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Directed Remodeling of the Mouse Gut Microbiome Inhibits the Development of Atherosclerosis [bacteria]

ABSTRACT: The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic D,L-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

ORGANISM(S): feces metagenome

PROVIDER: GSE104913 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.

Project description:We investigate the hypothesis that consistent changes in the human gut microbiome are associated with Crohn's disease, a form of inflammatory bowel disease, and that altered microbiota contributes to pathogenesis. Analysis of this problem is greatly complicated by the fact that multiple factors influence the composition of the gut microbiota, including diet, host genotype, and disease state. For example, data from us and others document a drastic impact of diet on the composition of the gut microbiome. No amount of sequencing will yield a useful picture of the role of the microbiota in disease if samples are confounded with uncontrolled variables. We aim to characterize the composition of the gut microbiome while controlling for diet, host genotype, and disease state. Diet is controlled by analyzing children treated for Crohn's disease by placing them on a standardized elemental diet, and by testing effects of different diets on the gut microbiome composition in adult volunteers. Genotype is analyzed by large scale SNP genotyping, which is already underway and separately funded--team member Hakon Hakonarson is currently genotyping 50 children a week at ~half a million loci each and investigating connections with inflammatory bowel disease. Clinical status is ascertained in the very large IBD practice in the UPenn/CHOP hospital system. Effects of diet, host genotype, and disease state on the gut microbiome are summarized in a multivariate model, allowing connections between microbiome and disease to be assessed free of confounding factors. This project is divided into four sub-studies. In the Fecal Storage Methods (FSM) study, methods of stool storage and DNA extraction are compared to examine their impact on DNA sequence analysis results. The Controlled Feeding Experiment (CaFE) addresses the effects of controlled diets on the gut microbiome. In the Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO), the effects of diet analyzed using surveys and deep sequencing of stool specimens. The fourth study, Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE), examines the effects of an elemental diet treatment on pediatric patients diagnosed with inflammatory bowel disease (IBD), particularly Crohn's disease. <ul> <li>Fecal Storage Methods (FSM): Cross-sectional study</li> <li>Controlled Feeding Experiment (CaFE): Controlled trial</li> <li>Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO): Cross-sectional study</li> <li>Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE): Longitudinal cohort study</li> </ul>

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Directed Remodeling of the Mouse Gut Microbiome Inhibits the Development of Atherosclerosis [bacteria]

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