This study investigates the role of the intestinal microbiota and Toll-like receptors (TLRs) in promoting hepatocellular carcinoma (HCC), a common complication of chronic liver disease. The authors found that TLR4 activation and the intestinal microbiota are crucial for HCC promotion but not initiation. Specifically, TLR4 and the intestinal microbiota mediate increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis in non-bone marrow-derived resident liver cells. Gut sterilization, germ-free status, or TLR4 inactivation significantly reduced HCC development by 80-90%. The study also suggests that the intestinal microbiota and TLR4 provide survival signals that are essential for the survival of tumor precursors, and that apoptosis prevents the development of tumor lesions. These findings highlight the potential of targeting the intestinal microbiota and TLR4 for the prevention or treatment of advanced liver disease and HCC.This study investigates the role of the intestinal microbiota and Toll-like receptors (TLRs) in promoting hepatocellular carcinoma (HCC), a common complication of chronic liver disease. The authors found that TLR4 activation and the intestinal microbiota are crucial for HCC promotion but not initiation. Specifically, TLR4 and the intestinal microbiota mediate increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis in non-bone marrow-derived resident liver cells. Gut sterilization, germ-free status, or TLR4 inactivation significantly reduced HCC development by 80-90%. The study also suggests that the intestinal microbiota and TLR4 provide survival signals that are essential for the survival of tumor precursors, and that apoptosis prevents the development of tumor lesions. These findings highlight the potential of targeting the intestinal microbiota and TLR4 for the prevention or treatment of advanced liver disease and HCC.