Open Access

The human microbiome links to prostate cancer risk and treatment (Review)

  • Authors:
    • Bowen Xia
    • Jingwei Wang
    • Dongxu Zhang
    • Xiaopeng Hu
  • View Affiliations

  • Published online on: May 4, 2023
  • Article Number: 123
  • Copyright: © Xia et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Prostate cancer (Pca) is the second most common cancer type worldwide. Microorganisms colonized in different body parts may affect the development/progression and treatment of Pca through direct or indirect interactions. The composition of microorganisms in different colonization sites and their effects on Pca may differ. In recent years, several studies have focused on the differences in the microbiota of patients with Pca, and dysbiosis may affect the inflammatory status, hormone levels and microbial metabolites leading to Pca progression. However, little is known about the interaction between Pca treatment and microorganisms; for example, how androgen deprivation therapy and androgen receptor axis‑targeting therapeutics for Pca affect microbiota composition and metabolism, and how the microbiota affects treatment response in patients with Pca remain to be understood. The present review explored the current studies on the relevance of microbiota to Pca progression and treatment to provide direction for future microbiome‑Pca research. Due to the complexity of the potential interconnections between Pca and the microbiota, further investigation is critical.


The human body contains microbiota, which plays a vital role in health and disease; the number of microorganisms is estimated to be ~1013, and constitutes 1–3% of the body mass (1). Microbiota is in a symbiotic equilibrium with the host. Environmental factors including age, diet, disease and drug metabolism can lead to microbial imbalance, which can induce inflammatory responses or lead to drug resistance (2,3). Disruption of this equilibrium also has an impact on cancer; the microbiota can influence every stage of cancer as well as the therapeutic process through direct and indirect actions, the main mechanisms of which may be associated with the metabolites produced by microorganisms and the inflammatory state they cause (4,5). There are also beneficial effects of microbiota on cancer treatment, as confirmed by recent clinical trials on fecal microbiota transplantation (FMT) in combination with immunotherapy for cancer treatment, potentially opening up new targets for cancer treatment (6).

Prostate cancer (Pca) is the second most common cancer type globally, with nearly 1.4 million new cases and ~0.4 million Pca-associated mortalities worldwide in 2020 (7). Radical surgery and radiotherapy continue to be the options for treating localized diseases. Androgen deprivation therapy (ADT), hormone therapy and chemotherapy are also effective in male patients with Pca (8). However, certain patients progress to castration-resistant prostate cancer (CRPC) within 2–3 years after starting ADT treatment, resulting in a poor prognosis (9). However, there is still a lack of effective tests to distinguish between indolent and resistant Pca at an early stage. Thus, there is an urgent need for improved risk stratification tools to avoid overtreatment and under-treatment of aggressive Pca (10).

Next-generation sequencing (NGS) and metagenomics are expected further to establish the link between microbiota and Pca, opening up new areas of Pca research (11). Microbiota may not only be a stratification factor to predict risk, but may also provide new options for treating Pca by clarifying the interaction between cancer and microbiota (12). Therefore, understanding the link between the microbiome and Pca is critical.

It has been proposed that the microbiota may have a direct or indirect effect on Pca tumorigenesis and progression. However, further research is needed to provide definitive evidence in this area (13). In the present review, focus was addressed on the effect of prostate cancer treatment on the microbiome and the scope of the microbiome was expanded to include the entire body, not just the intestinal microbiome. The present review provides a detailed overview of the current research on the role of human microorganisms in the risk, progression and treatment of Pca from the aspects of direct and indirect mechanisms.

Microbiota and Pca

Since 2015, studies on Pca and microbiota have mainly focused on the association between prostate microbiota and Pca. As gut microbiota research has further developed, studies focusing on the indirect effects of microbiota and Pca have increased in the last 5 years, which have explored the effects of gastrointestinal microbiota and urinary microbiota on Pca, and evaluated the association of prostatic fluid or semen with Pca.

As shown in Table I, Table II, Table III, the present study systematically searched for studies related to the microbiome and Pca based on PubMed and Web of Science databases. The search included articles published up to March 11, 2023 in English language. Search keywords included ‘prostate cancer OR prostatic carcinoma OR prostatic tumor’ AND ‘microbiome OR microbiota’. After excluding review articles (n=21), original studies related to Pca and prostate tissue, urine, semen, prostatic fluid and gut microbiota analysis were selected (n=36).

Table I.

Selected studies up to 2023 investigating on the prostate microbiome and Pca.

Table I.

Selected studies up to 2023 investigating on the prostate microbiome and Pca.

