Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease.

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.

• Authors: Russell R Fling, Timothy R Zacharewski
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 22 (Nov 18 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34830313 (Publication Type: Journal Article)

Chemical References

• AHR protein, human
• Ahr protein, mouse
• Basic Helix-Loop-Helix Transcription Factors
• Polychlorinated Dibenzodioxins
• Receptors, Aryl Hydrocarbon

Topics

• Animals
• Bacteroidetes (genetics, growth & development, isolation & purification)
• Basic Helix-Loop-Helix Transcription Factors (agonists, genetics, metabolism)
• Dysbiosis (chemically induced, genetics, metabolism, pathology)
• Gastrointestinal Microbiome (drug effects, genetics)
• Gene Expression Regulation
• Humans
• Lactobacillus (classification, genetics, growth & development, isolation & purification)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (genetics, metabolism, pathology)
• Male
• Metabolic Networks and Pathways (genetics)
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (chemically induced, genetics, metabolism, pathology)
• Polychlorinated Dibenzodioxins (pharmacology)
• Receptors, Aryl Hydrocarbon (agonists, genetics, metabolism)