Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth Via Igf-1 Signaling In Obese Mice

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut cells. microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiotamediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igfl expression and circulating insulin-like growth factor-1 (IGFI) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGFI receptor, were suppressed by Abx administration. IGFI directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGFI levels. In humans, IGFI was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGFI-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment.Significance: These results suggest that intestinal bacteria, acting through short-chain fatty adds, regulate systemic and local prostate IGFI in the host, which can promote proliferation of prostate cancer cells.[GRAPHICS].