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Review

Navigating the Gut–Prostate Axis: The Gut Microbiome in Prostate Cancer Resistance and Targeted Interventions

by
Zeyu Ai
1,†,
Ping Dai
2,†,
Kangnan He
1,
Ruilong Nie
1,
Shimin Zou
2,* and
Liang Chen
1,*
1
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2
Department of Urology, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Microbiol. Res. 2026, 17(3), 55; https://doi.org/10.3390/microbiolres17030055
Submission received: 26 January 2026 / Revised: 24 February 2026 / Accepted: 3 March 2026 / Published: 5 March 2026
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Abstract

In recent years, the gut microbiome has been increasingly recognized as an important factor in regulating treatment responses and disease progression in prostate cancer (PCa). We synthesized literature published over the past five years, focusing on preclinical and clinical studies linking the microbiome to PCa treatment outcomes. There is accumulating evidence that gut microbiota dysbiosis and its associated metabolites can modulate key biological processes, such as androgen metabolism, inflammatory signaling pathways, and antitumor immune responses. These processes affect the sensitivity of PCa patients to androgen deprivation therapy (ADT) and other systemic treatments. The available evidence suggests that the gut microbiome has the potential to serve as a predictive biomarker for treatment response and could represent a novel target for interventional precision therapy in PCa. This narrative review summarizes the latest research on the “gut–prostate axis”, focusing on the role of the gut microbiome in regulating therapeutic responses in PCa and the underlying mechanisms. Finally, we address current limitations, including the predominance of preclinical evidence, methodological heterogeneity, and the critical need for longitudinal clinical validation to distinguish causality from association.

1. Introduction

Prostate cancer (PCa) represents one of the most prevalent malignancies affecting men worldwide. It has been recognized as a malignancy that is highly dependent on androgen signaling. Androgen deprivation therapy (ADT), together with treatment modalities including chemotherapy, radiotherapy, and immunotherapy, constitutes the treatment approach across various stages of the disease [1]. However, treatment resistance is frequently observed in patients receiving ADT. This has been shown to lead to the development of castration-resistant prostate cancer (CRPC), a stage in the progression of PCa that is difficult to treat [2].
Traditionally, the resistance exhibited to PCa therapies has been predominantly ascribed to intrinsic mechanisms, such as AR amplification or mutation, augmented intratumoral androgen biosynthesis, lineage plasticity, and the activation of alternative signaling pathways [3]. While these mechanisms play critical roles in disease progression, they are insufficient to fully account for the heterogeneity of treatment responses observed in clinical practice and the frequently rapid emergence of therapeutic resistance. In recent years, accumulating evidence has suggested that tumor responses to therapy are also significantly influenced by host systemic metabolism, immune status, and the surrounding microecological environment [4]. This view has been substantiated across multiple cancer types.
The gut microbiome is increasingly recognized as a key regulator of host metabolic homeostasis, immune responses, and the efficacy of pharmaceutical interventions [4]. The gut microbiome is regarded as a highly metabolically active ecosystem that extensively interacts with the host endocrine and immune systems. This ecosystem is often considered as a functional distal organ capable of exerting systemic regulatory effects on tumor initiation, progression, and therapeutic response [5]. Gut microbiota dysbiosis can significantly influence the effectiveness of various anticancer therapies by modulating inflammatory processes, affecting immune cell function, and altering drug metabolism and pharmacokinetics [6].
An increasing number of studies are beginning to explore the association between the gut microbiota and PCa treatment, revealing the distal regulatory effects of gut microbial changes on prostate tumor biology [7]. Although this association is predominantly supported by mechanistic inferences and cross-tumor evidence, its potential significance in PCa progression and treatment resistance is gradually gaining recognition.
While prior reviews have largely concentrated on the molecular mechanisms linking the microbiome to PCa initiation or specific metabolic alterations, a comprehensive synthesis of its impact on multimodal treatment outcomes remains limited. In this review, we further highlight the concept of the “gut–prostate axis” and shift the focus to therapeutic response rather than tumorigenesis. We systematically integrate the latest evidence on the role of the microbiome in driving resistance across various standard therapeutic modalities, including ADT, chemotherapy, radiotherapy and immunotherapy. Our goal is to offer a novel microbial perspective that informs the development of predictive biomarkers and precision interventions by bridging the gap between specific metabolic pathways and clinical efficacy.
To provide a comprehensive overview of the translational landscape, we summarize the specific bacterial taxa, key metabolites, molecular mechanisms, and critical limitations associated with each therapeutic modality in Table 1.

