June 5, 2018

Gut microbes affect antitumor activity in liver

At a Glance

  • A study in mice revealed a connection between bacteria in the gut and antitumor immune responses in the liver.
  • The findings have implications for understanding the mechanisms that lead to liver cancer and developing approaches to treat it.
Malignant breast cancer cells in liver Malignant breast cancer cells, which appear brown, seen in the liver. The researchers found that gut microbes can affect the development of such tumors in the liver. NCI

The microbiome is the community of bacteria and other microbes that live in or on the body. The greatest proportion of the human microbiome is in the intestine, or gut. Recent research has found that the gut microbiome can influence many conditions, including cancer growth.

Cancer is commonly found in the liver. Most of the time, it’s from a cancer that started somewhere else in the body, broke off, and spread to the liver. About 75% of the blood that reaches the liver travels through the portal vein from the digestive tract. That blood includes substances from the gut microbiome. To understand how certain gut bacteria may influence the development of tumors in the liver, a team led by Dr. Tim Greten at NIH’s National Cancer Institute (NCI) carried out a series of experiments in mice. Their study was published on May 25, 2018, in Science.

The scientists tested mouse models of liver cancer. They first depleted certain bacteria from the animals’ guts using antibiotics. Mice given the antibiotics developed fewer and smaller liver tumors.

To understand how the depletion of gut bacteria suppressed tumor growth, the investigators examined immune cells in the liver. They found that antibiotic treatment increased the numbers of natural killer T (NKT) cells, a type of immune cell. Further experiments showed that, in all the mouse models tested, the reduction in liver tumor growth from the antibiotic treatment was dependent on NKT cells.

NKT cells interact with a protein on cell surfaces called CXCL16. The team examined CXCL16 in the cells that line the inside of capillaries in the liver. They found that the accumulation of NKT cells in the liver resulted from an increase in CXCL16.

The scientists next searched for the link between gut microbes and CXCL16. Gut microbes are known to modify bile acids, which are made by the liver to help break down fats during digestion. Through a series of experiments, the team showed that altered bile acids from the gut reduced CXCL16 levels when they traveled back into the liver. Confirming this idea, the team fed different types of bile acids to the mice and found that they affected tumor growth differently in the liver.

The researchers identified a type of bacterium in the gut, Clostridium, that modifies bile acids. Antibiotics that kill Clostridium allow bile acids from the gut to increase levels of CXCL16 and NKT cells in the liver, which inhibits liver tumor growth.

“What we found using different tumor models is that if you treat mice with antibiotics and thereby deplete certain bacteria, you can change the composition of immune cells of the liver, affecting tumor growth in the liver,” Greten says. “This is a great example of how what we learn from basic research can give us insight into cancer and possible treatments.”

These findings in mice may also apply to people with liver cancer. In preliminary work, the researchers showed that different bile acids can also control CXCL16 levels in human liver samples. Further work will be needed to understand the significance of these mechanisms in people.

Related Links

References: Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, Ritz T, Longerich T, Theriot CM, McCulloch JA, Roy S, Yuan W, Thovarai V, Sen SK, Ruchirawat M, Korangy F, Wang XW, Trinchieri G, Greten TF. Science. 2018 May 25;360(6391). pii: eaan5931. doi: 10.1126/science.aan5931. PMID: 29798856.

Funding: NIH’s National Cancer Institute (NCI) and National Institute of General Medical Sciences (NIGMS); and Deutsche Forschungsgemeinschaft DFG.