The human gut harbors an extensive microbial ecosystem comprising over 10 trillion diverse microorganisms (Zmora et al., 2019). These coevolved microorganisms establish a symbiotic relationship with their host, thriving in the nutrient-dense intestinal environment. They perform crucial physiological functions while simultaneously being involved in disease processes by synthesizing a myriad of bioactive metabolites (Erny et al., 2021; Jugder et al., 2021). Applying the specific mode of producing small molecules, gut microbiota acts as a fundamental factor in the execution of protective, metabolic, and structural homeostasis (Adak and Khan, 2019; Gomaa, 2020). For instance, compelling evidence suggests that gut microbiota comprising its metabolic products significantly influence antitumor immune response, modulate immune checkpoint inhibitor efficacy, and impact cancer progression across multiple tumor types (Lu et al., 2022). In a like manner, gut microbiota affects prostatic pathophysiology by means of the above modes (Matsushita et al., 2021; Zhong et al., 2022).

Specific inflammatory conditions like CP/CPPS are also relevant to gut microbiota dysbiosis. In 2016, Shoskes et al. (2016b) conducted comparative analyses of gut microbiota composition between CP/CPPS patients and healthy controls. Their findings showed great interindividual variability in the gut microbiota and a lower α-diversity in CP/CPPS subjects, particularly in cases with symptom duration exceeding 48 months. In addition, several specific bacterial taxa were over- or under-represented, a case in point with the abundance of Prevotella (Shoskes et al., 2016b). Not limited to studies of the human microbiota, analogous results have been corroborated in animal models. Experimental autoimmune prostatitis (EAP) mouse model, established through subcutaneous injection of prostate antigens (PAg) along with adjuvants, remains the most widely utilized preclinical system for CP/CPPS research. The model recapitulates symptoms and immunologic features resembling human CP/CPPS (Breser et al., 2017). In 2019, Konkol et al. (2019) identified distinct microbial signatures in CP/CPPS rats, with five taxa showing increased abundance and four demonstrating decreased levels compared to healthy controls. Not coming solely but in pairs, Du et al. (2020) also noted comprehensive microbial alterations across all taxonomic levels (phylum, class, order, family, genus, and species) in the EAP models. Supporting these findings, subsequent investigations by the same team identified specific microbial alterations across multiple taxonomic hierarchies. It warrants mentioning that the EAP group showed a decrease in all nine bacterial groups at the genus level, except for Lactobacillus, which increased (Du et al., 2022), enhancing the synthesis of short-chain fatty acids (SCFAs) (Markowiak-Kopeć and Śliewska, 2020). Parallel research revealed distinct β-diversity patterns and identified three enriched and seven depleted bacterial taxa in CP/CPPS cohorts (Wang S. et al., 2023). Taken together, the findings above provide a compelling association between gut microbiota alterations and CP/CPPS pathogenesis. Interestingly, recurrent observation in α-diversity alterations might suggest its potential utility as a diagnostic biomarker for CP/CPPS. Whereas, such abnormal α-diversity may also reflect confounding factors including prolonged antibiotic exposure, aging, or systemic physiological changes (Haak et al., 2019; Odamaki et al., 2016). Furthermore, specific microbial alterations might represent either protective or etiological features. Prevotella, a dietary fiber-responsive bacterial genus that predominates in individuals consuming plant-rich diets, has been implicated in energy metabolism optimization and anti-inflammatory processes. Its established health-promoting properties and observed depletion in CP/CPPS patients suggest its potential dual role as both a diagnostic biomarker and therapeutic target for this condition (Ley, 2016).

Of note, mounting lines of evidence enlightened that there are evident interrelationships between gut microbiota composition and psychological status in CP/CPPS patients (Huang et al., 2019; Kelly et al., 2019). In clinical diagnosis and treatment, psychological dysfunction may be concomitant with physical discomfort in patients suffering from CP/CPPS. Up to 78% of patients showed comorbid depression when compared with the general male population (Egan and Krieger, 1994). Analogous to CP/CPPS, depression exhibits complex etiology, and while the causal relationship remains undefined, their parallel progression is elucidated (Stamatiou et al., 2023). It has been verified, at least in animal models, that prostate inflammation induces depressive symptomatic behavior and cognitive declines (Šutulović et al., 2023). Extensive gut-brain axis-related studies have emerged to provide supporting evidence for the development of depression, and one of the contributors appears to be tied to the gut microbiota (Stower, 2019). Given the fact that altered gut microbiota exists in patients with CP/CPPS, researchers have actively explored the hypothesis that CP/CPPS primarily mediates the gut microbiota leading to depression. Concentrating on this area, Du and his colleagues utilizing the EAP model successively conducted animal experiments that showed much support for such theory that CP/CPPS may lead to the alteration of gut microbiota and induce depressive symptoms (Du et al., 2020; Du et al., 2022).

