2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism

abstract: ...2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.0130g/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1 . Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci ( bsh , baiCD ) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters ( Slc10a2 , Slc51a ) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression ( Slco1a1 , Slc10a1 , Slco2b1 , Slco1b2 , Slco1a4 ) and hepatocyte-to-blood transporter induction ( Abcc4 , Abcc3 ). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.

... taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci ( bsh , baiCD ) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters ( Slc10a2 , Slc51a ) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile

... levels of hepatic conjugated primary bile acids likely caused spill-over into the sinusoidal blood and systemic circulation. Conjugated primary bile acids stored in the gallbladder are released into the duodenum in response to the intestinal hormone cholecystokinin following a meal, and progressively pass through the small intestine. Upon reaching the ileum, they are taken up into enterocytes by apical SLC10A2, and exported to the portal circulation by basal SLC51A and SLC51B. TCDD induced ileal expression of Slc10a2 and Slc51a 1.6- and 1.5-fold, respectively, while ileal Slc51b was unchanged (Fig. 6 ). Induction of these intestinal transporters likely promotes active reabsorption of bile acids across the ileum. Circulating bile acids are then transported into hepatocytes by Slc10a1 , Slco1a1 , Slco1a4 , Slco1b2 , and Slco2b1 , which were repressed 17.9-, 1186.3-, 2.5-, 7.9-, and 12.9-fold, respectively, by TCDD (Fig. 6 ). Specifically, SLC10A1 is primarily responsible for taurine- and glycine

... 4.1h in 30g/kg TCDD-treated mice, indicating a 1.6-fold reduction in gut motility (Fig. 7D,E ). Induction of active ileal transporters ( Slc10a2 , Slc51a ), increased passive para-cellular duodenal and colonic transport, and decreased gut motility are in accordance with increased intestinal reabsorption and decreased fecal excretion of bile acids. These changes in intestinal function are also consistent with TCDD-elicited increases in total serum bile acids and decreases in total fecal bile acids

... of Abcb11 , a known FXR target gene. TCDD also repressed transporters involved in hepatic uptake from the blood ( Slco1a1 , Slc10a1 , Slco2b1 , Slco1b2 , and Slco1a4 ) and induced hepatic efflux transporters ( Abcc4 , Abcc3 ). Accordingly, bile acid accumulation was greater in the serum compared to the liver. Serum bile acid accumulation may also be facilitated by enhanced enterocyte uptake ( Slc10a2 ) and efflux ( Slc51a ), as well as passive reabsorption due to reduced gut motility and

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Gene: SLC51A - solute carrier family 51, alpha subunit - (NCBI)

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