ReferenceTissueSamplesMain findings
Cohen et al, 2005 (14)Fresh tissue34 patients with Pca Propionibacterium acnes was the predominant microbiome in Pca tissue and positive association with prostatic inflammation
Sfanos et al, 2008 (15)Fresh Prostatectomy tissues30 patients with PcaPca tissue presence of 83 distinct microorganisms, there was no significant association between the presence of particular species of bacteria and histologic evidence of acute or chronic inflammation
Alexeyev et al, 2006 (16)Formalin-fixed and embedded in paraffin352 patients with BPH of which 171 progressed to Pca Propionibacterium acnes was the most common bacterium in BPH and associated with Pca development
Yow et al, 2017 (17)Fresh-frozen tissue10 patients with Pca Enterobacteriaceae and Propionibacterium acnes was the most common species
Cavarretta et al, 2017 (18)Formalin-fixed and embedded in paraffinTumor, Peri-tumor, and non-tumor tissues in 16 patients with Pca Propionibacterium spp. was the most abundant in all regions of the tumor, Staphylococcus spp. were more represented in the tumor/peri-tumor tissue
Feng et al, 2019 (22)Fresh-frozen tissue6 African and 16 Australian with Pca Proteobacteria was the predominance bacterial genera. Compared with Australian and Chinese, African samples had significantly increased bacterial abundance
Feng et al, 2019 (23)Fresh-frozen tissue65 patients with PcaEscherichia, Propionibacterium, Acinetobacter and Pseudomonas were most abundant in the prostate and constituting the core of the prostate microbiome
Banerjee et al, 2019 (24)Formalin-fixed and embedded in paraffin50 patients with PcaSome viral genomic sequences were inserted into the host Pca sample
Miyake et al, 2019 (25)Formalin-fixed and embedded in paraffin45 patients with Pca and 33 BPHMycoplasma genitalium infection was significantly different and associated with Pca and with high Gleason scores
Ma et al, 2020 (26)Fresh-frozen tissue242 Pca sequencing data from The Cancer Genome AtlasListeria monocytogenes, Methylobacterium radiotolerans JCM 2831, Xanthomonas albilineans GPE PC73, and Bradyrhizobium japonicum were overrepresented in tumor samples
Salachan et al, 2022 (27)Fresh-frozen tissue23 benign and 83 malignant Under-representation of Staphylococcus saprophyticus and Vibrio parahaemolyticus, over-abundance of Shewanella in Pca tissue

[i] Pca, prostate cancer; BPH, benign prostate hyperplasia.

Table II.

Selected studies up to 2023 investigating on the urinary microbiome and Pca.

Table II.

Selected studies up to 2023 investigating on the urinary microbiome and Pca.

ReferenceTissueSamplesMain findings
Shrestha et al, 2018 (36)Fresh urine samples handled using sterile technique63 benign and 66 with PcaNo significant difference in alpha/beta-diversity of urine microbiome between benign/tumor patients
Ma et al, 2019 (37)Fresh-frozen prostatic fluid32 Pca and 27 non-PcaThe diversity of microbiota in prostatic fluid of Pca patients is reduced, the abundance of Alkaliphilus, Enterobacter, Lactococcus, Cronobacter, Carnobacterium, and Streptococcus were significantly different
Yu et al, 2015 (38)Urinary, EPS and seminal fluid samples without contamination13 patients with Pca and 21 BPHEscherichia coli was decrease in urine sample and Escherichia coli was increase in EPS and seminal fluid, Enterococci increased in semen in the Pca group
Alanee et al, 2019 (39)First voided urine samples16 benign and 14 with PcaIncreased abundance of clostridium XVIII & IV, lachnospira, acetanaerobacterium, and faecalibacterium in Pca patients
Tsai et al, 2022 (40)Fresh-frozen urine samples62 BPH and 62 Pca and benignCompared with the control group, Faecalibacterium, Staphylococcus, Ruminococcaceae_UCG_002, Neisseria, and Agathobacter had significant abundance differences in the Pca group

[i] Pca, prostate cancer; BPH, benign prostate hyperplasia; EPS, expressed prostatic secretions.

Table III.

Selected studies up to 2023 investigating on the gut microbiome and Pca.

Table III.

Selected studies up to 2023 investigating on the gut microbiome and Pca.