2. Endocrine Therapy and the Gut Microbiome

2.1. Gut Microbiome Regulates Androgen Metabolism

The AR signaling axis has been identified as a central driver of PCa progression [29]. Traditionally, androgen sources have been considered to be largely restricted to the testes and adrenal glands [11]. However, accumulating evidence suggests that the gut microbiome plays a potential regulatory role in androgen homeostasis, acting as an extrinsic modifier.
Androgen metabolism is subject to enterohepatic circulation, allowing gut bacteria to modulate systemic androgen levels. On the one hand, specific bacterial taxa promote androgen recycling and reactivation. Conjugated androgens entering the intestinal lumen can be deconjugated by bacterial β-glucuronidases, releasing free androgens for intestinal reabsorption [30,31,32]. Genomic analyses and in vitro assays have demonstrated that specific commensal bacteria such as Clostridium scindens encode the steroid-17,20-desmolase (desAB or desF), which activates androgen precursors and enhances the proliferation of PCa cells in culture systems [8,16].
On the other hand, certain strains of gut bacteria possess the capacity for androgen catabolism via the steroid 9,10-seco pathway [12,33,34]. Metagenomic surveys indicate that this pathway is predominantly found in environmental Actinobacteria and Proteobacteria, rather than being ubiquitous in the human gut [12]. In a murine model, the denitrifying β-proteobacterium Thauera strain GDN1 has been demonstrated to disrupt enterohepatic androgen circulation and reduce serum androgen levels in mice by approximately 50% [11]. Collectively, specific components of the gut microbiome modulates androgen metabolism and enterohepatic cycling, thus emerging as an independent regulatory node of the host “androgen pool”.

2.2. ADT-Induced Microbiota Dysbiosis

ADT suppresses tumor growth by systemically reducing androgen levels [35]. However, the concomitant endocrine perturbation has been shown to act as a potent ecological stressor, which in turn disrupts intestinal homeostasis [36]. Cross-sectional clinical studies utilizing 16S rRNA sequencing have shown that patients receiving ADT exhibit significant intestinal microbiota dysbiosis, which is characterized by a substantial decrease in both α-diversity and β-diversity [37]. Concurrently, metagenomic functional predictions suggest a shift towards a pro-inflammatory profile, with marked enrichment of lipopolysaccharide (LPS) biosynthesis pathways, providing a biological basis for systemic inflammation [13].
Prolonged castration has been associated with specific compositional shifts, though findings vary across cohorts. It results in changes to the composition and function of the gut microbiota. The depletion of beneficial short-chain fatty acid (SCFA)-producing bacteria that maintain intestinal barrier integrity (e.g., Lachnospira and Roseburia) has been observed, and in contrast, pathogenic bacteria (e.g., Ruminococcus gnavus and Bacteroides spp.) have been found to be significantly enriched [13,14]. Metagenomic analyses reveal that these enriched taxa often possess genetic potential for steroid metabolism, suggesting that the castrate environment may selectively favor microbial subpopulations capable of metabolic compensation.
However, the impact of ADT appears to be time-dependent. Contrary to the dysbiosis seen in long-term treatment, the initial phase of ADT may partially reverse the depletion of beneficial bacteria (e.g., Akkermansia muciniphila and Lachnospiraceae) in some mouse models [38]. This transient restoration might be linked to reduced tumor burden. Nevertheless, interpreting these clinical associations requires caution due to potential confounders such as antibiotic usage, dietary habits, and ADT-induced metabolic comorbidities (e.g., obesity), which were not uniformly controlled across studies. This underscores the need to consider treatment duration and patient-specific variables when evaluating ADT-induced dysbiosis.

2.3. Gut Microbiome as an Alternative Androgen Source

In androgen-depleted environments induced by ADT, the gut microbiota has the potential to use non-androgenic steroids, particularly glucocorticoids, as substrates for androgen biosynthesis. In vitro mechanistic studies have identified Clostridium scindens (specifically strain ATCC 35704) as a key species expressing enzymes with steroid-17,20-desmolase/oxidase activity (encoded by the desAB gene cluster). This enzymatic machinery enables the conversion of host cortisol into the potent androgen precursor 11β-hydroxyandrostenedione (11β-OHA) in bacterial cultures [8,9]. 11β-OHA can be further metabolized into 11-ketotestosterone (11-KT) in xenograft models, which activates AR signaling with high affinity and drives PCa progression towards CRPC [10].
Building on these mechanistic insights, recent studies report that ADT-induced castration pressure enriches specific Ruminococcus species (e.g., R. gnavus) capable of androgen biosynthesis from pregnenolone [13,14]. In a cohort of CRPC patients, these strains were found to harbor steroid biosynthesis gene clusters and were significantly overrepresented compared to hormone-sensitive patients, correlating with poor clinical outcomes [15,39]. While these findings suggest a synergistic role for dysbiosis in tumor adaptation, the quantitative contribution of this microbiome-derived androgen pool relative to adrenal sources in patients remains to be fully defined.
Collectively, preclinical evidence demonstrates that specific components of the microbiota can supply alternative ligands to tumors via de novo synthesis or precursor conversion, thereby sustaining AR pathway activation in murine models [40,41,42]. This mechanism provides an explanation for how PCa cells might retain proliferative capacity under castrate conditions. However, further translational studies are required to validate whether eliminating these specific bacterial taxa can reverse castration resistance in human patients. In summary, the dysbiotic gut microbiota under ADT may establish an auxiliary alternative androgen source.

