Eiji Hara/Japanese Foundation for Cancer Research

At risk. Changes in gut flora could help explain why obese mice are more likely to develop liver tumors (inset).

Gut Bugs Could Explain Obesity-Cancer Link

Why does obesity raise the risk of developing cancer? A new study suggests that the wrong mix of gut bacteria could be to blame. Researchers report that obese mice carry altered communities of intestinal bugs, which produce DNA-damaging acid that leave the mice more susceptible to liver cancer. The findings hint that bacteria help drive cancer development and may eventually help scientists better predict and prevent the disease.

Obesity increases the odds of falling victim to certain types of cancer, including colorectal and liver tumors, but scientists haven't been able to identify the mechanism behind this link. They've suspected that our gut microbiota—the complex community of trillions of microbes living in our intestines—play a role. After all, gut bugs have been linked to other diseases, including inflammatory bowel disease, allergies, and even heart disease, and are known to differ between lean and obese individuals.

Molecular biologist Eiji Hara of the Cancer Institute at the Japanese Foundation for Cancer Research in Tokyo and colleagues set out to connect the dots between cancer and gut microbes by studying the development of cancer in obese and lean mice. They began with two groups of mice: lean mice that grew up on a normal diet and mice that ate a fat-laden diet until they were obese. To induce the rodents to develop cancer—"Mice don't smoke or drink alcohol, so they're fairly cancer-free," Hara says—they exposed the animals to a cancer-causing chemical shortly after birth.

The mice revealed the same obesity-cancer link observed in humans and other animals. Only 5% of the lean mice exposed to the carcinogen developed cancer later in life, whereas all the obese mice did. When the researchers reproduced the experiment using mice bred to be obese even on a normal diet, they also saw a greater incidence of cancer, which suggests that obesity itself—and not the animals' diet—increased their cancer risk.

The obese mice were prone to liver cancer, and their tumors showed high concentrations of molecules, called proinflammatory cytokines, that trigger inflammation. The obese mice also had higher levels of deoxycholic acid (DCA), a byproduct left over after certain gut microbes break down bile acids produced by the liver. DCA damages DNA and has been associated with some cancers in humans.

To trace the origins of these two signs—the presence of inflammation-promoting cytokines and the higher levels of DCA—the researchers scrutinized the animals' guts. They found that the obese mice hosted a different mix of bacteria. So-called Gram-positive bacterial strains, in particular, seemed to thrive in the plumper mice. When Hara and his colleagues treated the mice with vancomycin, an antibiotic that targets Gram-positive bacteria, the animals showed a reduction in their cancer incidence and their levels of DCA. Moreover, reducing the animals' DCA levels directly (by stimulating more bile acid secretion or slowing down bile acid breakdown) also reduced their cancer risk, and giving them extra DCA increased their risk, the team reports online today in Nature.

Together, the findings suggest that obesity triggers a cancer-causing domino effect in which DCA plays a key part, Hara says. The gut microbiota changes, boosting the populations of gut bugs that produce more DCA. Then the excess DCA causes DNA damage and inflammation in the liver, which, in turn, leads to liver cancer.

"I was very surprised by the process," Hara says. "We never expected that changes in the gut microbiota could cause the higher risk of cancer."

"I think this study is very exciting," says Peter Turnbaugh, a microbiologist from Harvard University who was not involved in the work. "It's been a mystery for quite some time why obesity leads to higher cancer risk. They make a compelling case that the microbial community is involved."

Turnbaugh notes that more research is needed to show that a similar mechanism is at work in humans. But if it is, the results could pave the way for better methods of predicting and preventing cancer. Tracking DCA levels, for example, could enable doctors to assess cancer risk and take steps toward prevention, he says.

"If it's true that production of this acid leads to cancer, there could be ways to inhibit the production by manipulating diet or fine-tuning people's microbial communities," Turnbaugh says. "But there's definitely a lot more to be learned first."

Posted in Health, Biology