ReferenceTissueSamplesMain findings
Zhong et al, 2022 (47)Frozen fecal samples15 patients with Pca and 20 BPHAntibiotic exposure leads to elevated relative abundance of Proteobacteria and increased LPS affects Pca progression through the NF-κB-IL6-STAT3 axis in mice
Amirian et al, 2013 (48)N/AN/AThere may be significant differences in the composition of the gut microbiome among individuals at higher risk of Pca
Liss et al, 2018 (49)Frozen rectal swab samples64 with Pca and 41 without cancerThe abundant of Bacteroides and Streptococcus was significantly increased in Pca, with no significant differences in microbiome diversity
Golombos et al, 2018 (50)Frozen fecal samples8 benign and 12 with PcaHigher relative abundance of Bacteriodes massiliensis was in Pca patients
Matsushita et al, 2021 (51)Frozen fecal samples96 with Pca and 56 without cancerHigh-risk Pca patients had an increased relative abundance of SCFAs-producing bacteria, including Rikenellaceae, Alistipes and Lachnospira
Liu et al, 2019 (54)Frozen fecal samplesN/A11 phylotypes were decreased in abundance in HFD-fed Pca-mcie, including equol-producing bacterium Adlercreutzia
Liu et al, 2019 (55)Frozen fecal samplesN/AHigher abundance of Lachonospiraceae, Roseburia and Amycolatopsis, increased serum L-methionine decreased α-linolenic acid in combined maternal and post-weaning HFD-fed Pca mice
Matsushita et al, 2021 (57)Frozen fecal samplesN/AGut microbiome affects IGF-1 levels in serum and prostate tissue via SCFAs, which promote Pca cell proliferation
Matsushita et al, 2022 (57)Frozen fecal samplesN/ADysbiosis of gut microbiota leads to elevated LPS and promotes Pca progression through histamine H1 receptor signaling in HFD-fed mice
Sato et al, 2022 (59)Fresh-frozen tissue203 Pca, 150 Pca and 50 Pca sequencing data from GEOLD-fed Pca mice abundance of Clostridiales and Lactobacillales. The proportion of the order Lactobacillales was negatively related with PCa progression.
Liu et al, 2020 (66)Frozen fecal samples21 matched patients with HSPC and CRPCThe abundance of Phascolarctobacterium and Ruminococcus increased in CRPC, and there was no significant difference in microbiota diversity
Li et al, 2021 (67)Frozen fecal samples56 patients on ADT and 30 patients underwent RRPThere are significant differences in the diversity of the microbiota, Ruminococcus Gnavus and Bacteroides spp. were enriched in the ADT group
Kure et al, 2022 (68)Frozen fecal samples23 Pca patients under going ADTThe abundance of Proteobacteria changed significantly after ADT and was positively correlated with lactate concentration
Pernigoni et al, 2021 (69)Frozen fecal samples19 patients with HSPC and 55 patients with CRPCThe gut microbiota of CRPC patients or castrated mice, including Ruminococcus gnavus, can convert androgen precursors into active androgens
Liu et al, 2021 (70)Frozen fecal samples5 patients with PcaFMT from CRPC patients to prostate mice increased the abundant of Ruminococcus, resulting in Pca growth
Huang et al, 2021 (71)Frozen fecal samplesN/A Akkermansiaceae was elevated in the first three weeks of the cancer-bearing Pca mice
Sfanos et al, 2018 (75)Frozen fecal samples6 control, 3 benign and 21 Pca patientsThe relative abundance was high in Pca patients taking ATT, Akkermansia muciniphila and Ruminococcaceae spp.
Daisley et al, 2020 (76)Frozen fecal samples33 Pca patients without treatment, 21 with ADT alone and 14 with ADT + AACompared with patients without treatment, Corynebacterium spp. abundance was reduced in patients with ADT or ADT+AA, and Akkermansia muciniphila abundance was increased in patients receiving oral AA
Terrisse et al, 2022 (79)Frozen fecal samples10 patients with HSPC and 32 patients with CRPCPC reduced the relative abundance of Akkermansia muciniphila, ADT reversed the effects of Pca on thymic cortical areas and increased circulating recent thymic emigrant cells
Peiffer et al, 2022 (80)Frozen fecal and oral swish samples23 with mCRPC of which 12 patients classified as responderDecrease the abundance of Akkermansia muciniphila in the responded to ITT treatment samples

[i] Pca, prostate cancer; BPH, benign prostate hyperplasia; LPS, lipopolysaccharide; SCFAs, short-chain fatty acid; HFD, high-fat diet; LD, lard diet; IGF-1, insulin-like growth factor-1; ADT, androgen deprivation therapy; HSPC, hormone-sensitive prostate cancer; CRPC, castration-resistant prostate cancer; FMT, fecal microbiota transplantation; ATT, androgen receptor axis-targeting therapeutics; AA, Abiraterone acetate; N/A, not available.