2.4. Non-Androgenic Pathways Driving Castration Resistance: Inflammation and Metabolic Reprogramming

Beyond supplying alternative androgens, dysbiotic gut microbiota promotes CRPC progression by activating non-androgenic signaling pathways. Emerging preclinical evidence highlights the pivotal role of the gut–prostate inflammatory axis and microbial metabolic reprogramming in this process.
In TRAMP mouse models, ADT-induced disruption of intestinal barrier integrity has been shown to promote the translocation of microbiota-derived LPS. It activates the TLR4/MyD88/NF-κB inflammatory cascade, resulting in the upregulation of AR expression and enhanced tumor cell survival [17]. In CRPC mouse models, dysbiosis-induced abnormalities in α-linolenic acid metabolism similarly activate TLR4 signaling. Notably, restoration of microbial balance via fecal microbiota transplantation (FMT) from responsive donors effectively blocked this pathway and delayed tumor growth in mice [43].
Microbial metabolic reprogramming plays a pivotal role in tipping the balance between pro-tumorigenic and anti-tumorigenic forces, often in a strain-specific manner. On the pro-tumorigenic side, specific taxa such as Ruminococcus species have been shown to accelerate PCa progression in mice by disrupting host glycerophospholipid metabolism and increasing lysophosphatidylcholine acyltransferase 1 (LPCAT1) expression [44]. On the anti-tumorigenic side, the depletion of protective metabolites weakens tumor suppression. For instance, Akkermansia muciniphila has been shown to secrete inosine, a molecule that enhances intestinal barrier function and reduces LPS translocation in mouse models [17]. Consistent with this mechanism, clinical observations indicate a decreased abundance of A. muciniphila in ADT-treated patients with poor outcomes [17]. Additionally, in vitro studies reveal that sodium butyrate (NaB), a metabolite produced by butyrate-producing bacteria (e.g., Faecalibacterium), inhibits the JAK2/STAT3/Nrf2/Glo1 pathway, thereby inducing tumor cell death [18]. However, the levels of NaB are often reduced during the castration-resistant stage.
In summary, the role of the gut microbiome in castration resistance is multifaceted. It acts not only as a passive recipient of ADT stress but also as an active modulator of CRPC progression. The “gut–prostate axis,” mediated through alternative androgen supply, systemic inflammation, and metabolic reprogramming, represents a significant challenge and a potential therapeutic target (Figure 1).

2.5. Pharmacomicrobiomics of Novel Hormone Therapy

The advent of novel hormone therapies (NHTs) has led to significant alterations in the composition of the gut microecosystem. Metagenomic analyses indicate that microbial gene pathways involved in steroid biosynthesis are significantly enriched in patients receiving androgen receptor-targeted therapy (ATT), acting as oncogenic factors by supplying alternative androgens [45]. On the contrary, a specific effect has been observed with abiraterone acetate (AA). Clinical cohort studies show that oral AA induces marked community shifts, characterized by the depletion of potential androgen-utilizing Corynebacterium spp. and the enrichment of Akkermansia muciniphila [46]. The enrichment of Akkermansia muciniphila is accompanied by the upregulation of bacterial vitamin K2 biosynthesis pathways. In vitro and mouse model data further indicate that vitamin K2 can suppress both androgen-dependent and androgen-independent tumor growth [46]. These findings suggest that AA may offer additional therapeutic benefits by promoting beneficial microorganisms.
The gut microbiota has also been demonstrated to influence the efficacy of AA through its impact on drug metabolism processes. A recent study identified that the microbial gene desF, encoding a steroid-17,20-desmolase, is enriched in the gut of PCa patients and is associated with non-responsiveness to AA therapy. Mechanistically, bacteria expressing desF can cleave the side chain of AA, converting it into inactive metabolites, thereby reducing its therapeutic concentration [16]. Additionally, in vitro studies using rat fecal suspensions demonstrated that certain gut bacteria can degrade AA, potentially affecting its enterohepatic recycling and biotransformation [45]. These microbial metabolic activities may represent a fundamental mechanism underlying the pharmacokinetic variability observed among patients.
In summary, the microbiota not only synthesizes alternative androgens to counteract castration effects but also directly degrades steroid drugs like AA, thereby limiting therapeutic efficacy. Consequently, the identification of microbial biomarkers, such as the desF gene, holds promise for predicting treatment response. Moreover, therapeutic modulation of the microbiota via dietary interventions, prebiotics or FMT, to deplete drug-metabolizing bacteria or enrich beneficial taxa like A. muciniphila represents a highly promising avenue to reverse drug resistance.

