The gut microbiota of metastatic prostate cancer patients receiving ARPI therapy showed reduced alpha diversity and distinct taxonomic and functional signatures compared to untreated localized PCa, with specific microbial features associated with disease progression during treatment.
Key Findings
Results
Metastatic prostate cancer patients receiving ADT plus ARPI therapy showed reduced microbial alpha diversity compared to untreated, clinically localized PCa patients.
Study compared GM of 15 patients with metastatic PCa receiving ARPIs against 39 patients with untreated (UT) PCa using shallow shotgun metagenomic sequencing.
The metastatic PCa cohort receiving ADT plus ARPI therapy showed 'reduced microbial alpha diversity' as a statistically significant finding.
The untreated cohort served as a clinically localized PCa reference group.
5 of the 15 metastatic patients experienced disease progression during the study period.
Results
Microbial functions related to dietary carbohydrate utilization, fermentation, epithelial interaction, and microbial structural maintenance were predominantly underrepresented in patients with advanced disease.
These functional depletions were identified in the metastatic PCa cohort receiving ARPI therapy compared to the untreated reference cohort.
The authors interpret these findings as reflecting 'reduced metabolic and ecological versatility' in the advanced disease group.
Analysis was performed using shallow shotgun metagenomic sequencing enabling functional potential assessment.
These functional categories represent core microbiome activities associated with host-microbiome homeostasis.
Results
Stress-responsive and redox-associated microbial functions were overrepresented in patients with advanced metastatic prostate cancer receiving ARPI therapy.
These overrepresented functions were identified relative to the untreated, clinically localized PCa cohort.
The authors suggest these alterations reflect 'increased adaptation to host-associated stress conditions.'
These findings were part of 'significant taxonomic and functional differences' between the metastatic and untreated cohorts.
Functional profiling was derived from shallow shotgun metagenomic sequencing data.
Results
Bifidobacterium longum, Anaerobutyricum hallii, Ruminococcus sp., and Blautia obeum were enriched in patients with disease progression compared to the untreated group.
LinDA coefficients for enriched taxa were: Bifidobacterium longum (5.7), Anaerobutyricum hallii (2.6), Ruminococcus sp. (2.6), and Blautia obeum (2.4).
This comparison was made between the 5 patients with disease progression and the 39 untreated PCa patients.
LinDA (Linear model for Differential Abundance analysis) was used as the statistical method for taxa comparisons.
These taxa represent potential candidate biomarkers for progression during ARPI treatment.
Results
Sutterella wadsworthensis, Butyricimonas, Bilophila wadsworthia, Alistipes indistinctus, and Intestinimonas were depleted in patients with disease progression compared to the untreated group.
LinDA coefficients for depleted taxa were: Sutterella wadsworthensis (-8.4), Butyricimonas (-5.9), Bilophila wadsworthia (-5), Alistipes indistinctus (-5), and Intestinimonas (-3).
Sutterella wadsworthensis showed the largest magnitude of depletion with a LinDA coefficient of -8.4.
Comparisons were made between the 5 progression patients and 39 untreated PCa patients.
These depleted taxa represent additional potential biomarker candidates for ARPI treatment resistance.
Results
Significant taxonomic differences were observed between the metastatic PCa cohort receiving ARPI therapy and the untreated localized PCa cohort.
Both taxonomic and functional differences were identified between the two groups.
Shallow shotgun metagenomic sequencing was the analytical method employed.
The study design compared 15 metastatic patients on ARPIs to 39 untreated PCa patients.
The authors note these findings identify 'distinct taxonomic and functional features associated with metastatic PCa under systemic therapy.'
Conclusions
The authors conclude that the gut microbiome represents a potential source of biomarkers for advanced prostate cancer and progression under ARPI therapy, but note that longitudinal and multi-omics studies are required.
The study was cross-sectional in design, comparing 15 metastatic ARPI-treated patients to 39 untreated patients.
Authors explicitly state 'longitudinal and multi-omics studies are required to determine their predictive value and functional relevance.'
The findings are described as 'providing potential candidates for biomarker development and generating testable hypotheses regarding microbiome-host metabolic interactions in treatment resistance.'
The small sample size, particularly the progression subgroup (n=5), is an acknowledged limitation implied by the call for larger studies.
What This Means
This research suggests that the community of bacteria living in the gut (the gut microbiome) looks distinctly different in men with advanced, metastatic prostate cancer who are being treated with hormone-blocking drugs called androgen receptor pathway inhibitors (ARPIs), compared to men with early-stage, untreated prostate cancer. Specifically, men on ARPI therapy had less microbial diversity — meaning fewer different types of bacteria — and their gut bacteria showed reduced capacity for functions like breaking down dietary carbohydrates and fermenting foods, while showing increased signs of stress-related activity. Among the 5 patients whose cancer progressed despite treatment, specific bacteria were found at higher or lower levels than in the untreated group, including higher levels of Bifidobacterium longum and lower levels of Sutterella wadsworthensis.
This research suggests that these microbial differences could potentially serve as biological markers (biomarkers) to identify which patients are at risk of their cancer progressing during treatment. The specific bacteria identified as enriched or depleted in progression patients — identified using a statistical method called LinDA analysis — represent candidates for future investigation. The authors propose that the gut microbiome may interact with cancer treatment response, possibly through metabolic pathways, though the exact mechanisms remain unclear.
This was a relatively small study (15 metastatic patients, 5 of whom had progression, compared to 39 untreated patients), and the authors themselves emphasize that larger, longer-term studies combining multiple types of biological data are needed before these findings can be used clinically. The results do not establish cause and effect — it is not yet known whether changes in the gut microbiome drive cancer progression, result from it, or are influenced by the treatment itself. Nonetheless, the study identifies specific microbial targets worth investigating further as potential tools for predicting treatment outcomes in advanced prostate cancer.
Pérez-Castro S, Carballo-Quinta M, Rodríguez-Costas N, Freire-Rodríguez A, Davina-Nunez C, Bellas-Pereira A, et al.. (2026). Gut Microbiota Signatures Associated with Metastatic Prostatic Cancer Treated with Androgen Receptor Pathway Inhibitor (ARPI) Therapy.. International journal of molecular sciences. https://doi.org/10.3390/ijms27198454