Pca and prostate microbiome (direct): Alteration of prostate microbiota in patients with Pca

Several studies have confirmed the existence of pathogens related to the risk of disease in cancerous prostate tissue, including bacteria, viruses or fungi. However, direct evidence that microorganisms contribute to the development of Pca and how microorganisms influence the progression of Pca is still lacking. In 2005, using bacterial cultures of prostate tissue, Cohen et al (14) found that Propionibacterium acnes spp. was the predominant microorganism detected in 35% of the Pca samples. In 2008, Sfanos et al (15) analyzed prostate tissue from 30 post-operative patients with Pca for bacterial culture and 16S ribosomal RNA (rRNA) gene sequencing. The majority of individual bacterial cultures were negative, while 16S rRNA gene sequencing showed the presence of 83 distinct microorganisms, and the authors suggested that the species present in the prostate may be ‘unculturable’.

Certain studies using 16S rRNA have found that Propionibacterium acnes may be associated with the occurrence and progression of Pca (1618). Cavarretta et al (18) assessed microbiome profiles in prostate tumors, peri-tumor and non-tumor tissues. It was found that Propionibacterium spp. was the predominant genera in tumor tissues, but no significant differences were found in peri-tumor and non-tumor tissues. However, considering that Propionibacterium acnes is one of the common sequencing contaminants and should be treated with skepticism, further studies are still needed to clarify the role of Propionibacterium acnes in Pca (19,20).

Geographical and ethnic diversity exists in all parts of the human microbiome (21). Feng et al (22) used metagenomic analysis of microbial content within prostate tumor tissue from different regions. A significant increase was identified in α-diversity from the African sample compared with the European-derived sample (P=0.004), and high-risk Pca tissues in Africa contained an abundance of anaerobic bacteria. In another study, Feng et al (23) analyzed the microbial content of postoperative prostate tissue from 65 Chinese patients with Pca, and it was revealed that Escherichia, Propionibacterium, Acinetobacter and Pseudomonas were the most abundant microbiome, which forms the core of the prostate tissue, which was also consistent with previous studies (1618). Such study may be the first to investigate the association between Pca and prostatic microbiota in a Chinese population (23).

Pca and prostate microbiome (direct): Resulting chronic inflammation produced by prostate microbiota

Several studies identified viruses or infection factors from Pca tissues such as Human papillomaviruses and Mycoplasma genitalium (24,25). However, these studies were limited by the factor of sample size, and lacked supporting evidence. Another study utilized large-scale RNA-sequencing data along with matched clinical data from 242 patients with Pca from The Cancer Genome Atlas, and found that the microbiome from prostate tissue played a major anticancer role in Pca by recruiting immune cells, which were negatively correlated with Pca Gleason score, Tumor-Node-Metastasis stage, prostate-specific antigen level, and androgen receptor (AR) expression (26). Further in vitro and in vivo experiments are necessary to validate these results. A recent study compared the microbiota profile from 94 patients with Pca with tumor and benign tissue sequencing by meta-transcriptomic analysis (27). It was demonstrated that Shewanella was enriched in malignant prostate tissues, while Staphylococcus saprophyticus and Vibrio parahaemolyticus were decreased in malignant prostate tissues. In addition, the researchers also observed that Microbacterium was significantly enriched in pathologically advanced T3 (P<0.01) (27).

These studies suggested that Pca tissue contained different microbial species, which may be related to prostatic inflammation and carcinogenesis (2427). It is generally accepted that healthy prostate tissue appears unlikely to have commensal microbiota, prostatic fluid containing high levels of zinc and antimicrobial immune proteins or prostatic epithelial cells expressing pathogen pattern recognition receptors such as Toll-like receptor 4, which block the entry and colonization of the microbiota in prostate tissue (28,29). In the pathological state, the prostate epithelial cell barrier is disrupted, and the reduction of antibacterial components in the prostatic fluid may lead to microbial infiltration and the development/progression of Pca (30). Future research is needed to investigate further the reasons for colonization of the prostate by the microbiota and the direct mechanisms of their interaction. However, ethical concerns make it difficult to truly analyze the prostate tissue of healthy individuals. The emerging organoid method may help to clarify the mechanism of prostate microbiota and Pca (31).

Pca and urinary microbiome (indirect): Differences in urethral microbiota between patients with Pca and healthy individuals are inconclusive

Compared with prostate microbiota, urinary microbiota samples are easy to obtain, non-invasive and have the potential to be used as screening biomarkers that can improve prediction of Pca risk (32). Previous studies have suggested that healthy urine is sterile, while thanks to the advancement of NGS methods, recent studies have revealed that urine microbiota has unique structures that are different from gut microbiota and show diversity in different sex, ages and disease states (3335). Urinary microbiota was associated with various female urinary diseases, including emergency urinary incontinence and overactive bladder (33). There are differences in the abundance of urinary microbiota between males and females (34). However, few studies have investigated the association between urinary microbiota and Pca.

