Upregulation of bile acid metabolism induced by AF6 promotes anti-tumor immunity via Cxcl14 in HCC

We for the first time elucidate how alterations in primary BAs metabolism affect the liver immune microenvironment through the gut microbiota and its metabolites butyric acid. By developing a mouse liver cancer model with bile acid metabolism changes induced by AF6, we identify changes in the bile acid pool altered the gut microbiota and its metabolites, which affect the liver cancer tumor microenvironment. Mechanistically, we show that liver-specific knockdown of AF6 in liver cancer mice strengthened the synthesis of primary bile acids, thereby inducing characteristic changes in the intestinal microbiota and its metabolites, such as the increase in butyric acid levels. In addition, it is not primary BAs but butyric acid subsequently controls the hepatic tumor immune microenvironment via enterohepatic circulation. By mouse and human liver cancer organoid assays, we identified that butyric acid is capable to upregulates the expression of chemokine CXCL14 and its secretion in hepatocytes. Through a combination of single-cell and bulk RNA-sequencing analysis, here we found hepatocytes-secreted Cxcl14 recruits activated dendritic cells to promote and enhance the cytotoxic effects of CD8 T cells in liver cancer. Ultimately, we discovered that overexpression of Cxcl14 could form a tumor-suppressive immune microenvironment, thereby inhibiting the progression of liver cancer. Taken together, indeed, we describe how primary BAs alters gut microbiota and its metabolic alterations, which specifically affect the hepatic immune microenvironment by mimic a condition of series of primary BAs accumulation.