The gut microbiota drives hormone resistance in castration-resistant prostate cancer (CRPC).
Major Finding: The gut microbiota drives hormone resistance in castration-resistant prostate cancer (CRPC).
Concept: Defined bacterial species are expanded after androgen deprivation and increase androgen synthesis.
Impact: This study reveals the gut microbiome as an alternative androgen source that promotes resistance in CRPC.
Androgen deprivation therapy (ADT) is the primary treatment for advanced prostate cancer, but patients often develop resistance. Given the role of microbiota in tumorigenesis and therapy response, Pernigoni, Zagoto, Calcinotto, and colleagues investigated how the gut microbiota affects CRPC progression. Microbiota ablation using broad-spectrum antibiotics reduced tumor growth and delayed onset of CRPC in murine models. 16S ribosomal DNA sequencing revealed the enrichment of specific microbiota species in castrated mice, notably Ruminococcus gnavus and Bacteroides acidifaciens, with R. gnavus being sufficient to increase tumor growth in castrated mice. Fecal microbiota transplantation (FMT) from castration-resistant (CR) mice resulted in the rapid emergence of CRPC, as well as increased cell proliferation and reduced animal survival. Targeted metabolomic analysis revealed that castrated mice with post–CR-FMT and R. gnavus–administered mice all had increased levels of circulating androgens. Both R. gnavus and B. acidifaciens were found to convert intermediate metabolites of the androgen synthesis pathway, such as pregnenolone and hydroxypregnenolone, into androgens and increase expression of androgen receptor (AR) genes in CRPC cells. Hypothesizing that intermediate metabolites enter the gut through the enterohepatic circulation and are converted to androgen by the gut microbiota, the authors intravenously injected deuterated pregnenolone into castrated mice and observed that microbiota ablation resulted in a significant reduction of deuterated androgens. Whole-genome metagenome (WGM) sequencing of metastatic CRPC patient rectal swabs were also enriched for species in the Ruminococcus genera, able to convert androgen precursors, and stimulate AR signaling in patient-derived organoids. Additionally, Prevotella stercorea was found to delay the onset of CRPC in castrated mice, and detection of this species in patient fecal samples was associated with favorable prognosis. In summary, this study highlights the gut microbiota as a key player in driving CRPC tumorigenesis by inducing androgen synthesis, and identifies a promising human patient fecal bacterial signature that may be used as an effective biomarker for identifying patients with prostate cancer who might benefit from microbiota-targeted intervention.
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