Gut microbiota affects prostate cancer risk through steroid hormone biosynthesis

Purpose Although prostate cancer is the most common cancer in men in Western countries, there is significant variability in geographical incidence. This might result from genetic factors, discrepancies in screening policies or differences in lifestyle. Gut microbiota has been recently associated with cancer progression, but its role in prostate cancer is unclear. Methods In a prospective multicenter clinical trial ([NCT02241122][1]), the gut microbiota profiles of 181 men with a clinical suspicion of prostate cancer were assessed utilizing 16S rRNA gene sequencing. Sequences were assigned to operational taxonomic units, and differential abundance analysis, α- and β-diversities, and predictive functional (PICRUSt) analyses were performed. Additionally, plasma steroid hormone levels were correlated with the predicted microbiota functions. Results Several differences in the gut microbiota between the subjects with and without prostate cancer were noted. Prevotella 9 , members of the Erysipelotrichaceae family and Escherichia-Shigella were higher, and Jonquetella, Moryella, Anaeroglobus, Corynebacterium and CAG-352 were lower in the cancer group. Predictive functional analyses revealed higher 5-α-reductase, copper absorption, and retinal metabolism in the prostate cancer associated microbiome. Plasma testosterone associated negatively with the microbial 5-α-reductase activity (p=0.030). In a subgroup of men taking 5-α-reductase inhibitors (n=17), plasma estrone (p=0.027) and estradiol (p=0.059) levels were lower in men with predicted elevation of the microbial 5-α-reductase function. Conclusions Gut microbiota of the prostate cancer patients differed significantly compared to benign subjects. Microbial 5-α-reductase, copper absorption and retinol metabolism are potential mechanisms of action. These findings could explain the observed association of lifestyle, geography, and prostate cancer incidence. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02241122 ### Funding Statement Finnish Cancer Society ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethichs Committee of the Hospital district of Southwest Finland I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Clinical data available at * PCa : Prostate cancer GM : Gut microbiota ISUP : International Society of Urological Pathology BMI : Body mass index IBD : Inflammatory bowel disease OTU : Operational Taxonomical Unit PICRUSt : Phylogenetic Investigation of Communities by Reconstruction of Unobserved States DHT : Dihydrotestosterone DHEA : Dehydroepiandrosterone T : Testosterone 17-α-OHP : 17-α-hydroxyprogesterone 5-AR 5-α-reductase 5-ARI : 5-α-reductase inhibitor [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02241122&atom=%2Fmedrxiv%2Fearly%2F2022%2F09%2F09%2F2021.08.19.21262274.atom