Antibiotics Protect against Liver Tumors in Mice

Researchers have known for some time that the gut microbiome affects tumor development in the liver. Recently, scientists uncovered the first compelling explanation for this phenomenon. By treating mice with antibiotics, they showed that depleting commensal bacteria enhances certain primary bile acids in the liver (Science 2018;360:eaan5931). This change signals natural killer T (NKT) cells to accumulate there, inhibiting tumors.

“Most studies on the microbiome and cancer are based on correlations,” says Tim Greten, MD, of the NIH, senior author of the article. “Here we show a clear mechanism for how commensal bacteria use bile acids as a messenger to regulate natural killer T cells in the liver.”

Investigators found that the protective effects of antibiotic treatment—a “cocktail” of vancomycin, neomycin, and primaxin—were similar in mouse models of primary hepatocellular carcinoma (HCC) and mouse models of liver metastasis from melanomas, lymphomas, or thymomas. “The effect is completely independent of the tumor type,” says Greten. “The genetics are irrelevant.”

What mattered was the location of the tumor. Antibiotics protected against liver tumors—both primary and metastatic—but they did not protect against tumor formation elsewhere in the body. For example, antibiotics did not slow the growth of subcutaneous tumors in mice. Further, lung metastases increased in treated mice after they were injected with melanoma or lymphoma cells. Christian Jobin, PhD, of the University of Florida in Gainesville, says that the fact that the rate of lung metastasis was not reduced “really highlights the specific impact of microbes on carcinogenesis.”

The researchers found that after antibiotics depleted commensal bacteria from the gut microbiome in mice, levels of some secondary bile acids, such as ω-MCA, in the liver fell. This relieved inhibition of the cytokine CXCL16, a potent recruiter of NKT cells. At the same time, levels of certain primary bile acids that were shown to induce CXCL16, such as T-β-MCA, increased. This resulted in the accumulation of hepatic NKT cells and a reduction in liver tumors. Consistent with this bile-mediated mechanism, when mice were treated with antibiotics for just a week and subsequently inoculated with Clostridium scindens, a commensal bacterium that produces secondary bile acids, the protective effect against liver tumors disappeared.

Eiji Hara, PhD, of Osaka University in Japan, says that previous research in mice had established that secondary bile acids can promote liver cancer by damaging DNA, but the idea that they can also cause cancer by preventing NKT cells from accumulating in the liver is new. Moreover, he says that the opposing roles of primary and secondary bile acids demonstrated in the study is both novel and surprising.

Greten says that the next step is to investigate how these findings apply to humans. In the current study, his team demonstrated that certain primary bile acids correlated with CXCL16 expression in tumor-free liver tissue from patients with HCC or cholangiocarcinoma, whereas certain secondary bile acid levels were inversely correlated with the cytokine, as in mice. Now they are planning a human trial to investigate the therapeutic potential of antibiotics for patients with primary liver tumors or liver metastases. –Kristin Harper

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