The gut microbiota and its metabolites play key roles in drug resistance mechanisms in advanced prostate cancer treatment, and microbiome-targeted therapies represent potential novel approaches to overcome this resistance and improve prognosis.
Key Findings
Results
Gut microbiota contributes to resistance against androgen deprivation therapy (ADT) in prostate cancer through androgen metabolism.
Certain gut bacteria possess the enzymatic capacity to synthesize androgens de novo or convert adrenal precursors into active androgens, bypassing the intended suppression of ADT.
Bacteria such as Clostridiales and Bacteroidales have been identified as capable of androgen biosynthesis within the gut environment.
This microbial androgen production can maintain tumor cell proliferation even under castrate levels of serum testosterone, contributing to castration-resistant prostate cancer (CRPC).
The gut microbiome may reactivate androgen receptor signaling pathways that ADT aims to suppress.
Results
Gut microbiota metabolites, including short-chain fatty acids (SCFAs), bile acids, and urolithins, are implicated in modulating drug resistance in prostate cancer.
SCFAs such as butyrate can influence histone deacetylase activity, thereby altering gene expression patterns related to tumor cell survival and drug response.
Secondary bile acids produced by gut bacteria have been shown to interact with androgen receptor signaling and may influence resistance to enzalutamide and other androgen receptor pathway inhibitors.
Urolithins, produced from polyphenol metabolism by gut bacteria, have demonstrated both pro- and anti-tumor effects depending on the microbial composition of the host.
These metabolites can modulate immune responses and tumor microenvironment conditions that affect therapeutic efficacy.
Results
The gut microbiome influences resistance to docetaxel-based chemotherapy in advanced prostate cancer.
Gut microbiota can affect the pharmacokinetics and bioavailability of chemotherapeutic agents, including docetaxel, by altering drug metabolism in the gastrointestinal tract.
Microbial dysbiosis has been associated with altered immune activation, which can diminish the efficacy of chemotherapy.
Specific bacterial taxa have been associated with either enhanced sensitivity or resistance to docetaxel treatment in prostate cancer patients.
The microbiome may modulate drug efflux pump expression and DNA repair mechanisms that contribute to chemoresistance.
Results
Gut microbiota composition affects the efficacy of immunotherapy, including immune checkpoint inhibitors, in prostate cancer.
Prostate cancer is generally considered immunologically 'cold,' with limited response to checkpoint inhibitors such as anti-PD-1/PD-L1 therapies.
Specific gut microbial signatures have been associated with improved responses to immunotherapy in cancer patients broadly, and similar associations are being investigated in prostate cancer.
Microbial metabolites can influence T cell infiltration and activation within the tumor microenvironment, potentially modulating immunotherapy response.
Dysbiosis-associated inflammation may promote immunosuppressive conditions that reduce checkpoint inhibitor efficacy.
Results
Microbiome-targeted therapeutic strategies are identified as potential approaches to overcome drug resistance in advanced prostate cancer.
Strategies discussed include fecal microbiota transplantation (FMT), probiotic supplementation, prebiotic use, and dietary interventions to modulate gut microbial composition.
FMT from responders to non-responders has shown promise in other cancer types as a means of restoring treatment sensitivity.
Targeted antibiotic use to eliminate resistance-conferring bacterial species is proposed, though concerns about broader dysbiosis are noted.
Combination approaches pairing microbiome modulation with standard therapies such as enzalutamide or docetaxel are highlighted as future research directions.
Results
Androgen receptor pathway inhibitors such as enzalutamide face resistance mechanisms that are partly mediated by gut microbiota.
Gut bacteria capable of metabolizing enzalutamide or its precursors may reduce effective drug concentrations at the tumor site.
Microbial modulation of androgen receptor splice variants, particularly AR-V7, may contribute to enzalutamide resistance.
The gut microbiome can influence glucocorticoid metabolism, providing an alternative pathway for tumor growth that bypasses enzalutamide's mechanism of action.
Alterations in gut permeability ('leaky gut') associated with dysbiosis may activate systemic inflammatory pathways that promote treatment resistance.
Background
Prostate cancer incidence is increasing worldwide and drug resistance remains a critical clinical challenge in the management of advanced disease.
Prostate cancer is identified as 'a leading cause of cancer-related deaths among men' with increasing worldwide incidence.
Current treatments include androgen deprivation therapy, surgery, radiotherapy, chemotherapy, and immunotherapy.
Surgical treatment 'has a less effective therapeutic effect in patients with advanced PCa.'
Drug-based treatments 'often lead to the development of drug resistance, highlighting the need to adopt new treatment strategies.'
What This Means
This research suggests that the trillions of microorganisms living in the human gut — collectively called the gut microbiota — play an important and previously underappreciated role in why advanced prostate cancer becomes resistant to treatment. The review examines how gut bacteria and the chemical compounds they produce (metabolites) can interfere with several types of prostate cancer treatments, including hormone-blocking therapies (like enzalutamide and androgen deprivation therapy), chemotherapy (like docetaxel), and immunotherapy. For example, certain gut bacteria can actually produce male hormones (androgens) on their own, essentially refueling the cancer even when medical treatment is designed to starve it of those hormones.
The review also highlights how bacterial metabolites — byproducts of microbial activity such as short-chain fatty acids and bile acids — can alter gene activity, affect immune responses, and change how the body processes cancer drugs. These changes can make tumors less sensitive to treatment or help cancer cells survive despite therapy. This means that two patients receiving the same treatment could have very different outcomes simply because of differences in their gut microbial communities.
This research suggests that targeting the gut microbiome — through approaches like fecal microbiota transplantation, probiotics, dietary changes, or selective antibiotic use — could become a new strategy to help restore drug sensitivity and improve outcomes for men with advanced prostate cancer. The authors call for more research to identify specific bacterial signatures associated with treatment resistance and to develop microbiome-based interventions that can be combined with existing prostate cancer therapies.
Song J, Cui H, Yang P, Xu Y, Liu Y, Zhang G, et al.. (2026). Gut microbiota and its metabolites: Key factors of drug resistance in the treatment of advanced prostate cancer (Review).. Molecular medicine reports. https://doi.org/10.3892/mmr.2026.13900