Shrestha et al (36) collected urine samples from 135 patients assessed by 16S rRNA sequencing analysis and found that the abundance of Propionibacterium lymphophilum was significantly increased in patients with Pca; however, there was no significant difference in diversity. In the study by Guest et al (32), there was no significant difference in the microbiota diversity in urine samples from patients with Pca compared with controls. Previous studies have demonstrated differences in certain urinary microbiota in patients with Pca; however, the exact role of these microorganisms in Pca tumorigenesis and progression remains unclear. Further research is needed to establish a concrete connection between urinary microbiota and Pca.

The microbiota in semen and prostatic fluid appears to be more associated with prostate tissue than urine. Few studies have evaluated the association between seminal and prostatic fluid microbiota and Pca. In a study by Ma et al (37), 16S rRNA sequencing was used to analyze the prostatic fluid microbiota of patients with Pca. It was identified that the diversity of prostatic fluid microbiota in patients with Pca was reduced compared with the non-cancer group. No specific microbial species existed in the Pca or non-cancer groups. It was suggested that the prostatic fluid microbiome may contribute to maintaining the stability of the prostatic microenvironment.

In another Chinese cohort study, prostate/seminal fluid and urine samples from patients with Pca/benign prostatic hyperplasia (BPH) were collected for analysis. In seminal fluid, the abundance of Enterococcus was decreased in the Pca group, but there was little change in prostatic fluid and urine (38). Notably, in the study of prostate microbiota, several studies found that Enterobacteriaceae was one of the most abundant microbiotas in prostate tissue (17,27). The limitations of the study were the small sample size and the control of contamination during sampling of the urinary microbiome, which remains a problem to be solved.

In 2019, Alanee et al (39) found that patients with Pca had similar bacterial communities within their urinary microbiome profile, and increased abundance of Veillonella, Streptococcus and Bacteroides, as well as decreased abundance of Faecalibacterium, Lactobaccili and Acinetobacter in patients with Pca compared with patients with BPH. The researchers also collected the fecal microbiota of the patients for analysis, and no clustering was found in the fecal microbiota with benign or malignant tumor. In a similar study, researchers also found significant differences in the abundance of Faecalibacterium in the urine flora of the Pca group (40). The articles did not investigate whether the gut microbiome affected the urinary microbiome, although some studies have found that gut microbiota was associated with recurrent urinary tract infections (41), and FMT could reduce urinary tract infections (42). The association between gut and urine microbiota needs to be further explored.

Pca and gut microbiome (indirect): Differences in the composition of gut microbiota in patients with Pca

Although all body sites were colonized, the highest microbial counts were found in the colon (43). Gut microbiota can regulate numerous functions of the tumor-bearing organism, and thus influence tumor development and treatment (43,44). The known mechanisms include modulating the intestinal epithelial barrier, regulating the functional activity of lymphoid organs, regulating the tumor microenvironment and influencing the function of anticancer drugs (44). certain studies have been conducted to investigate if the composition of gut microbiota may be involved in the progression of Pca, particularly CRPC. However, numerous mechanisms by which gut microbiota affects Pca remain unclear, and further research is needed to support the translation of these current results into clinical practice.

Antibiotics not only act on the bacteria that cause infections but also affect the microbiome in the body. Treatment with antibiotics affected the abundance of 1/3 of the gut microbiota and there were individual differences in recovery time (45). The use of penicillin, quinolones and sulfonamides increased the risk of Pca, which the investigators hypothesized may be associated with the human microbiota (46). In a study by Mao et al (47) in 2022, it was found that disruption of the intestinal barrier and dysbiosis of the gut microbiota due to antibiotic exposure exacerbated the progression of Pca. Previous studies have also found that antibiotic-induced gut microbiota disturbances affect the efficacy of docetaxel in Pca (47).

Amirian et al (48) hypothesized in 2013 that the composition of the gastrointestinal microbiome may be significantly different in individuals with a higher risk of Pca. This hypothesis was completed in 2018 by Liss et al (49), who developed a microbiome-derived risk factor to predict the future risk of Pca. The aforementioned study assessed the gut microbiota composition, and found that Bacteroides and Streptococcus were enriched in the Pca group. A previous study also illustrated an increased relative abundance of Bacteroides in the gut microbiome of patients with Pca compared with patients with BPH (50). Similarly, Matsushita et al (51) identified that patients with high-risk Pca had an increased relative abundance of short-chain fatty acids (SCFAs)-producing bacteria. These studies have suggested a correlation between gut microbiota composition and Pca risk, potentially due to microbiota metabolites, which has implications for identifying high-risk patients and may provide additional insights into the development of Pca.