The underlying mechanism of CP/CPPS remains incompletely characterized. One of the mechanisms, by which the gut microbiota exerts their protective effects, is to occupy the intestine surfaces and maintain intestinal barrier integrity to block the invasion of foreign pathogenic microbes (Karczewski et al., 2010). This mechanism provides substantial support for the hypothesis that CP/CPPS pathogenesis may involve compromised microbial barrier function, permitting pathogen translocation (Song et al., 2023).

Aside from the direct pathway, CP/CPPS bears a relation to disrupting the homeostasis of gut microbiota and the secondary changes it engenders in metabolites resulting from compositional changes (Konkol et al., 2019). In the study of Liu et al. (2021b), they used multi-omics analysis to explore the alteration in the composition of gut microbiota, gene expression, and DNA methylation in the CP/CPPS rat model. Their analysis displayed 185 differentially expressed genes in the intestinal epithelium and identified 73,232 differentially methylated sites (DMSs). In another study by Du et al. (2022), a significant imbalance in the ratio of Th17 cells to Treg cells in the EAP group drew extensive concerns from researchers. Thus, they proposed that the propionate might modulate T cell differentiation through the GPR43-HDAC6 axis, restoring the balance of Th17 and Treg cell ratios. Their updated findings indicated alcohol-mediated gut microbiota alterations stimulate Th17 differentiation and response via the cholesterol biosynthesis metabolic pathway, which ultimately exacerbated CP/CPPS symptoms. The cholesterol biosynthesis regulator SREBP2 played an integral function in this pathway (Du et al., 2024). Taking all results into account, the changes in gut microbiota might alter epithelial gene expression, successively modulating the immunocytes such as Th17/Treg cells balance and their respective pro-/anti-inflammatory cytokine profiles, thus ultimately exerting systemic effects (Wang J. et al., 2023). In addition, the outstanding performance of propionate captured our attention. SCFAs, particularly propionate, domain a leading part of metabolites generated by the gut microbiota through colonic fermentation of undigested carbohydrates, with well-established roles in inflammatory regulation (Cummings et al., 1987; Hamer et al., 2008; Trompette et al., 2014). They exert their effects in a manner of binding to the corresponding G protein-coupled receptors (GPR) such as GPR43 or by interacting with histone deacetylase (HDACs), initiating downstream signaling cascades thus resulting in the corresponding cellular effects (Rooks and Garrett, 2016; Sivaprakasam et al., 2016). Collectively, these findings position gut microbiota as a crucial agent in driving the regulation of host immunity, primarily through microbial metabolites including SCFAs (Schluter et al., 2020; Smith et al., 2013). These mechanistic insights into gut microbiota affecting CP/CPPS have led to the proposal of a gut-prostate axis, which resembles the gut-brain axis, gut-lung axis, and gut-liver axis, etc., (Cryan et al., 2019; Du et al., 2022). The gut-prostate axis builds bidirectional communication between intestinal and prostatic systems which paved the way for researchers to increasingly recognize various domains (Figure 2), but it still warrants further investigation.

A majority of investigators have predominantly attempted to explain the causative efficacy in CP/CPPS of the microbiota which is located in the urogenital system, yet they seldom notice that oral microbiota has unique interest in CP/CPPS. Existing research suggests that oral health status is firmly associated with the development of several systemic diseases (Babaev et al., 2017; Suresh et al., 2016). Accumulating oral microbiota-centric research has substantiated this phenomenon, with a wealth of evidence that oral microbiota may act as suspicious etiologic agents in the onset of prostatic diseases (Boland et al., 2013; Wu et al., 2019). More critically, a couple of important studies have also exemplified both direct and indirect mechanistic links between the oral microbiota and CP/CPPS.

To start with, several studies have provided indirect evidence of the association of oral microbes with CP/CPPS. Elevated serum prostate-specific antigen (PSA), a well-established prostate cancer biomarker, showed a statistical association with CP/CPPS (Nadler et al., 2006). It is indicated that prostatic inflammation contributes greatly to elevating serum PSA concentrations (Nickel et al., 1999; Yaman et al., 2003). Zooming into previous epidemiological studies, PSA level also seems to be statistically associated with periodontal disease (Boyapati et al., 2018; Joshi et al., 2010). Merging epidemiological studies have shown an indirect correlation between CP/CPPS and periodontal disease through the intermediary of PSA. Interestingly, periodontal treatment has been shown to reduce serum PSA level and alleviate CP/CPPS symptoms (Nabil and Bissada, 2015). Herein, there may be potential PSA-mediated connections between periodontal health and CP/CPPS.

