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Gut Microbiome Controls Antitumor Immune Function in the Liver


The microbiome is the collection of bacteria and other microorganisms that live in or on the body. In humans, the greatest proportion of the body’s total microbiome is in the gut. Despite extensive research into the relationship between the gut microbiome and cancer, the role of gut bacteria in the formation of liver cancer has remained poorly understood. According to an article published online in Science (24 May 2018), a connection has been found between bacteria in the gut and antitumor immune responses in the liver. The study showed that bacteria found in the gut of mice affect the liver’s antitumor immune function. The findings have implications for understanding the mechanisms that lead to liver cancer and for therapeutic approaches to treat them.


To investigate whether gut bacteria affect the development of tumors in the liver, the authors used three mouse models of liver cancer. Results showed that when the gut bacteria were depleted using an antibiotic “cocktail,“ the mice that had the antibiotics developed fewer and smaller liver tumors and had reduced metastasis to the liver. The authors then studied the immune cells in the liver to understand how the depletion of gut bacteria suppressed tumor growth in the liver of the antibiotic-treated mice. Results showed that antibiotic treatment increased the numbers of a type of immune cell called NKT cells in the livers of the mice. Further experiments showed that, in all three mouse models, the reduction in liver tumor growth that resulted from antibiotic treatment was dependent on these NKT cells. Next, it was found that the accumulation of the NKT cells in the liver resulted from an increase in the expression of a protein called CXCL16 on cells that line the inside of capillaries in the liver. The authors than asked why do mice treated with antibiotics have more CXCL16 production in these endothelial cells? The authors added that ended up being the critical point, when they found that bile acids can control the expression of CXCL16. They then did further studies, and found that if the mice were treated with bile acids, it can change the number of NKT cells in the liver, and thereby the number of tumors in the liver.


Finally, the investigators found that one bacterial species, Clostridium scindens, controls metabolism of bile acids in the mouse gut  — and ultimately CXCL16 expression, NKT cell accumulation, and tumor growth in the liver. The authors explained that while many studies have shown an association between gut bacteria and immune response, this study is significant in that it identifies not just a correlation, but a complete mechanism of how bacteria affect the immune response in liver. In the same study, the authors found that bile acids also control the expression of the CXCL16 protein in the liver of humans and wrote that, although these results are preliminary, the novel mechanism described in this study could potentially apply to cancer patients.



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