How do gut bacteria (depicted here) control cancer immunity?
Working with mouse models, they found that gut bacteria can regulate the liver's immune response to both primary and metastatic tumors.
Although previous studies had already revealed that the huge colonies of bacteria that live in the gut can influence how the immune system deals with cancer, it was not clear how this happened in the liver.
The new study now reveals that a particular species of the Clostridium genus that is present in the gut can block antitumor activity in the liver by altering bile acids.
A report on the research — which was led by the National Cancer Institute (NCI) in the National Institutes of Health (NIH) at Bethesda, MD — can be found in the journal Science.
Not only do they give new insights into the development of cancer in the liver, but the findings also raise the question of whether reducing the particular microbes might help the immune system to fight the cancer.
Gut microbes and liver cancer
The human digestive tract is home to a "complex and dynamic population" of microbes, commonly termed the gut microbiota.
These vast colonies of bacteria and other microorganisms have a big impact on human health and disease; they help the immune system to fight pathogens and they are essential for digestion and metabolism. In the liver, for example, they help to regulate the production of bile acids.
Disturbance in the composition of gut microbiota has been linked to the development of many infections and diseases that cause inflammation, including those that affect the liver.
There are two types of tumor that can develop in the liver: primary and secondary tumors. Primary liver tumors arise from cancer that starts in the liver.
Secondary liver tumors — or metastatic liver tumors — are tumors that arise from cancers that start somewhere else in the body, such as the colon.
The researchers note that primary and metastatic liver cancer "is a leading cause of cancer-related death in the United States."
Liver and gut are in 'intimate' contact
In their study paper, the researchers explain that the liver "intimately cross-talks with the gut" and is continually exposed to byproducts of gut bacteria through contact with blood from the intestines. In fact, blood from the gut accounts for 70 percent of the liver's blood supply.
With this — together with the fact that gut microbiota can influence the liver's immune function and are involved in the production of bile acids, and that bile acids play a role in the development of liver cancer — in mind, the researchers decided to investigate how all this comes together to influence the growth of liver tumors.
By running tests in mouse models of primary and metastatic liver cancer, they discovered that treating the animals with antibiotics not only reduced their gut bacteria, but that it also led to smaller and fewer tumors.
They also found that these effects coincided with an increase in the number of natural killer cells (NKCs) in the liver. NKCs are powerful killers of cancer cells.
Further tests showed that the rise in NKCs was the result of antibiotics increasing expression of a cell protein called CXCL16, which summons NKCs. The cells with this protein form the tissue, or endothelium, that lines the tiny blood vessels that permeate the liver.
"We asked ourselves," says corresponding study author Dr. Tim F. Greten, of the NCI's Center for Cancer Research, "why do mice treated with antibiotics have more CXCL16 production in these endothelial cells?"
He says that the "critical point" of the study was when they found that "bile acids can control the expression of CXCL16."
He and his colleagues then found that if they "treated mice with bile acids," they could "actually change the number of NKT cells in the liver, and thereby the number of tumors in the liver."
More Clostridium promoted cancer spread
A final set of experiments revealed that Clostridium — a genus of bacteria that is present in humans as well as mice — played a key role in this activity.
A particularly interesting finding was that Clostridium influences the amount of CXCL16 present in the liver, as the bile recycles between the gut and the liver.
Increasing the amount of these bacteria in the gut not only reduced levels of NKCs present in the liver, but it also promoted cancer spread in the mice, note the authors.
In a related Perspective article, Drs. Nadine Hartmann and Mitchell Kronenberg, from the La Jolla Institute for Allergy and Immunology in California, draw on highlights from the study and explain that "as for most biological systems, bile function has different facets."
And, paradoxically, not only does bile function help the digestive system to "emulsify fats and help absorb dietary lipids, but after modification by the microbiome, secondary bile acids alter immune function to promote liver cancer and liver metastases."
"This [study] is a great example of how what we learn from basic research can give us insight into cancer and possible treatments."
Dr. Tim F. Greten