3. Chemotherapy and the Gut Microbiome

3.1. Inflammation-Driven Chemotherapy Resistance

For patients diagnosed with metastatic castration resistant prostate cancer (mCRPC), docetaxel based chemotherapy remains a standard first-line treatment [46,47,48]. However, the clinical benefit is often limited by intrinsic or acquired resistance, leading to disease progression [49]. Increasing evidence indicates that the gut microbiome may influence chemotherapy sensitivity by modulating drug pharmacokinetics and altering the immune microenvironment [19]. While direct causal evidence in humans is still evolving, mechanistic studies in animal models have identified gut microbiota dysbiosis as a potential biological driver of docetaxel resistance.
In a mice model of PCa, broad-spectrum antibiotic-induced dysbiosis leads to the expansion of opportunistic pathogens, particularly Proteobacteria [20]. This ecological shift disrupts intestinal barrier integrity, promoting the translocation of LPS into the tumor microenvironment and triggering the NF-κB-IL-6-STAT3 inflammatory cascade [20]. Aberrant activation of this axis has been shown to confer survival advantages to tumor cells and to induce resistance to docetaxel in vivo. Pharmacological inhibition of STAT3 phosphorylation (Stattic) effectively reversed the resistant phenotype and restored chemosensitivity in tumor-bearing mice [20]. These findings indicates that microbiota-induced inflammation can contribute to chemotherapy resistance in a preclinical setting.
Translating these mechanistic insights to the clinic, Zhong et al. analyzed fecal samples from PCa patients and observed a positive correlation between the abundance of Proteobacteria and distant metastasis, as well as elevated plasma IL-6 levels [41]. However, it is important to note that these clinical findings are currently associative. Whether this specific dysbiosis directly causes chemotherapy resistance in human patients, or is a consequence of the disease and its treatment, requires confirmation through longitudinal interventional trials.

3.2. Reversing Resistance Through Microbiome Modulation

Although microbiota-based interventions for PCa chemotherapy are still in their infancy, evidence from other urologic oncology models provides a theoretical proof of concept. It is demonstrated in urothelial carcinoma models that probiotic combination therapy (including Lactobacillus and Bifidobacterium) significantly enhanced gemcitabine/cisplatin-induced anti-tumor immune responses, yielding synergistic effects superior to chemotherapy alone [21]. While this suggests that a healthy gut microbiome can serve as an immunological foundation for chemotherapy efficacy, generalizing these findings to PCa requires caution. Unlike urothelial carcinoma, PCa is typically characterized as an immunologically “cold” tumor with a distinct microenvironment. Therefore, the applicability of specific probiotic strains effective in bladder cancer must be rigorously tested in PCa-specific models before clinical translation.
Furthermore, the complexity of microbiome modulation in the context of chemotherapy is highlighted by conflicting outcomes involving antibiotics. While antibiotics are often used to prevent infection during chemotherapy, their indiscriminate use may be detrimental. Broad-spectrum antibiotic exposure in PCa models induced dysbiosis that actively promoted docetaxel resistance rather than improving outcomes [20]. This serves as a cautionary note that simply depleting the microbiota is not a viable strategy for overcoming resistance and may instead exacerbate it.

4. Radiotherapy and the Gut Microbiome

4.1. Radiotherapy-Induced Dysbiosis

The bidirectional interactions between the gut microbiome and the host influence both radiotherapy-associated toxicity and therapeutic efficacy in PCa. Pelvic radiotherapy has been shown to act as a potent ecological stressor, which has been demonstrated to disrupt gut microbial homeostasis and trigger gastrointestinal (GI) toxicities. Clinical evidence shows that radiotherapy significantly reduces microbial α-diversity [50,51] and promotes the overgrowth of opportunistic pathogens [23,52]. This community shift is characterized by an increase in the abundance of the dysbiosis marker phylum Proteobacteria and depletion of beneficial barrier-maintaining commensals such as Lactobacillus and Bifidobacterium [24]. Increased abundance of Clostridium cluster IV, Roseburia, and Phascolarctobacterium correlates positively with the severity of radiation enteropathy [53]. Specific microorganisms may intervene in radiation enteropathy by modulating mucosal immune homeostasis and tissue radiosensitivity [54]. However, the impact of radiation on the microbiome may vary depending on the specific radiotherapy modalities and target volumes employed. For instance, while one study found no substantial differences in overall microbiota stability when comparing prostate (bed)-only radiotherapy (PBRT) with whole pelvis radiotherapy (WPRT) [55], the volume of irradiated tissue and the specific fractionation schemes inevitably introduce variables with distinct effects on the gut ecosystem [56]. Furthermore, the interpretation of radiation-induced dysbiosis must consider potential conflicts with standard clinical workflows. For example, prophylactic broad-spectrum antibiotics (e.g., azithromycin and ciprofloxacin) and rectal enemas, which are routinely administered prior to gold fiducial marker implantation for image-guided radiotherapy, significantly deplete the gut microbiome even before radiation commences, deeply confounding the baseline microbiota landscape [56].

4.2. Microbiome-Based Biomarkers for Predicting Radiotherapy Toxicity

Before treatment, the baseline gut microbiome profiles of patients can be used to predict individual responses to radiotherapy. The employment of machine learning algorithms in the analysis of the relative abundance of core genera such as Faecalibacterium and Bacteroides in pretreatment fecal samples facilitates effective risk stratification for acute gastrointestinal toxicity in patients with PCa [23]. To ensure clinical reliability and mitigate the risk of overfitting, predictive models have incorporated strict performance constraints and transparency metrics. For example, the interpretable MICLIDE (Microbiota-based Clinical Decision) tree model was deliberately pruned to the minimum number of nodes required to achieve an 80% prediction accuracy on the high-risk class. Crucially, its robustness was validated on a geographically distinct external cohort (the MARS study), demonstrating its predictive generalizability across different sequencing platforms and populations [23]. Furthermore, quantitative indices such as the Microbial Community Polarization Index (MCPI) further underscore the potential of microbiome-based tools to assist clinical decision-making and objectively identify high-risk populations [52].

