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.

Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice

“…Specifically, bacterial-derived urease (cleaves urea into ammonia and carbon dioxide) ( 59 ) and deaminase ( 60 ) in the large intestine, and glutaminase activity in the small intestine ( 61 , 62 ) contribute to ammonia formation that accumulates in the portal circulation at levels ∼3 times higher than arterial blood ( 58 ). TCDD has been shown to disrupt the homeostasis of gut microbiota and metabolism in mice ( 63 , 64 , 65 , 66 ). Sustained hyperammonemia may be a direct consequence of low circulating acetyl-CoA levels, which is required for the formation of N-acetyl-glutamate, an essential urea cycle cofactor that allosterically regulates CPS1.…”

Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome

“…Moreover, Supplement of tryptophan derivatives IAAld or IAA, or treated with AhR activator Ficz obviously alleviated the liver injury induced by MCT. Notably, AHR activation by microbial tryptophan metabolites were shown to improve alcohol-related liver disease [ 15 ] and non-alcoholic fatty liver disease [ 40 ]. These evidence and current results highlight the association of tryptophan metabolites and AhR with liver damage for various causes, including the MCT-induced HSOS-like liver injury.…”

Sex, Nutrition, and NAFLD: Relevance of Environmental Pollution

“…Several epidemiological studies have reported an increased risk of developing cancers, nervous system degeneration, immune damage, thyroid disease, metabolic disorders, and reproductive and sexual development disorders in the general population as well as in subgroups such as Vietnam War veterans heavily exposed to dioxins [ 100 , 102 ]. With respect to liver health, TCDD (2, 3, 7, 8-tetrachlorodibenzo- p -dioxin), the most toxic dioxin, has been shown to alter blood and hepatic lipid levels, disrupt bile synthesis, impair the microbiome, and strongly contribute to NAFLD development and progression through the activation of aryl hydrocarbon receptor (AhR) [ 103 , 104 , 105 , 106 , 107 ]. Several other dioxins, including PCBs, have become a major concern for liver health, given their strong association with IR and NAFLD/NASH, especially under diet-inducing obesogenic conditions [ 86 , 108 , 109 , 110 , 111 ].…”