Liver cancer: improving the immune response through the modulation of microbiota?

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Decreased levels of bacteria from the Clostridium family in the gut are thought to promote the accumulation of primary bile acids. This phenomenon may contribute to enhanced expression in antitumor NKT cells in the liver.

 

The microbiota and its metabolites are transported to the liver through the portal vein and can affect the progression of liver cancer. This observation led an international team to look into the possibility of up-regulating antitumor immunity by acting on the intestinal microbiota. The objective was to better understand the impact of reduced levels of commensal bacteria on changes in primary and secondary bile acid levels*, and consequently on the immune response. Primary acids promote the accumulation of Natural Killer T-cells (NKT) which produce antitumor interferon-gamma, while secondary acids have the opposite action.

Dysbiosis and up-regulation of NKT cells

After administering an antibiotic cocktail to mice suffering from primary or metastatic hepatic carcinoma in order to destroy intestinal commensal bacteria, the researchers assessed the effect of this procedure on tumor growth kinetics. Conclusion: the reduction in species belonging to the Clostridium genus led to the rise in the number of NKT cells, regardless of the type of mouse, its line or tumor type. The correlation was confirmed after colonization by a bacterium known to metabolize primary bile acids into secondary acids–Clostridium scindens–in the mice that presented a degraded microbiota. The consequence of this “renormalization” was a reduction in the number of NKT cells, and therefore the end of the inhibition of tumor growth.

Transposition to humans

The study in mice was then extended to humans, using samples of non-tumoral liver tissue sampled from individuals suffering from primary liver cancer. Result: an up-regulation identical to that observed in mice showing an accumulation of primary bile acid. This is enough to suggest a link between the intestinal microbiota, its metabolites, and the hepatic immune response; an association which could herald new therapeutic approaches in liver cancer, a major cause of death in oncology.

 

* Gram-positive bacteria metabolize primary bile acids into secondary acids.

** Primary bile acids increase production by liver sinusoid endothelial cells of the ligand CXCL16 on CXCR6+ receptors expressed on the surface of NKT-cells responsible for cell survival and their accumulation in the liver.

 

Sources:

C. Ma, M. Han, B. Heinrich, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360 (6391), eaan5931. DOI: 10.1126/science.aan5931.