4.3. Immunomodulation of Radiotherapy Efficacy

In addition to the modulation of toxicity, emerging evidence suggests that the gut microbiome plays a crucial role in regulating tumor radiosensitivity, primarily via the “gut–immune–tumor” axis. Mechanistically, radioresistant mice exhibit an enrichment of Lachnospiraceae and Enterococcaceae. These bacteria produce propionate and tryptophan-derived metabolites (indole-3-acetic acid and kynurenic acid), which have been found to attenuate radiation-induced damage to the hematopoietic system and gut while preserving or even enhancing immune surveillance [22]. Liu et al. demonstrated that the microbiota and its metabolites enhance antigen presentation by dendritic cells and promote the infiltration of cytotoxic CD8+ T cells, thereby synergizing with radiotherapy to combat tumors [54]. Crucially, when employing microbiome modulation, the balance between normal tissue radioprotection and tumor control must be rigorously scrutinized. Preclinical investigations have explicitly addressed this concern, demonstrating that the administration of radioprotective taxa, such as Lachnospiraceae, significantly attenuates gastrointestinal injury but does not negatively affect the tumoricidal efficacy of localized radiotherapy in tumor-bearing models [22]. These findings provide substantial theoretical support for the exploitation of microbial metabolites to achieve radioprotection without compromising anti-tumor immunity.

4.4. Microbiome Interactions in Specialized Radiotherapy Modalities

The intestinal excretion of the radionuclide frequently results in severe gastrointestinal adverse effects in mCRPC patients with bone metastases treated with the α-emitter radium-223 dichloride (223RaCl2). Fernandes et al. were the first to characterize microbiota dynamics during Ra-223 therapy, demonstrating increased abundance of pathogenic bacteria, including Proteobacteria, alongside depletion of beneficial microbes [24]. To address this clinical challenge, Xue proposed an innovative intervention using sodium alginate to adsorb radioactive nuclides within the gut [57]. This approach effectively alleviates intestinal oxidative stress, thereby maintaining microbial homeostasis. Importantly, it does not interfere with the absorption or therapeutic efficacy of Ra-223.
The diet, acting as the most direct modulator of the microbiota, also exerts a significant influence on radiotherapy outcomes. Dietary fibers (e.g., inulin and β-glucans) are fermented by gut microbes into SCFAs, which enhance the efficacy of radiotherapy and immunotherapy via epigenetic regulation (HDAC inhibition) or immune activation (STING pathway) [58]. Multicenter randomized controlled trials, such as the MicroStyle study, are prospectively evaluating the long-term impact of lifestyle interventions (diet combined with exercise) on microbiota remodeling and quality of life in patients with PCa undergoing radiotherapy [59].
In summary, the gut microbiome exacerbates radiation-induced injury and influences therapeutic efficacy in PCa radiotherapy. Future translational studies should concentrate on interventions based on specific probiotics (Alistipes onderdonkii) or microbial metabolites [60], with the aim of maximizing tumoricidal effects while minimizing treatment-related damage. To successfully integrate these strategies into practice, future trial designs must rely on strict evidence hierarchies, systematically evaluating whether microbiome-modulating interventions inadvertently alter tumor radiosensitivity or conflict with established clinical oncological workflows.

5. Immunotherapy and the Gut Microbiome

5.1. The Challenge of the “Cold Tumor”

Although ADT, chemotherapy, and radiotherapy currently comprise the therapeutic foundation, the ultimate clinical objective remains the attainment of durable tumor control through the activation of endogenous anti-tumor immunity. However, PCa exhibits a prototypical “immune-cold” phenotype, characterized by sparse T-cell infiltration, low tumor mutational burden, low PD-L1 expression, and enrichment of immunosuppressive myeloid-derived suppressor cells (MDSCs) [25]. Collectively, these characteristics underpin the constrained effectiveness of immune checkpoint blockade (ICB) in a substantial proportion of PCa patients. While the diversity and composition of gut microbiome have been identified as critical determinants of response to PD-1 therapy in highly immunogenic tumors, such as melanoma and small-cell lung cancer [61,62], their role in low-immunogenic PCa appears to be more complex.
A recent study has revealed that clinical data from mCRPC cohorts treated with pembrolizumab does not demonstrate significant disparities in microbial α-diversity between responders and non-responders. However, the study did identify distinct taxonomic differences, including a significant enrichment of Streptococcus salivarius in responders [58]. Akkermansia muciniphila, a prominent star ICB-sensitizing bacterium in pan-cancer studies, exhibits a paradoxical association with resistance in mCRPC [63,64]. This apparent contradiction underscores the context-dependent nature of microbiota-mediated immunomodulation. Specifically, immune signals induced by the same microbe may promote anti-tumor immunity in “hot” tumors yet fail in the MDSC-dominated “cold” microenvironment of PCa due to ineffective activation of effector T cells. Consequently, the oversimplified classification of microbes as either universally “beneficial” or “harmful” is inadequate, underscoring the urgent need to identify microbiome biomarkers tailored to the PCa-specific immune milieu.

