Abstract
Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids, including taurolithocholic acid and deoxycholic acid (microbial modified bile acids involved in host bile acid regulation signaling pathways). To investigate the effects of TCDD on the gut microbiota, the cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and o-succinylbenzoate synthase, a menaquinone biosynthesis associated gene. Analysis of the gut microbiomes from cirrhosis patients identified an increased abundance of genes from the mevalonate-dependent IPP biosynthesis as well as several other menaquinone biosynthesis genes, including o-succinylbenzoate synthase. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect ~25% of the global population and is defined as a spectrum of progressive pathologies, including steatosis, immune cell infiltration/inflammation, fibrosis, and cirrhosis
Previous studies have reported that TCDD elicited NAFLD-like pathologies, dysregulated bile acid metabolism and gut microbiome dysbiosis [9,11,12,28,30]
We show that TCDD dose-dependently shifted the gut microbiota composition by enriching for Lactobacillus species, consistent with hepatic disruption of host and microbial bile acid metabolism
Summary
Non-alcoholic fatty liver disease (NAFLD) is estimated to affect ~25% of the global population and is defined as a spectrum of progressive pathologies, including steatosis, immune cell infiltration/inflammation, fibrosis, and cirrhosis It is associated with increased risk for hepatocellular carcinoma and is the second leading cause of liver transplants in the USA [1]. The AhR plays an essential role in gut homeostasis through regulation of the immune system and bile acid metabolism [9,12,19,20] with endogenous and xenobiotic AhR ligands affecting the gut microbiome congruent with NAFLD-like pathology [8,9,10]. AhR knockout models, and treatment with TCDD or other endogenous compounds demonstrate strong correlations between AhR activation and enrichment of Lactobacillus species, i.e., L. reuteri [26,27,28,29,30]. The top enriched species were associated with increased abundances in bsh levels in the cecum
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