Disruptions in hepatic one carbon metabolism and the gut microbiome during the progression of non-alcoholic fatty liver disease
The etiology of non-alcoholic fatty liver disease is complex, with multiple contributing factors including dietary, environmental, gut microbiome and genetic mechanisms. Accumulating evidence suggests exposure to polychlorinated dibenzo-p-dioxins and similar compounds may increases risk for NAFLD development. These environmentally persistent dioxin-like compounds bind and activate the aryl hydrocarbon receptor, a transcription factor that regulates intestinal homeostasis, xenobiotic and central metabolism. In a AhR-dependent manner, mice orally gavaged with 2,3,7,8-tetracholordibenzo-p-dioxin (TCDD) exhibit steatosis progressing to steatohepatitis with fibrosis akin to NAFLD progression. NAFLD and hepatocellular carcinoma (HCC) is also closely correlated with dysregulation of central metabolism e.g., hepatic one carbon metabolism (OCM), and gut dysbiosis contributing to NAFLD progression and worsening prognosis. This report investigates mechanisms involved in the dysregulation of the gut microbiome and OCM associated pathways relevant to NAFLD progression through comparisons of molecular analyses of TCDD-treated mice to human NAFLD and HCC. OCM describes the biosynthesis, homeostasis, and utilization of the cell's main methyl donor, S-adenosylmethionine (SAM) including high flux anabolic biosynthesis of polyamines, phosphatidylcholine and creatine. In later stages of NAFLD, OCM is dysregulated with altered OCM gene expression as well as SAM and s-adenosylhomocysteine (SAH) levels. To assess TCDD-elicited effects on OCM, mice were orally gavaged with TCDD every 4 days for 28 days. Serum and livers collected at early (8 days) and late (28 days) time points were subjected to metabolomic analyses with integration of chromatin immunoprecipitation sequencing, transcriptomics and protein levels. Results from these studies suggest AhR-mediated repression of OCM required prolonged repeated TCDD-treatment and indirect effects elicited by AhR activation e.g., oxidative stress. Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with NAFLD and recapitulated in TCDD-treated mice. Similar to NAFLD, TCDD also increases systematic levels of secondary bile acids. These microbial transformed secondary bile acids are involved in modulation of host bile acid signaling pathways relevant to NAFLD. To investigate the effects of TCDD on the gut microbiota, the cecum contents of TCDD-treated mice were subjected to shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species, notably Lactobacillus reuteri. Top enriched species were also associated with increased abundances of bile salt hydrolase sequences, responsible for the initial deconjugation reaction in secondary bile acid metabolism. L. reuteri levels were also attributed to enrichment of mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis genes, a pathway that was also elevated in cirrhosis patients. These results extend the role of Lactobacilli in the AhR/intestinal axis and NAFLD progression as well as highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD. Collectively, these studies evaluated TCDD-elicited mechanisms involved in disruptions in host and microbial metabolism, highlighting the AhR's role in NAFLD progression.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- Attribution-NonCommercial 4.0 International
- Material Type
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Theses
- Authors
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Fling, Russell Ryan
- Thesis Advisors
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Zacharewski, Timothy R.
- Committee Members
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Vieille, Claire
Manning, Shannon D.
Mansfield, Linda S.
Jones, Arthur D.
- Date Published
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2022
- Subjects
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Microbiology
Biochemistry
Fatty liver
Liver--Diseases
Dioxins--Toxicology
Gastrointestinal system--Microbiology
- Program of Study
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Microbiology - Environmental Toxicology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xi, 139 pages
- ISBN
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9798438748250
- Permalink
- https://doi.org/doi:10.25335/1mwy-5475