5.2. Microbiome-Enhanced Therapeutic Response

Despite this heterogeneity, pan-cancer studies offer translational insights for overcoming immunotherapy resistance in PCa. The abundance of certain bacteria, including Bifidobacterium and Ruminococcaceae, has been demonstrated to correlate positively with favorable ICB responses in melanoma, with causality validated through FMT experiments [61,65]. Notably, frontline ATT has been observed to induce enrichment of Ruminococcaceae in PCa patients [66]. This suggests that ATT may potentially reverse immunosuppression by modulating the composition of gut microbiota, thereby providing a microbiota-based rationale for the combination of ATT and ICB. Mendelian randomization studies further support the immunomodulatory potential of these bacteria, indicating that Bifidobacterium may suppress PCa progression by downregulating regulatory T-cell (Treg) function [26]. However, these Mendelian randomization (MR) findings must be critically appraised and interpreted with caution. The causal inferences drawn from MR rely on instrumental variables (SNPs) that may carry unverified horizontal pleiotropic effects. Furthermore, current MR analyses predominantly utilize gut microbiome data from mixed populations while relying on prostate cancer and immune trait data derived exclusively from European cohorts, potentially introducing genetic and racial biases [65]. As MR relies on unverifiable assumptions and cannot account for dynamic microbiome-host interactions, rigorous in vivo experimental validation and large-scale prospective clinical trials are imperative to substantiate these statistical correlations before clinical translation [65,67]. Given that Tregs and MDSCs constitute central barriers to immune tolerance in PCa, targeting the gut microbiota to release these immunological “brakes” represents a promising strategy to fundamentally enhance immunotherapy responsiveness.

5.3. Microbial Metabolites in Tumor Immune Regulation

Mechanistically, the gut microbiome orchestrates a sophisticated network of remote tumor immune regulation through bioactive metabolites. Among these, SCFAs (particularly butyrate) exhibit pronounced anti-cancer potential. As a histone deacetylase inhibitor (HDACi), butyrate has been shown to enhance tumor immunogenicity through epigenetic remodeling and to induce apoptosis in tumor cells [68]. It has also been demonstrated to markedly downregulate AR expression in PCa cells and, via the microbiota-SCFAs-IGFBP2 axis, further restrains tumor progression [68,69]. Furthermore, the microbial polyphenol metabolite urolithin A has been demonstrated to activate natural killer (NK) cell cytotoxicity [27], thereby underscoring the capacity of microbial metabolites to stimulate innate immunity and compensate for deficient adaptive immune responses in PCa.
Crucially, the clinical translation of these microbial metabolites and modulators requires meticulous evaluation of dose–response relationships and safety profiles. For instance, butyrate exhibits a well-documented “butyrate paradox” in oncology: while high concentrations suppress tumor cell proliferation, low concentrations can paradoxically promote cancer cell growth by serving as an energy source for tumor cells [28]. Therefore, establishing the optimal therapeutic window is a prerequisite for SCFA-based interventions. Additionally, while manipulating the microbiome offers therapeutic promise, safety considerations remain paramount. Interventions such as FMT carry inherent risks of transmitting opportunistic pathogens, a vulnerability exacerbated in immunocompromised cancer patients, thus necessitating rigorous donor screening and standardized protocols. Even non-invasive dietary fiber supplementations aimed at naturally boosting SCFA production must be carefully dose-titrated, as excessive intake frequently elicits severe gastrointestinal toxicities, including bloating and cramping, which limits patient compliance during cancer treatments [58].
The gut microbiome may offer a variety of molecular targets for overcoming the immunosuppressive tumor microenvironment in PCa through epigenetic reprogramming and immune activation. The potential of postbiotics with well-defined pharmacological profiles and standardized dosing to enhance sensitivity to immune checkpoint inhibitors can be further explored in the future.

6. Conclusions

The gut microbiome is emerging as a potential dynamic regulatory factor in the progression of PCa and the development of treatment resistance. Preclinical and early clinical evidence suggest it functions as an alternative source of androgens, amplifying inflammatory responses, reshaping host and tumor metabolic states, and modulating antitumor immune activity. Collectively, these processes form a complex regulatory network of resistance, positioning the “gut–prostate axis” as an important biological determinant of therapeutic efficacy across endocrine therapy, chemotherapy, radiotherapy, and immunotherapy. A number of longstanding clinical challenges that are difficult to explain by a single mechanism may be better understood within this multidimensional regulatory framework. The integration of microbial, metabolic, and immune processes underlies the conceptual framework of the “gut–prostate axis”, offering a systems-level perspective for elucidating resistance mechanisms in PCa.
From a translational medicine perspective, the gut microbiome presents a compelling theoretical framework for novel interventions, though its direct clinical applicability remains in its nascent stages. While current preclinical models and retrospective cohorts suggest that the utilization of microbiome-based biomarkers has the potential to enhance patient stratification and facilitate the prediction of treatment response, these concepts have yet to be rigorously validated in routine practice. Furthermore, although modulation of the gut microbial ecosystem through dietary interventions, probiotic or postbiotic supplementation, and FMT may represent valuable adjunctive strategies to existing therapies, they must first overcome substantial translational hurdles. Distinguishing causal drivers of resistance from mere passenger effects amidst inter-individual variability, environmental influences and the structural complexity of microbial communities remains a significant challenge, underscoring the necessity for well-designed prospective clinical studies.
Overall, sustained mechanistic exploration and clinical translation of the “gut–prostate axis” may yield novel approaches for overcoming therapeutic resistance. However, to bridge the gap between current knowledge and clinical practice, future research must prioritize several critical knowledge gaps. First, there is an urgent need to transition from cross-sectional associative observations to establishing robust causality through large-scale, multi-center, and longitudinal prospective clinical trials. Second, future investigations should advance beyond broad taxonomic profiling (e.g., 16S rRNA sequencing) toward strain-level resolution and multi-omics integration such as incorporating metagenomics, metabolomics and metaproteomics to pinpoint the exact molecular mediators of drug resistance. Finally, standardizing microbiome sampling protocols and rigorously controlling for confounding variables (e.g., diet, antibiotic exposure, and host metabolic comorbidities) are essential for ensuring reproducibility. As microbiome research addresses these methodological challenges and becomes increasingly integrated into urologic oncology, treatment strategies and disease management paradigms for PCa may evolve, ultimately benefiting patients with advanced disease.