Pca and gut microbiome (indirect): Lifestyle habits affect Pca through the gut microbiome

Lifestyle, particularly dietary patterns, also have a significant impact on the occurrence and development of Pca (8). Previous studies have shown that obesity due to a high-fat diet (HFD) induces chronic systemic inflammation and participates in the progression of Pca, and one of the possible mechanisms involved may be the gut microbiota (52,53). One study found that the abundance of 21 bacterial phylotypes in the gut microbiota of HFD-fed mice with Pca was increased, and the abundance of equol-producing bacteria Adlercreutzia was decreased compared with the control group, and the serum equol of HFD-mice was significantly decreased (54). Another study by the same group found that post-weaning HFD significantly promoted Pca in the offspring, yet combined maternal HFD and post-weaning HFD decreased Pca progression in the offspring (55). The gut microbiota compositions are predominantly of vertical inheritance (56), and additional studies may be needed to clarify the correlation between vertically transmitted microbiota profile and Pca.

To investigate the effect of HFD on Pca progression, Matsushita et al (57) found that, in HFD-fed Pca mice, oral administration of an antibiotic mixture significantly altered the abundance of gut microbiota, inhibited the proliferation of Pca cells, and reduced circulating insulin-like growth factor-1 (IGF-1) levels and prostate IGF-1 expression. The results suggested the existence of a gut microbiota-IGF-1-prostate axis. The authors found that the gut microbiota may be associated with tumor progression through the generation of SCFAs, leading to elevated IGF-1 levels (57). In another study, HFD-fed mice prostate tissue expression of Hdc and gene levels of histamine receptors were upregulated. Fexofenadine, a histamine H1 receptor antagonist, significantly reduced the proliferation of Pca cells in HFD-fed mice by suppressing the IL6/STAT3 signaling pathway (58). There were also differences in the composition and diversity of gut microbiota in mice fed with different components of HFD, such as lard and fish oil diets, and it was revealed that a diet rich in saturated fatty acids could lead to the progression of Pca and change the abundance of gut microbiota (59). The gut microbiota dysbiosis caused by HFD leads to Pca progression through multiple pathways, which further supports the existence of the gut microbiota-prostate axis. Modifying dietary patterns and intervention of gut microbiota may reduce the risk of Pca development (5255,5759).

Microbiota and Pca therapy: Interaction of microbiota with Pca treatment

As shown in Fig. 1, antitumor treatment could potentially result in changes in the microbiota profile, and the microbiota could also affect the efficacy of the treatment or the absorption and metabolism of the drug (44,60). The mechanisms linking the human gut microbiome with treatment could be an important basis for a new generation of therapies. In 2018, Routy et al (61) found that patients treated with antibiotics developed resistance to anti-PD-1 immunotherapy drugs. By comparing the gut microbiome of patients with cancer who responded to this immunotherapy with that of patients with cancer who did not respond, it was found that the relative abundance of Akkermansia muciniphila correlated with clinical response to this immunotherapy in patients with cancer. It has also been found that patients with high levels of Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium have a higher propensity to respond to anti-PD-L1 therapy, and FMT from responding patients to germ-free mice may improve the efficacy of anti-PD-L1 therapy (62). Patients treated with chemotherapy/radiotherapy also showed significant changes in the composition of the microbiota. A recent study revealed significant differences in gut microbiota abundance at the end of chemo-radiation therapy for rectal cancer, and these changes were associated with ethnic or regional factors (63). Individual differences in microbiota resulted by regional, ethnic, dietary and genetic factors affect the efficacy of oncology treatment, and treatment also changes the composition of the microbiota. The interaction between cancer management and microbiota may be one of the key factors contributing to the individualized differences in oncology treatment (64).

For Pca, radiotherapy/chemotherapy as well as ADT treatment have the potential to influence the gut/urine/prostate microbiota composition; however, few studies have precisely elucidated the effect of specific microbial species or microbial profiles on the efficacy or toxicity of Pca treatment. FMT can alter the composition of the intestinal microbiota. A clinical trial (trial registration number NCT03341143) in 2021 found that treatment of PD-1-refractory melanoma with FMT in combination with anti-PD-1 drugs was effective in enhancing the efficacy of PD-1 drugs, and the results of the study showed that the use of FMT could alter the gut microbiome of patients and affect the tumor microenvironment to overcome anti-PD-1 therapy resistance in patients with melanoma (6). In addition, certain probiotics have been found to be effective in promoting cancer cell apoptosis and combating oxidative stress, and probiotic supplementation has also been shown to reduce the adverse effects of chemotherapy/radiotherapy and immunotherapy (60). In summary, recent studies have shown that microbiota composition is crucial to the efficacy of oncology treatment. On one hand, knowing the microbiota composition of a patient before treatment can assist physicians in determining the most appropriate treatment protocol for the patient; on the other hand, targeting therapy to the microbiota can also enhance the patient's response to other oncological treatments (62). It is necessary to gain an improved understanding of the correlation between different profiles of microbiota and treatment in Pca, so that the role of microbiota in the treatment of Pca can be comprehensively appreciated.

