Promotion and induction of liver cancer by gut microbiome-mediated modulation of bile acids

The liver, being closely connected to the gut via the hepatic portal vein, is the first recipient of gut microbiome metabolites and antigens, including bile acids (BAs), lipopolysaccharide (LPS), choline, indole derivatives, and short-chain fatty acids [7]. Clostridium species in the gut microbiome produce secondary BAs by 7α-dehydroxylation In the gut, bacteria from Clostridium cluster XIVa (including Clostridium scindens, C. hiranonis, and C. hylemonae) and Clostridium cluster XI (C. sordellii) can convert the primary 7α-hydroxyl BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA), into the secondary BAs deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, through a 7α/β-dehydroxylation reaction catalyzed by enzymes encoded by the BA-inducible (bai) operon [25]. [...]BaiN reduces the intermediates to form DCA or LCA, which are secreted from the bacterial cell and therefore released into the host intestine [28]. BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; COX2, cyclooxygenase 2; CXCL16, chemokine (C-X-C motif) ligand 16; CXCR6, C-X-C chemokine receptor type 6; DCA, deoxycholic acid; GLCA, glucuronic acid; HCA, hyocholic acid; HDCA, hyodeoxycholic acid; LCA, lithocholic acid; LTA, lipoteichoic acid; MCA, muricholic acid; MDCA, murideoxycholic acid; PGE2, prostaglandin E2; PTGER4, prostaglandin E receptor 4; UDCA, ursodeoxycholic acid. https://doi.org/10.1371/journal.ppat.1007954.g001 Secondary BAs regulate liver cancer via NKT cells Ma and colleagues demonstrated that primary and secondary BAs additionally mediate the opposing effects on liver tumor growth through NKT cells (Fig 1) [10].