Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer (PCa). Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-speciﬁc Pten knockout mice as a PCa model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and PCa.
Oral administration of an antibiotic mixture (Abx) in PCa-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 PCa cell proliferation, and reduced prostate Igf1 expression and circulating IGF-1 levels. In PCa tissue, MAPK and PI3K activities, both downstream of the IGF-1 receptor, were suppressed by Abx administration. IGF-1 directly promoted the proliferation of PCa 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 IGF-1 levels. In humans, IGF-1 was found to be highly expressed in PCa tissue from obese patients. In conclusion, IGF-1 production stimulated by SCFAs from gut microbes influences the growth of PCa via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF-1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in PCa prevention and treatment.
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