Biliatresone induces cholangiopathy in C57BL/6J neonates

Exposure to plant toxins or microbiota that are able to digest common food ingredients to toxic structures might be responsible for biliary atresia (BA). An isoflavonoid, biliatresone is known to effectively alter the extrahepatic bile duct (EHBD) development in BALB/c mice. Biliatresone causes a reduction of Glutathione (GSH) levels, SOX17 downregulation and is effectively countered with N-Acetyl-L-cysteine treatment in vitro. Therefore, reversing GSH-loss appears to be a promising treatment target for a translational approach. Since BALB/c mice have been described as sensitive in various models, we evaluated the toxic effect of biliatresone in robust C57BL/6J mice and confirmed its toxicity. Comparison between BALB/c and C57BL/6J mice revealed similarity in the toxic model. Affected neonates exhibited clinical symptoms of BA, such as jaundice, ascites, clay-colored stools, yellow urine and impaired weight gain. The gallbladders of jaundiced neonates were hydropic and EHBD were twisted and enlarged. Serum and histological analysis proved cholestasis. No anomalies were seen in the liver and EHBD of control animals. With our study we join a chain of evidence confirming that biliatresone is an effective agent for cross-lineage targeted alteration of the EHBD system.

Automated summary

Exposure to plant toxins or enzymatic digestion of common food by microbiota may cause biliary atresia (BA). Biliatresone, an isoflavonoid, can effectively disrupt the development of extrahepatic bile duct (EHBD) in mice. It reduces Glutathione levels, downregulates SOX17, and can be counteracted with N-Acetyl-L-cysteine treatment in vitro. The toxic effect of biliatresone was confirmed in robust C57BL/6J mice, showing similarity to BALB/c mice. Affected neonates displayed symptoms of BA, and histological analysis confirmed cholestasis. Our study adds to the evidence that biliatresone is an effective agent for targeted alteration of the EHBD system.