Gut microbiota-derived deoxycholic acid shapes an immunosuppressive tumor microenvironment and promotes breast cancer progression.

Abstract

The gut microbiota is increasingly recognized as a contributor to breast cancer progression. Here, we report that the gut bacterium Enteroclosterbolteae, a member of the Lachnospiraceae family, is progressively enriched during tumor development and is associated with increased levels of the microbiota-derived metabolite deoxycholic acid. Deoxycholic acid accumulates in tumors and activates the farnesoid X receptor in tumor cells, inducing interleukin-6 production through nuclear factor κB signaling. Interleukin-6 promotes the recruitment of granulocytic myeloid-derived suppressor cells and T helper 17 cells, establishing an immunosuppressive microenvironment. Inhibition or knockdown of the farnesoid X receptor, as well as blockade of interleukin-6 signaling, attenuates these effects. These findings identify a microbiota-metabolite-immune axis driving breast cancer progression and uncover microbial metabolites as potential therapeutic targets.