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Diet Modulation of Bacterial Sulfur and Bile Acid Metabolism and Colon Cancer Risk

ABSTRACT: Determine in the context of a controlled crossover diet-intervention trial the role of taurocholic acid metabolism by gut bacteria in African American subjects at elevated risk for colorectal cancer (CRC). Two isocaloric diets, an animal-based diet high in taurine and saturated fat (HT-HSAT) and a plant-based, low in taurine and low saturated fat (LT-LSAT) will be used to determine the extent to which the relationship between diet (independent variable) and mucosal markers of CRC risk including epithelial proliferation, oxidative stress, DNA damage, and primary and secondary bile acid pools and biomarkers of inflammation (dependent variables) is explained by the abundance of sulfidogenic bacteria and hydrogen sulfide (H2S) concentrations &/or deoxycholic acid (DCA) and DCA-producing bacteria clostridium scindens (mediator variables).

DISEASE(S): Colorectal Cancer,Colonic Neoplasms

PROVIDER: 2274903 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:The adult human gut microbial community is typically dominated by two bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from E. rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the former possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole genome transcriptional profiling of both organisms in their distal gut (cecal) habitat as well as host responses, high resolution proteomic analysis of cecal contents, and biochemical assays of carbohydrate metabolism. B. thetaiotaomicron adapts to E. rectale by upregulating expression of a variety of polysaccharide utilization loci (PULs) encoding numerous glycoside hydrolase gene families, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is utilized by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of major gut bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability. We assessed how E. rectale and B. thetaiotaomicron were affected by changes in host diet. Groups of age- and gender-matched co-colonized mice were fed one of three diets that varied primarily in their carbohydrate and fat content: (i) the standard low-fat, plant polysaccharide-rich diet used for the experiments described above (abbreviated âLF/PPâ for low-fat/plant polysaccharide), (ii) a high-fat, âhigh-sugarâ Western-type diet (abbreviated HF/HS) that contained sucrose, maltodextrin, corn starch as well as complex polysaccharides (primarily cellulose) that were not digestible by B. thetaiotaomicron or E. rectale, and (iii) a control diet that was similar to (ii) except that the fat content was 4-fold lower (âLF/HSâ for low-fat, high-sugar; n=5 mice per group).

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Diet Modulation of Bacterial Sulfur and Bile Acid Metabolism and Colon Cancer Risk

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