Intestinal microbiota contribution to toxicant-associated hepatic lipogenesis through aryl hydrocarbon receptor signaling

The toxicology community is increasingly appreciative of the important role the aryl hydrocarbon receptor (AHR) plays in modulating the host-microbiome metabolic axis. Interestingly, there are strong links between the gut microbiota and the development and/or exacerbation of toxicant-associated fatty liver disease (TAFLD), all of which are modulated by activation or repression of the AHR. Our published and preliminary data with 2,3,7,8-tetrachlorodibenzofuran (TCDF) indicates AHR activation profoundly alters the gut microbiota in a qualitative and quantitative manner and significantly alters hepatic metabolism through direct AHR activity (a proposed driver of TAFLD). Through the innovative use of cutting-edge techniques (16S rRNA gene-based community analysis, metagenomics and metabolomics) and unique mouse models (tissue specific knockouts of Ahr, gnotobiotic mice), we identified the functional changes imparted to the gut microbiota following dietary exposure to potent AHR ligands such as TCDF and evaluated the AHR-dependent drivers of TAFLD pathogenesis and progression. This combination of approaches allowed us to accurately assess bacterial phyla dynamics and its interaction with and impact on the host, and whether these changes resulted in increased susceptibility to TAFLD.