Biostatistics Department, Harvard School of Public Health, Boston, MA, USA.
Emma
E
Schwager
Biostatistics Department, Harvard School of Public Health, Boston, MA, USA.
Curtis
C
Huttenhower
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
Albert J
AJ
Fornace
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
Justin L
JL
Sonnenburg
F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Dermot P B
DP
McGovern
Department of Plant Pathology and Microbiology, University of California, Riverside, CA, USA.
James
J
Borneman
1] Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA [2] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jonathan
J
Braun
D000328:Adult; D000368:Aged; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000382:microbiology*; D008297:Male; D055442:Metabolome; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020543:Proteome / Q000378:metabolism; D012307:Risk Factors; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D005647:Fucosyltransferases; D020543:Proteome; D000097631:Galactoside 2-alpha-L-fucosyltransferase