Author Contributions

Conceptualization: Z.A., P.D.; Formal analysis and investigation: Z.A., P.D., K.H., R.N.; Writing—original draft preparation: Z.A.; Writing—review and editing: L.C., S.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China, grant number 82404024.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no competing interests.

Abbreviations

The following abbreviations are used in this manuscript:
PCaProstate cancer
ADTAndrogen deprivation therapy
ARAndrogen receptor
CRPCCastration-resistant prostate cancer
LPSLipopolysaccharide
SCFAShort-chain fatty acid
11β-OHA11β-hydroxyandrostenedione
11-KT11-ketotestosterone
TLR4Toll-like receptor 4
MyD88Myeloid differentiation primary response 88
NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells
FMTFecal microbiota transplantation
LPCAT1Lysophosphatidylcholine acyltransferase 1
NaBSodium butyrate
JAK2Janus kinase 2
STAT3Signal transducer and activator of transcription 3
Nrf2Nuclear factor erythroid 2-related factor 2
Glo1Glyoxalase 1
HSPCHormone-sensitive prostate cancer
NHTsNovel hormone therapies
ATTAndrogen receptor-targeted therapy
AAAbiraterone acetate
mCRPCMetastatic castration-resistant prostate cancer
IL-6Interleukin-6
GIGastrointestinal
PBRTProstate bed-only radiotherapy
WPRTWhole pelvis radiotherapy
MCPIMicrobial Community Polarization Index
CD8+ T cellCD8-positive T lymphocyte
223RaCl2Radium-223 dichloride
HDACHistone deacetylase
STINGStimulator of interferon genes
PD-L1Programmed death-ligand 1
MDSCsMyeloid-derived suppressor cells
ICBImmune checkpoint blockade
PD-1Programmed cell death protein 1
TregRegulatory T cell
MRMendelian randomization
SNPsSingle nucleotide polymorphisms
HDACiHistone deacetylase inhibitor
IGFBP2Insulin-like growth factor binding protein 2
NKNatural killer cell

