ABSTRACT
Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.
Subject(s)
Colitis, Ulcerative/immunology , Crohn Disease/immunology , Epigenesis, Genetic/immunology , Gastrointestinal Microbiome/immunology , Host Microbial Interactions/immunology , Adult , Aged , Bacteroides/genetics , Bacteroides/immunology , Bacteroides/isolation & purification , Biopsy , Caco-2 Cells , Case-Control Studies , Cohort Studies , Colitis, Ulcerative/genetics , Colitis, Ulcerative/microbiology , Colitis, Ulcerative/pathology , Colon/diagnostic imaging , Colon/immunology , Colon/microbiology , Colon/pathology , Colonoscopy , Crohn Disease/genetics , Crohn Disease/microbiology , Crohn Disease/pathology , DNA, Bacterial/isolation & purification , Enterobacteriaceae/genetics , Enterobacteriaceae/immunology , Enterobacteriaceae/isolation & purification , Epigenomics , Female , Gastrointestinal Microbiome/genetics , Host Microbial Interactions/genetics , Humans , Intestinal Mucosa/diagnostic imaging , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/pathology , Male , Middle Aged , RNA, Ribosomal, 16S/genetics , RNA-Seq , Young AdultABSTRACT
The effect of chronic ethanol consumption on acetaminophen (200, 400, and 600 mg/kg) toxicity was determined by maintaining mice for 10 days on diets consisting of chow and one of the following drinking solutions: 10% ethanol + 10% sucrose, 8% sucrose, or tap water. Toxicity as manifested by mortality, liver enlargement, and liver congestion was greatest in the ethanol-treated group. We suggest that the greater mortality was a result of the increased liver congestion and consequent hypovolemia. Despite the increased levels of cytochrome(s) P-450, covalent binding of [3H]acetaminophen reactive metabolite(s) to liver protein was not higher in ethanol-treated animals. This can be explained by the higher initial glutathione concentration and/or ability to replenish glutathione in the ethanol-treated group. We suggest that the enhancement of acetaminophen toxicity by ethanol is the result of an effect of ethanol on hepatocyte membranes which renders the cells more susceptible to toxic injury.
