Microbiome–Obesity–Liver Cancer Interaction: Senescence of Hepatic Stellate Cells and Bile Acids Play New Roles

Abstract

Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499:97–101. The increased prevalence of obesity is a significant health concern in developed countries. Epidemiologic human studies and experiments using rodents show that obesity is associated with not only the manifestations of metabolic disease, such as diabetes and cardiovascular disease, but also with increased incidence of a number of cancers, including hepatocellular carcinoma (HCC). The incidence of HCC is increased in patients with hepatosteatosis accompanied with liver inflammation (referred to as nonalcoholic steatohepatitis) rather than patients with simple steatosis. Emerging evidences demonstrate that intestinal microbiome is among the key components in the progression of obesity and HCC (Nature 2006; 444:1027–1031; Cancer Cell 2012;21:504–516). Yoshimoto et al demonstrated that senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) induced by a bacterial byproduct, deoxycholic acid (DCA), promotes obesity-associated HCC progression. The study initiated to confirm that chemical toxin-induced Ras mutation causes HCC only in obese mice fed a high-fat diet. This phenotype was reproduced in genetically obese ob/ob mice. This study found that cellular senescence markers such as p21Waf1/Cip1 and p16INK4a, as well as DNA damage markers (53BP1 and γ-H2AX), were up-regulated in HCC lesions, particularly in HSC. These HSC produced SASP cytokines, such as interleukin (IL)-6, GROα, and CXCL9, in which proliferation was inhibited, demonstrating that HSC in HCC lesions has become senescent. Although HSC do not produce IL-1α, a SASP contributor, HSC induced the expression of inflammasome components and IL-1β. In IL-1β−/− mice, a high-fat diet induced hepatosteatosis and HSC senescence, as demonstrated by the expression of 53BP1 and p21; however, the production of SASP cytokines and HCC formation were suppressed, suggesting that SASP is essential for obesity-associated HCC development. The study then highlighted the contribution of intestinal microbiome to HCC development in mice. Gut sterilization by oral administration of antibiotics cocktail or vancomycin that targets Gram-positive bacteria significantly suppressed SASP of HSC and growth of HCC. They also found that serum levels of DCA and the composition of Clostridium cluster XI and XIVa that convert primary bile acids to DCA were increased in obese mice, but the DCA content was decreased by antibiotic treatment. Because DCA produces reactive oxygen species that cause DNA damage and SASP, the researchers then focused on the crucial role of DCA in obesity-associated HCC growth. High-fat diet–driven HCC growth was dramatically suppressed by lowering DCA levels by administrations of difructose anhydride III, which inhibits 7α-dehydroxylation activity or by ursodeoxycholic acid, which promotes bile acid secretion. Conversely, oral DCA feeding enhanced HCC development along with HSC senescence and SASP in obese mice. Finally, the study confirmed the presence of senescent HSC and SASP in HCC developed in nonalcoholic steatohepatitis patients.