Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Tong M

PROVIDER: S-EPMC4992076 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Tong Maomeng M McHardy Ian I Ruegger Paul P Goudarzi Maryam M Kashyap Purna C PC Haritunians Talin T Li Xiaoxiao X Graeber Thomas G TG Schwager Emma E Huttenhower Curtis C Fornace Albert J AJ Sonnenburg Justin L JL McGovern Dermot P B DP Borneman James J Braun Jonathan J

The ISME journal 20140429 11

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 mic ...[more]

PMID: 24781901

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Project description:BackgroundThis study aims to characterize, the gut and oral microbiome in Asian subjects with Crohn's disease (CD) using whole genome shotgun sequencing, thereby allowing for strain-level comparison.MethodsA case-control study with age, sex and ethnicity matched healthy controls was conducted. CD subjects were limited to well-controlled patients without oral manifestations. Fecal and saliva samples were collected for characterization of gut and oral microbiome respectively. Microbial DNA were extracted, libraries prepared and sequenced reads profiled. Taxonomic diversity, taxonomic association, strain typing and microbial gene pathway analyses were conducted.ResultsThe study recruited 25 subjects with CD and 25 healthy controls. The oral microbe Streptococcus salivarius was found to be enriched and of concordant strains in the gut and oral microbiome of Crohn's disease subjects. This was more likely in CD subjects with higher Crohn's Disease Activity Index (184.3 ± 2.9 vs 67.1 ± 82.5, p = 0.012) and active disease status (Diarrhoea/abdominal pain/blood-in-stool/fever and fatigue) (p = 0.016). Gut species found to be significantly depleted in CD compared to control (Relative abundance: Median[Range]) include: Faecalibacterium prausnitzii (0.03[0.00-4.56] vs 13.69[5.32-18.71], p = 0.010), Roseburia inulinivorans (0.00[0.00-0.03] vs 0.21[0.01-0.53], p = 0.010) and Alistipes senegalensis (0.00[0.00-0.00] vs 0.00[0.00-0.02], p = 0.029). While Clostridium nexile (0.00[0.00-0.12] vs 0.00[0.00-0.00], p = 0.038) and Ruminococcus gnavus (0.43[0.02-0.33] vs 0.00[0.00-0.13], p = 0.043) were found to be enriched. C. nexile enrichment was not found in CD subjects of European descent. Microbial arginine (Linear-discriminant-analysis: 3.162, p = 0.001) and isoprene (Linear-discriminant-analysis: 3.058, p < 0.001) pathways were found at a higher relative abundance level in gut microbiome of Crohn's disease.ConclusionsThere was evidence of ectopic gut colonization by oral bacteria, especially during the active phase of CD. Previously studied gut microbial differences were detected, in addition to novel associations which could have resulted from geographical/ethnic differences to subjects of European descent. Differences in microbial pathways provide possible targets for microbiome modification.

Project description:Gut dysbiosis is closely related to dysregulated microRNAs (miRNAs) in the intestinal epithelial cells, which plays an important role in the pathogenesis of Crohn's disease (CD). We investigated the relationship between fecal gut microbiome (GM) and intestinal tissue miRNAs in different stages of pediatric CD. Metagenomic analysis and miRNA sequencing were conducted to examine the GM and intestinal miRNA profiles of CD patients before and after clinical induction therapy and the controls. Twenty-seven newly diagnosed, therapy-naïve pediatric patients with active CD and 11 non-inflammatory bowel disease (IBD) controls were recruited in this study. Among CD patients, 11 patients completed induction treatment and reached clinical remission. Both GM and miRNA profiles were significantly changed between CD patients and controls. Seven key bacteria were identified at species level including Defluviitalea raffinosedens, Thermotalea metallivorans, Roseburia intestinalis, Dorea sp. AGR2135, Escherichia coli, Shigella sonnei, and Salmonella enterica, the exact proportions of which were further validated by real-time quantitative PCR analysis. Eight key miRNAs were also identified including hsa-miR-215-5p, hsa-miR-194-5p, hsa-miR-12135, hsa-miR-509-3-5p, hsa-miR-212-5p, hsa-miR-4448, hsa-miR-501-3p, and hsa-miR-503-5p. The functional enrichment analysis of differential miRNAs indicated the significantly altered cyclin protein, cyclin-dependent protein, and cell cycle pathway. The close interactions between seven key bacteria and eight key miRNAs were further investigated by miRNA target prediction. The association between specific miRNA expressions and key gut bacteria at different stages of CD supported their important roles as potential molecular biomarkers. Understanding the relationship between them will help us to explore the molecular mechanisms of CD.ImportanceSince previous studies have focused on the change of the fecal gut microbiome and intestinal tissue miRNA in pediatric Crohn's disease (CD), the relationship between them in different stages is still not clear. This is the first study to explore the gut microbiota and miRNA and their correlations with the Pediatric Crohn's Disease Activity Index (PCDAI). Crohn's Disease Endoscopic Index of Severity (CDEIS), and calprotectin, by applying two omics approach in three different groups (active CD, CD in remission with exclusive enteral nutrition or infliximab induction therapy, and the healthy controls). Both gut microbiome structure and the miRNA profiles were significantly changed in the different stage of CD. Seven key gut microbiome at species and eight key miRNAs were found, and their close interactions were further fully investigated by miRNA target prediction.

Dataset Information

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

Publications

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

Similar Datasets

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