The senescence-associated secreted phenotype (SASP) is known to modulate tumorigenesis. Both secretion of inflammatory cytokines in SASP and gut microbiota changes have been seen in obese mice. Ohtani, Hara and colleagues have discovered that obesity leads to changes in gut microbial metabolites that induces SASP in hepatic stellate cells, the secretion of cancer-inducing inflammatory cytokines and liver tumorigenesis (Nature 499, 97–101; 2013).

The authors used two models of obesity in mice and a chemical carcinogen treatment that induces oncogenic Ras. They observed an increase in DNA damage and senescence in hepatic stellate cells. Strikingly, tumours were reduced in animals deficient for interleukin 1-beta (IL-1β) and in animals treated with antibiotics. The latter suggested that changes in gut microbiota may have led to the induction of hepatic stellate cell senescence and secretion of inflammatory cytokines. Indeed, the authors found that obese animals showed an increase in the levels of deoxycholic acid (DCA), a bacterial metabolite that is known to induce DNA damage and senescence. This metabolite is mainly produced by bacteria belonging to the Clostridium cluster, which the authors found were increased in the gut microbiota of obese animals. The authors were able to lower the tumorigenic development by using compounds limiting DCA production. However, as for IL-1β deficiency, some tumours persisted, indicating that other factors must contribute to liver tumorigenesis in this setting.