A Dual Coverage Monitoring of the Bile Acids Profile in the Liver-Gut Axis throughout the Whole Inflammation-Cancer Transformation Progressive: Reveal Hepatocellular Carcinoma Pathogenesis

Hepatocellular carcinoma (HCC) is the terminal phase of multiple chronic liver diseases, and evidence supports chronic uncontrollable inflammation being one of the potential mechanisms leading to HCC formation. The dysregulation of bile acid homeostasis in the enterohepatic circulation has become a hot research issue concerning revealing the pathogenesis of the inflammatory-cancerous transformation process. We reproduced the development of HCC through an N-nitrosodiethylamine (DEN)-induced rat model in 20 weeks. We achieved the monitoring of the bile acid profile in the plasma, liver, and intestine during the evolution of hepatitis-cirrhosis-HCC by using an ultra-performance liquid chromatography-tandem mass spectrometer for absolute quantification of bile acids. We observed differences in the level of primary and secondary bile acids both in plasma, liver, and intestine when compared to controls, particularly a sustained reduction of intestine taurine-conjugated bile acid level. Moreover, we identified chenodeoxycholic acid, lithocholic acid, ursodeoxycholic acid, and glycolithocholic acid in plasma as biomarkers for early diagnosis of HCC. We also identified bile acid-CoA:amino acid N-acyltransferase (BAAT) by gene set enrichment analysis, which dominates the final step in the synthesis of conjugated bile acids associated with the inflammatory-cancer transformation process. In conclusion, our study provided comprehensive bile acid metabolic fingerprinting in the liver-gut axis during the inflammation-cancer transformation process, laying the foundation for providing a new perspective for the diagnosis, prevention, and treatment of HCC.

Automated summary

Hepatocellular carcinoma (HCC) is the terminal stage of chronic liver diseases, and chronic inflammation may contribute to its formation. Dysregulation of bile acid homeostasis in the enterohepatic circulation is a key factor in the development of HCC. This study used a rat model to reproduce HCC and monitored the bile acid profile in plasma, liver, and intestine. Differences in bile acid levels, including potential biomarkers for early diagnosis of HCC, were identified. The study also identified a key enzyme, bile acid-CoA:amino acid N-acyltransferase (BAAT), involved in bile acid synthesis and the inflammatory-cancer transformation process. This research provides insights into the role of bile acid metabolism in the liver-gut axis during the inflammation-cancer transformation process and has implications for HCC diagnosis, prevention, and treatment.