###### Abstract  
Gut dysbiosis with disrupted enterobepatic 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-tetrachloroidenzo-\(p\)-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 eccentric contents of male C57 BL/6 mice orally gavageed with sesame oil vehicle or 0.3, 3, or 30 ug/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 meanquinone 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. 2021 16 November 2021 18  
resembling human NAFLD development [9; 12; 13; 14]. TCDD-induced dyslipidemia also exhibits other similar NAFLD characteristics, such as decreased VLDL secretion, free fatty acid accumulation, inhibition of \(\beta\)-oxidation, and disrupted cholesterol and bile acid metabolism [9; 12; 15; 16; 17]. The effects of TCDD and other related polychlorinated dibenzo-\(p\)-dioxins (PCDDs), dibenzofurans (PCDFs), and coplanar biphenyl (PCBs) as well as polyaromatic hydrocarbons (PAHs), are mediated through activation of the aryl hydrocarbon receptor (AhR), a basic helix-loop-helix/Per-Arnt-Sim transcription factor typically associated with xenobiotic metabolism [18]. In addition, 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]. Moreover, gut dysbiosis is commonly reported in NAFLD, making the gut microbiome an attractive target for non-invasive diagnostic tools and a potential target for intervention [21; 22]. Although the AhR exhibits promiscuous binding activity for a wide variety of structurally diverse xenobiotics, natural products, and endogenous metabolites, its endogenous role remains unknown [23]. Upon ligand binding, the cytosolic AhR translocates to the nucleus where it disassociates from its chaperone proteins and dimerizes with the AhR nuclear transporter (ARNT). The AhR/ARNT heterodimer complex then binds to dioxin response elements located throughout the genome, affecting gene expression [24]. Endobiotic ligands for the AhR include host-derived metabolites, such as tryptophan catabolites (e.g., L-kynurene), microbial-produced indole derivatives (e.g., indole-3-aldehyde produced by _Lactobacillus reuteri_), and compounds derived from fruits and cruciferous vegetables (e.g., indole-3-carboniol [ICZ]) [23]. Microbially produced indices activate AhR in the intestine, affecting barrier function and homeostasis by regulating the intestinal immune system through CD4\({}^{+}\) T-cell differentiation and the induction of interleukin (IL)-22 and IL-10 cytokine production [24]. AhR-dependent IL-22 induction subsequently increases antimicrobial peptide expression in intestinal epithelial cells, thus, inhibiting pathogen infection and inflammation [24; 25; 26].