ADT remains the primary treatment for patients with advanced Pca. Although nearly all patients respond to ADT, which is termed hormone-sensitive prostate cancer (HSPC), the duration of ADT treatment sensitivity varies from months to years, and patients often develop resistance to ADT, which is termed CRPC (65). Several studies have hypothesized that intestinal microbiota may play a role in the resistance of Pca to ADT. Liu and Jiang (66) used 16S rRNA to compare the microbiota of patients with Pca (n=21) before and after ADT treatment, and 12 microbial phylotypes including Phascolarctobacterium and Ruminococcus were found to have increased abundance in the gut microbiota of patients with CRPC after ADT treatment. Another study similarly found significant differences in microbiota diversity among patients with Pca treated with ADT (n=56), with an increased abundance of the pro-inflammatory bacteria Ruminococcus gnavus and Bacteroides spp. (67). It was identified that the gut microbiota changed over time not only before and after ADT, but also after ADT. Kure et al (68) revealed that microbiota diversity decreased significantly at 24 weeks after ADT, and the abundance of Proteobacteria changed significantly after ADT, and was positively correlated with lactate concentration. Previous studies have found that ADT can lead to significant changes in the microbiota of patients with CRPC. These findings suggest a possible link between ADT and alterations in the microbiota, but there is a lack of evidence on how gut microbiota affects Pca progression after ADT.

In 2021, Pernigoni et al (69) showed that the expansion of androgen-synthesizing gut microbiota may mediate resistance to ADT. The study used two mouse models of Pca that initially showed tumor shrinkage after surgical castration and subsequent progression to CRPC, and Ruminococcus gnavus was significantly enriched in CRPC mice. In patients with CRPC, Ruminococcus was also shown to be significantly enriched and associated with phospholipid metabolism (70). Next, the investigators performed FMT from CRPC mice and healthy mice on recipient mice in the castration-sensitive phase. The results revealed that FMT from healthy mice inhibited tumor growth, while FMT from CRPC mice led to tumor progress. Metabolomic analysis showed that the dehydroepiandrosterone (DHEA) and testosterone levels were significantly elevated in FMT-CRPC mice. Similarly, functional analysis in a previous study showed an increase in the taxa of bacteria with steroid biosynthesis functions in Pca mice (71). In vivo and in vitro, Pernigoni et al (69) demonstrated the ability of Ruminococcus gnavus to convert pregnenolone into active DHEA and testosterone. The aforementioned studies observed increased abundance of certain gut microbiota, including Ruminococcus (66,69,70), Bacteroides (67,69) and Phascolarctobacterium (66), which act as antagonists to ADT, potentially due to the additional androgens provided by specific genus. While most studies have primarily focused on increasing the fraction of microbiota after ADT treatment, few have investigated which microbiota exhibit decreased in abundance post-treatment, which may be a potential target for probiotic supplementation in CRPC. For instance, Prevotella enrichment in HSPC has been found to inhibit Pca progression in mice (69).

There is an interactive association between gut microbiota and drug therapy. On one hand, it has been shown that gut microbiota impacts drug absorption, disposal, metabolism, pharmacology or toxicity. On the other hand, drug treatment can also lead to changes in gut microbiota and affect the host (47,72). However, few studies have clarified the effect of specific microbial species on the efficacy/toxicity of drug therapy for Pca.

In patients with CRPC, there were still small concentrations of extragonadal androgens present even after the end of ADT treatment, part of which was synthesized by the gut microbiota (69), and systemic upregulation of androgen synthesis could also activate the AR pathway in Pca cells (73). Based on these observations, oral AR axis-targeting therapeutics (ATT) have become one of the prominent treatment options for patients with advanced CRPC, including abiraterone acetate and enzalutamide (74). Sfanos et al (75) found that the abundance of Akkermansia muciniphila and Ruminococcaceae spp. was higher in patients with Pca receiving ATT (including bicalutamide, enzalutamide and abiraterone acetate), and functional enrichment analysis suggested a significant enrichment in the oral ATT group for functions involved in steroid/hormone biosynthesis. A previous study has shown a correlation between the relative abundance of Akkermansia muciniphila and clinical responses to immune checkpoint inhibitors (ICIs), and it was observed that oral supplementation with Akkermansia muciniphila restored the efficacy of PD-1 blockers (61). Following treatment with ATT in patients with Pca, a study found that treatment with abiraterone acetate resulted in enrichment in Akkermansia muciniphila, which, through a specific interaction with abiraterone acetate, increased the ability to synthesize vitamin K2 and influenced treatment response in patients with Pca (76). These current results suggested that the role of gut microbiota in ATT treatment was inconsistent. Part of genera may attenuate the effect of ATT treatment by synthesizing extra-tumoral androgens, while part of genera may play a synergistic role with ATT through other pathways, and different genera could play different roles.

