Promotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4

TLDR

In chronic liver disease, increased translocation of intestinal bacteria drives hepatic inflammation and fibrosis. The study tested whether the intestinal microbiota and Toll‑like receptor 4 promote hepatocellular carcinoma as a long‑term consequence of chronic liver injury. Hepatocarcinogenesis in chronically injured livers required intestinal microbiota and TLR4 activation in resident liver cells, not for initiation but for promotion through increased proliferation, epiregulin expression, and anti‑apoptosis, and late‑stage gut sterilization reduced HCC, indicating these pathways as therapeutic targets.

Abstract

Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.