Stealth Attack by the Gut Microbiota

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Science Translational Medicine  17 Jul 2013:
Vol. 5, Issue 194, pp. 194ec117
DOI: 10.1126/scitranslmed.3006924

Obesity is an increasing problem in the developed world and a leading cause of serious health problems, including heart disease, diabetes, and cancer. However, the mechanisms by which obesity contributes to these diseases are not fully understood. Now, Yoshimoto and colleagues report that alterations in the normal bacterial flora (microbiota) in the gut of laboratory mice trigger a cascade of deleterious events that ultimately lead to hepatocellular carcinoma, a common cancer in humans worldwide.

The authors treated neonatal mice with a chemical carcinogen known to induce a variety of tumors throughout the body. Then, the mice were fed either a high-fat or normal diet for several weeks. The mice treated with the high-fat diet became obese and had a higher rate of hepatocellular carcinoma than did their lean counterparts. The obese mice displayed complex changes in inflammatory cytokines, chemokines, and proteases in liver stellate cells, a pattern known as the senescence-associated secretory phenotype (SASP). By blocking SASP in the stellate cells or by removing SASP expressing cells from the liver, the authors were able to stop the development of hepatocellular cancer. Furthermore, the obese mice had increased numbers of OTU-1105 bacteria in their gut, a bacterium that belongs to the Clostridium genus. These bacteria produce deoxycholic acid, which is taken up by the liver and induces SASP in stellate cells. Notably, depletion of the gut microbiota with antibiotics or reduction in tissue concentrations of deoxycholic acid by difructose anhydride III and ursodeoxycholic acid inhibited the expression of SASP and halted the development of hepatocellular carcinoma.

These results implicate perturbations in the gut microbiota as critical events in the development of hepatocellular carcinoma in obesity. Whether modifications of the gut microbiota by antibiotics, probiotics, or general dietary intervention can prevent tumors from forming in humans warrants further investigation. Nevertheless, the present study is yet another fascinating example of how the trillions of bacteria that make up the microbiome stealthily affect critical aspects of normal body function.

S. Yoshimoto et al., Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013). [Abstract]

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