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Microbiolres 17 00055 g001
Figure 1. ADT reshapes the gut microbiome and promotes CRPC. At physiological androgen levels before ADT (blue background), a balanced and diverse gut microbiota maintains intestinal barrier integrity, limits systemic inflammation, and supports controlled growth of hormone-sensitive prostate cancer (HSPC, shown as blue cell clusters). In contrast, continuous ADT (red background) induces gut dysbiosis characterized by reduced microbial diversity and pro-inflammatory shifts. Microbiota-related functional alterations, including alternative androgen production, enhanced inflammation and metabolic adaptations, promote tumor adaptation and contribute to the transition from HSPC to castration-resistant prostate cancer (CRPC, shown as red cell clusters). Created in BioRender. A, Z. (2026) https://BioRender.com/r2nz6tw (accessed on 28 February 2026).
Figure 1. ADT reshapes the gut microbiome and promotes CRPC. At physiological androgen levels before ADT (blue background), a balanced and diverse gut microbiota maintains intestinal barrier integrity, limits systemic inflammation, and supports controlled growth of hormone-sensitive prostate cancer (HSPC, shown as blue cell clusters). In contrast, continuous ADT (red background) induces gut dysbiosis characterized by reduced microbial diversity and pro-inflammatory shifts. Microbiota-related functional alterations, including alternative androgen production, enhanced inflammation and metabolic adaptations, promote tumor adaptation and contribute to the transition from HSPC to castration-resistant prostate cancer (CRPC, shown as red cell clusters). Created in BioRender. A, Z. (2026) https://BioRender.com/r2nz6tw (accessed on 28 February 2026).
Microbiolres 17 00055 g001
Table 1. Gut microbiome-mediated mechanisms in prostate cancer therapy.
Table 1. Gut microbiome-mediated mechanisms in prostate cancer therapy.
Therapeutic Modality Specific Taxa Key
Metabolites 		Mechanism Model Limitation Refs.
Endocrine TherapyClostridium scindens (Gene: desAB)11β-OHA, 11-KTCleaves cortisol side-chains to synthesize potent androgen precursors (11β-OHA), reactivating AR signaling.In vitro/XenograftMechanisms largely derived from in vitro assays; quantitative contribution in patients is undefined.[8,9,10]
Thauera strain GDN1N/A 1Disrupts enterohepatic androgen circulation via the steroid 9,10-seco catabolic pathway.Murine modelThis taxon is predominantly environmental and not ubiquitous in the human gut.[11,12]
Ruminococcus gnavusPregnenolone (substrate)Possesses steroid biosynthesis genes to convert pregnenolone into androgens under castration stress.Clinical cohortCross-sectional associations; difficult to distinguish cause from consequence of ADT.[13,14,15]
Bacteria expressing desFSteroid-17,20-desmolaseMetabolizes abiraterone acetate (AA) into inactive forms, reducing systemic therapeutic concentrations.Clinical/MechanisticHighlights pharmacokinetic variability; requires validation in larger longitudinal cohorts.[16]
Akkermansia muciniphilaInosineSecretes inosine to reinforce intestinal barrier; depletion leads to LPS leakage and TLR4/NF-κB activation.Mouse/ClinicalInfluenced by diet and metabolic comorbidities (e.g., obesity) common in ADT patients.[17]
Butyrate producing bacteria (e.g., Faecalibacterium)Sodium Butyrate (NaB)Inhibits the JAK2/STAT3/Nrf2/Glo1 signaling axis to induce tumor cell death.In vitroLevels of NaB are often naturally reduced during the castration-resistant stage.[18]
ChemotherapyProteobacteria (pathogenic expansion)Lipopolysaccharide (LPS)Translocates to tumor microenvironment, triggering NF-κB-IL-6-STAT3 cascade to confer docetaxel resistance.Murine model/ClinicalAntibiotic-induced dysbiosis models may not fully mimic patient gut ecology.[19,20]
Lactobacillus, BifidobacteriumN/A 1Enhances anti-tumor immune responses, showing synergy with cisplatin/gemcitabine.Urothelial modelsFindings from urothelial carcinoma may not directly translate to the “cold” PCa microenvironment.[21]
RadiotherapyLachnospiraceae, EnterococcaceaePropionate, Indole-3-acetic acidAttenuates radiation-induced GI damage and enhances immune surveillance via tryptophan metabolites.Murine modelsRequires careful balancing to ensure radioprotection does not extend to tumor cells.[22]
Faecalibacterium, BacteroidesN/A 1Baseline abundance serves as a biomarker for predicting acute radiation-induced gastrointestinal toxicity.Machine LearningPredictive models risk overfitting; requires external cohort validation (e.g., MARS study).[23]
ProteobacteriaN/A 1Opportunistic overgrowth following Radium-223 therapy, linked to intestinal oxidative stress.Clinical cohortConfounded by prophylactic antibiotics/enemas used in standard radiotherapy workflows.[24]
ImmunotherapyStreptococcus salivariusN/A 1Significantly enriched in mCRPC patients responding to pembrolizumab.Clinical cohortDistinct from “ICB-beneficial” taxa (e.g., A. muciniphila) seen in other solid tumors; context-dependent.[25]
BifidobacteriumN/A 1May suppress PCa progression by downregulating regulatory T-cell (Treg) function.Mendelian RandomizationMR analysis relies on instrumental variables (SNPs) which may have horizontal pleiotropy.[26]
Gut microbiota (general)Urolithin AMicrobial metabolite that activates Natural Killer (NK) cell cytotoxicity to boost innate immunity.Preclinical Clinical translation requires standardized dosing and safety profiling.[27]
Butyrate-producing bacteriaButyrate (SCFA)Acts as an HDAC inhibitor to downregulate AR expression and enhance immunogenicity.In vitro“Butyrate Paradox”: low concentrations may promote cancer growth; requires optimal therapeutic window.[28]
1 N/A means Not Applicable.
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Ai, Z.; Dai, P.; He, K.; Nie, R.; Zou, S.; Chen, L. Navigating the Gut–Prostate Axis: The Gut Microbiome in Prostate Cancer Resistance and Targeted Interventions. Microbiol. Res. 2026, 17, 55. https://doi.org/10.3390/microbiolres17030055

AMA Style

Ai Z, Dai P, He K, Nie R, Zou S, Chen L. Navigating the Gut–Prostate Axis: The Gut Microbiome in Prostate Cancer Resistance and Targeted Interventions. Microbiology Research. 2026; 17(3):55. https://doi.org/10.3390/microbiolres17030055

Chicago/Turabian Style

Ai, Zeyu, Ping Dai, Kangnan He, Ruilong Nie, Shimin Zou, and Liang Chen. 2026. "Navigating the Gut–Prostate Axis: The Gut Microbiome in Prostate Cancer Resistance and Targeted Interventions" Microbiology Research 17, no. 3: 55. https://doi.org/10.3390/microbiolres17030055

APA Style

Ai, Z., Dai, P., He, K., Nie, R., Zou, S., & Chen, L. (2026). Navigating the Gut–Prostate Axis: The Gut Microbiome in Prostate Cancer Resistance and Targeted Interventions. Microbiology Research, 17(3), 55. https://doi.org/10.3390/microbiolres17030055

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