Prevotella copri exhausts host’s intrinsic indol-3-pyruvid acid to promote breast cancer development: Inactivation of AMPK via UHRF1-mediated negative regulation

Abstract

Background Emerging evidence has revealed the novel role of gut microbiota in the development of cancer, and it has been reported that gut microbiota of breast cancer patients displayed certain characteristics. However, direct causation between gut microbiota and breast cancer remains uncertain. Results In the present study, it was found that Prevotalla is a significantly enriched and prevalent genus in gut microbiota of breast cancer patients. Prevotella copri is the dominate species of Prevotalla genus in gut microbiota. Prior-oral administration of P. copri could promote breast cancer growth in specific germ-free (SPF) mice and germ-free (GF) mice. Mechanistically, the excess P. copri consumed large amount of tryptophan (Trp), thus hampering the physiological accumulation of indol-3-pyruvid acid (IPyA) in host, in which the energy-controlling AMPK signaling pathway was inactivated by UHRF1-regulated DNA methylation as indicated by the alternation in profiles of protein expression and DNA methylation. As discovered in our data, IPyA is an intrinsic anti-cancer reagent in host at physiological level, and such potent cytotoxicity on breast cancer cells is mainly relied on the activation of AMPK via suppressing UHRF1-mediated negative regulation, which was just opposite to the effect of P. copri on tumor growth. Conclusions The exhaustion of IPyA by excess P. copri makes great contribution to the promotion of breast cancer. Our findings, for the first time, highlighted P. copri as a risk factor in development of breast cancer.