Meanwhile, recent studies have advanced our understanding of how diet-influenced gut microbiota affects the pathology of various diseases, such as colorectal cancer and diabetes. Reports indicate that prostate cancer patients have a gut microbiota composition distinct from that of healthy individuals.2,3 Given that prostate cancer is influenced by diet, it is suggested that gut microbiota may also be involved, but the underlying mechanisms remain unclear. This study aims to elucidate the effects of gut microbiota on prostate cancer progression and its mechanisms using a prostate cancer model mouse.
Prostate cancer model mice [Pb-Cre+; Pten(fl/fl)] were fed either a high-fat diet (62.2% energy from fat) or a control diet (12.5% energy from fat）and were administered a mixture of antibiotics (ampicillin, vancomycin, metronidazole, and neomycin) in drinking water from 5 weeks of age. Evaluations were conducted at 22 weeks of age when detailed cancer assessment became feasible. In high-fat diet mice, antibiotics significantly reduced prostate weight and Ki-67 positivity in cancer cells. In contrast, in control diet mice, antibiotics did not cause significant changes in prostate weight and Ki-67 positivity. Analysis of gut microbiota composition using 16S rRNA gene sequencing revealed that the gut microbiota of antibiotic-administered high-fat diet mice was significantly different from that of the other groups. Gene expression profiling of prostate tissue in high-fat diet mice showed that the expression of 64 genes, including Igf1, a known prostate cancer-promoting factor, was significantly reduced by antibiotic administration.
Serum IGF-1 levels were significantly reduced by antibiotics. Immunostaining of prostate tissue confirmed that IGF-1 was expressed in cancer cells. Additionally, the expression of phosphorylated IGF-1 receptor, AKT, and ERK, which are activated by IGF-1 signaling in cancer cells, was also reduced by antibiotics. These findings suggest that gut microbiota affected by antibiotics in high-fat diet mice suppressed prostate cancer growth via the IGF-1 signaling pathway.
Next, we investigated the mechanism by which gut microbiota influences IGF-1. A comparative analysis of gut microbiota composition showed that Rikenellaceae and Clostridiales, bacteria associated with short-chain fatty acid (SCFA) production, were significantly reduced in antibiotics-administered mice. Notably, Rikenellaceae have also been found to be increased in the gut microbiota of high-risk prostate cancer patients.3 SCFAs such as acetate, propionate, and butyrate are metabolic products of gut bacteria known to promote IGF-1 production. Mass spectrometry analysis revealed that fecal SCFA concentrations were significantly reduced in mice with antibiotics. Furthermore, when SCFAs were orally supplemented in high-fat diet mice with antibiotics, serum IGF-1 levels increased, and prostate cancer progression was promoted. These results demonstrate that SCFAs produced by gut microbiota promote IGF-1 production in the host and facilitate prostate cancer growth.
Finally, we examined the relationship between obesity and IGF-1 expression in human prostate cancer specimens using immunohistochemistry. IGF-1 expression was significantly increased in cancer cells from severely obese patients.
In conclusion, this study using a prostate cancer mouse model revealed the existence of a gut-prostate axis mediated by microbiota-derived SCFAs through IGF-1 signaling. Based on the similarities of gut microbiota changes in our model mice and prostate cancer patients, the same mechanism is likely to exist in humans. Since this report, several studies have indicated that, although SCFAs are widely recognized as beneficial metabolites of the gut microbiota, they can also promote prostate cancer through various mechanisms.4,5 In addition to SCFAs, several other factors associated with prostate cancer have been identified, including dysbiosis and testosterone production in the gut microbiota.6,7 These findings suggest that the gut-prostate axis could serve as a novel target for the prevention and treatment of prostate cancer.
Written by:
- Makoto Matsushita, MD, PhD, Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
- Kazutoshi Fujita, MD, PhD, Department of Urology, Kindai University, Faculty of Medicine, Osakasayama, Japan
- Hayashi T, Fujita K, Nojima S, Hayashi Y, Nakano K, Ishizuya Y, et al. High-fat diet-induced inflammation accelerates prostate cancer growth via IL6 signaling. Clin Cancer Res 2018;24:4309–18.
- Liss MA, White JR, Goros M, Gelfond J, Leach R, Johnson-Pais T, et al. Metabolic biosynthesis pathways identified from fecal microbiome associated with prostate cancer. Eur Urol 2018;74:575–82.
- Matsushita M, Fujita K, Motooka D, Hatano K, Fukae S, Kawamura N, et al. The gut microbiota associated with high-Gleason prostate cancer. Cancer Sci 2021;112:3125-35.
- Lachance G, Robitaille K, Laaraj J, Gevariya N, Varin TV, Feldiorean A, et al. The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids. Nat Commun 2024;15:3431.
- Liu Y, Zhou Q, Ye F, Yang C, Jiang H. Gut microbiota-derived short-chain fatty acids promote prostate cancer progression via inducing cancer cell autophagy and M2 macrophage polarization. Neoplasia 2023;43:100928.
- Matsushita M, Fujita K, Hatano K, Hayashi T, Kayama H, Motooka D, et al. High-fat diet promotes prostate cancer growth through histamine signaling. Int J Cancer 2022;151:623-36.
- Matsushita M, Fujita K, Motooka D, Hatano K, Hata J, Nishimoto M, et al. Firmicutes in Gut Microbiota Correlate with Blood Testosterone Levels in Elderly Men. World J Mens Health. 2022;40:517-25.