Gut Environment Changes Due to Androgen Deprivation Therapy in Patients With Prostate Cancer

Abstract

Background: It is estimated that up to 2040 there will be 1,017,712 new cases of prostate cancer worldwide. Androgen deprivation therapy (ADT) is widely used as a treatment option for all disease stages. ADT, and the resulting decline in androgen levels, may indirectly affect gut microbiota. Factors affecting gut microbiota are wide-ranging; however, literature is scare on the effects of ADT on gut microbiota and metabolome profiles in patients with prostate cancer. \n \nMethods: This 24-week observational study investigated the relationship between testosterone levels in Japanese patients with prostate cancer undergoing ADT, with changes in gut microbiota. Sequential faecal, and serum blood samples were collected 1 and 2 weeks before ADT, and 1, 4, 12, 24 weeks after ADT. Bacterial 16S rRNA gene-based microbiome analyses, and capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses were performed. \n \nFindings: A total of 23 patients completed the study. The α- and s-diversity of gut microbiota decreased significantly at 24 weeks after ADT (p=0.017, p<0.001, respectively). Relative abundances of Proteobacteria, Gammaproteobacteria, Pseudomonadales, Pseudodmonas, and concentrations of urea, lactate, butyrate, 2-hydroxyisobutyrate and S-adenosylmethionine (SAM) changed significantly after ADT (p<0.05). There was a significant positive correlation between the abundance of Proteobacteria, a known dysbiosis indicator, and the concentration of lactate (R=0.49, p<0.01). \n \nInterpretation: The decline in testosterone levels resulted in detrimental changes in gut microbiota. This dysbiosis may contribute to an increase in frailty and an increased risk of adverse outcomes in patients with prostate cancer. \n \nClinical Trial Registration Information: This study was also registered in the UMIN clinical registry (UMIN000021161). \n \nFunding Information: This work was supported in part by JSPS KAKENHI (18H04805 to S.F.), AMED-CREST (JP20gm1010009 to S.F.), JST ERATO (JPMJER1902 to S.F.), the Takeda Science Foundation (to S.F.), the Food Science Institute Foundation (to S.F.), the Programme for the Advancement of Research in Core Projects under Keio University’s Longevity Initiative (to S.F.). \n \nDeclaration of Interests: The authors declare no conflicts of interest. \n \nEthics Approval Statement: This study was conducted in accordance with the ethical principles of Declaration of Helsinki. The samples and clinical information used in this study were obtained by written informed consent, and with the approval of the institutional review boards of Juntendo University school of Medicine (Approval number: 14-117).