Significant variability in the response of ICIs such as anti-CTLA-4 and anti-PD-L1 in different individuals and tumor types could also be attributed to the effect of gut microbiota (61,77). The gut microbiota composition was found to predict response to anti-PD-1 therapy (78), and FMT from immunotherapy-responsive patients into tumor xenograft mouse models enhanced antitumor immunity (61,77). Terrisse et al (79) found that the immune system and gut microbiota determined the efficacy of ADT in Pca, and that ADT reversed the effects of Pca on thymic cortical areas and increased circulating thymic emigrant cells. However, treatment with ICI in patients with Pca did not enhance the efficacy of ADT.

To investigate whether different gut microbiota composition affects the efficacy of ITT therapy in Pca, Peiffer et al (80) performed 16S rRNA gene sequencing of the profile of gut microbiota of patients with CRPC before and after anti-PD-1 treatment, and inconsistent with previous results from other oncology studies (61), the study found a decrease in the relative abundance of Akkermansia muciniphila in the responding samples. Shaikh et al (78) combined sequencing data from multiple ICI-related microbiome studies to develop an integrated microbiome prediction index to identify whether or not there was a response to ICI therapy. However, the study found no significant difference in the index results between responders and non-responders (80). In the area of Pca, the interactive effect of microbiota and ICI needs further investigation.

Conclusions and future directions

The present review aimed to clarify the direction of subsequent research by providing the current state of research in Pca and microbiota research. An increasing number of studies have been conducted to analyze the correlation between microbiota and Pca. Microbiota is recognized as one of the potentially critical factors influencing Pca development/progression. However, there is still a lack of adequate understanding of the mechanisms of microbiota at different locations in the development/progression and treatment of Pca. Recent studies have demonstrated that, compared with healthy individuals, there may be differences in the abundance of microbiota in patients with Pca, whether in the urethra, prostate tissue or intestine. Nevertheless, the research provided in the present review often presents conflicting information, emphasizing the need for further study in this area using a standardized approach.

Research on the association between urinary and prostate microbiota and Pca has progressed slowly. Previous studies suggest that epithelial structural disruption and inflammatory states leading to colonization may be potential mechanisms for Pca progression. However, this mechanism is not yet understood. Gut microbiota may act indirectly through different microbiota metabolites and sex hormone levels, and influence Pca progression and treatment (Fig. 2). Understanding how gut microbiota affects Pca will help to stratify in an improved manner the risk of Pca progression and develop new treatments. The impact of the microbiome on cancer (including Pca) treatment is bilateral. On one hand, the microbiome can significantly influence the treatment of cancer, while cancer treatment can in turn shape the composition of the microbiome. As therapeutic tools continue to evolve, particularly ATT treatment for Pca, it is critical to explore and understand the complex underlying links between Pca and the microbiome.


Not applicable.


Funding: No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

BWX and JWW wrote the manuscript. BWX was a major contributor in writing the manuscript. DXZ made substantial contributions to conception and design. XPH designed this review and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.





androgen deprivation therapy


androgen receptor


androgen receptor axis-targeting therapeutics


benign prostatic hyperplasia


castration-resistant prostate cancer




fecal microbiota transplantation


hormone-sensitive prostate cancer


immune checkpoint inhibitor


insulin-like growth factor-1


next-generation sequencing


prostate cancer


short-chain fatty acids



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Xia B, Wang J, Zhang D and Hu X: The human microbiome links to prostate cancer risk and treatment (Review). Oncol Rep 49: 123, 2023
Xia, B., Wang, J., Zhang, D., & Hu, X. (2023). The human microbiome links to prostate cancer risk and treatment (Review). Oncology Reports, 49, 123.
Xia, B., Wang, J., Zhang, D., Hu, X."The human microbiome links to prostate cancer risk and treatment (Review)". Oncology Reports 49.6 (2023): 123.
Xia, B., Wang, J., Zhang, D., Hu, X."The human microbiome links to prostate cancer risk and treatment (Review)". Oncology Reports 49, no. 6 (2023): 123.