Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis‐hepatocellular carcinoma (NASH‐HCC) mouse model. Additionally chronic HFD‐fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH‐HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD‐induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down‐regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.

Distinctly altered gut microbiota in the progression of liver disease

Clinical prediction of advanced hepatic fibrosis (HF) and cirrhosis has long been challenging due to the gold standard, liver biopsy, being an invasive approach with certain limitations. Less invasive blood test tandem with a cutting-edge machine learning algorithm shows promising diagnostic potential. In this study, we constructed and compared machine learning methods with the FIB-4 score in a discovery dataset (n = 490) of hepatitis B virus (HBV) patients. Models were validated in an independent HBV dataset (n = 86). We further employed these models on two independent hepatitis C virus (HCV) datasets (n = 254 and 230) to examine their applicability. In the discovery data, gradient boosting (GB) stably outperformed other methods as well as FIB-4 scores (p < .001) in the prediction of advanced HF and cirrhosis. In the HBV validation dataset, for classification between early and advanced HF, the area under receiver operating characteristic curves (AUROC) of GB model was 0.918, while FIB-4 was 0.841; for classification between non-cirrhosis and cirrhosis, GB showed AUROC of 0.871, while FIB-4 was 0.830. Additionally, GB-based prediction demonstrated good classification capacity on two HCV datasets while higher cutoffs for both GB and FIB-4 scores were required to achieve comparable specificity and sensitivity. Using the same parameters as FIB-4, the GB-based prediction system demonstrated steady improvements relative to FIB-4 in HBV and HCV cohorts with different cutoff values required in different etiological groups. A user-friendly web tool, LiveBoost, makes our prediction models freely accessible for further clinical studies and applications.

Hepatic encephalopathy (HE), a severe neuropsychiatric complication, is associated with increased blood levels of ammonia and bile acids (BAs). We sought to determine (1) whether abnormally increased blood BAs in liver cirrhotic patients with HE is caused by elevation of apical sodium-dependent BA transporter (ASBT)-mediated BA reabsorption; and (2) whether increased BA reabsorption would exacerbate ammonia-induced brain injuries. We quantitatively measured blood BA and ammonia levels in liver cirrhosis patients with or without HE and healthy controls. We characterized ASBT expression, BA profiles, and ammonia concentrations in a chronic liver disease (CLD) mouse model induced by streptozotocin-high fat diet (STZ-HFD) and an azoxymethane (AOM) - induced acute liver failure (ALF) mouse model. These two mouse models were treated with SC-435 (ASBT inhibitor) and budesonide (ASBT activator), respectively. Blood concentrations of ammonia and conjugated BAs were substantially increased in cirrhotic patients with HE (n = 75) compared to cirrhotic patients without HE (n = 126). Pharmacological inhibition of the enterohepatic BA circulation using a luminal- restricted ASBT inhibitor, SC-435, in mice with AOM-induced ALF and STZ-HFD -induced CLD effectively reduced BA and ammonia concentrations in the blood and brain, and alleviated liver and brain damages. Budesonide treatment induced liver and brain damages in normal mice, and exacerbated these damages in AOM-treated mice. ASBT mediated BA reabsorption increases intestinal luminal pH and facilitates conversion of intestinal ammonium to ammonia, leading to abnormally high levels of neurotoxic ammonia and cytotoxic BAs in the blood and brain. Inhibition of intestinal ASBT with SC-435 can effectively remove neurotoxic BAs and ammonia from the bloodstream and thus, mitigate liver and brain injuries resulting from liver failure.