Beyond indirect associations, some evidence also objectively suggests a relatively direct potential relationship between CP/CPPS and oral microbiota. Initial small-scale case analyses isolated exact oral pathogens from EPS of comorbid patients with periodontal disease and CP/CPPS. The investigators found that a total of 8 of 14 (57.1%) subjects had no less than one oral pathogen in their samples (Estemalik et al., 2017). In another cross-sectional study by Boyapati et al. (2018), they found the mean clinical attachment level, a standard parameter that reflects the extent of periodontal tissue destruction, notably increasing in moderate-to-severe CP/CPPS patients in spite of mild CP/CPPS patients (Sanz et al., 2020). A cohort study selected periodontitis patients who were excluded from prior CP/CPPS diagnosis into two cohorts of patients with and without periodontitis treatment, and a matched control cohort without periodontitis was set. At the endpoint, the characteristic patterned increased CP/CPPS susceptibility among periodontitis patients, regardless of treatment status (Fu et al., 2021). Alluri et al. (2021) isolated Fusobacterium nucleatum subsp. fusiform strain ATCC 51190, a periodontal pathogen, in histologically abnormal prostate tissues, suggesting its potential role in linking periodontal disease and prostatic inflammation. As noted above, we can hypothesize that there is a correlation between oral microbiota and CP/CPPS. However, cross-sectional studies are limited to probing causality, and further randomized controlled trials (RCTs) and experimental validations remain necessary to elucidate oral microbiota’s role in CP/CPPS pathogenesis.

The precise mechanism through which oral microbiota affects CP/CPPS pathogenesis remains elusive, with the available evidence principally supporting two primary direct pathways, microbial translocation and indirect systemic inflammation. For the direct pathway, previously mentioned results suggest the hypothesis that hematogenous dissemination of oral microorganisms to the prostate triggers histological changes that contribute to the occurrence of CP/CPPS (Alluri et al., 2021; Estemalik et al., 2017). For the indirect pathway, increasingly circulating levels of periodontal-derived pro-inflammatory factors, including interleukins (IL-1β, IL-2, IL-6, IL-8), tumor necrosis factor (TNF-α), and C-reactive protein (CRP), may act as indirect agents in the onset of CP/CPPS (Boyapati et al., 2018; Hegde and Awan, 2019). These locally produced, periodontitis-derived inflammatory mediators can trigger a systemic inflammatory response through the circulatory system, which in turn causes or exacerbates CP/CPPS (Figure 3).

Chen Y. et al. (2020) administered whey protein-derived early glycation products (EGPs) at 600 mg/kg/day to non-obese diabetic (NOD) mice with concurrent spontaneous autoimmune prostatitis. After undergoing 6 months of rearing, EGP-treated mice exhibited significantly improved survival rates compared to controls. Moreover, attenuated prostate inflammation, decreased splenic M1 macrophage and lymphocyte populations, as well as increased systemic anti-inflammatory factor levels were exhibited in the group with EGPs. Changes in the relative abundance of gut microbiota and increased Bacteroides acidifaciens counts paralleled the alleviation of inflammation, perhaps correlating the intrinsic mechanism of EGP in regulating the systemic immune status in a manner.

In Konkol et al. (2017) study, galactoglucomannan (GGM) was clarified to possess the ability to improve lower urinary tract symptoms (LUTS) associated with chronic prostatic inflammation in rat models. In subsequent experiments, they established a non-bacterial prostatitis model with subcutaneous testosterone and 17β-estradiol hormone pellets on adult male Wister rats, administering water containing 2% GGM orally for feeding whilst the control group was given tap water. Following 5 weeks of treatment, GGM normalized prostate inflammation-induced elevations in Odoribacter and Clostridiaceae levels while increasing Bacteroides uniformis abundance. In addition, GGM was demonstrated to significantly increase the serum levels of butyric acid and caproic acid while lipopolysaccharide binding protein (LBP) concentrations, thereby contributing to relieving the LUTS of prostatitis (Konkol et al., 2019).

Liu et al. (2020, 2021a) found that Poria cocos Polysaccharides (PPs) pre-treated with 250 mg/kg per day by gavage for 7 days alleviated inflammation in a non-bacterial prostatitis model induced by intraperitoneal injections of 1% λ-carrageenan in male Sprague Dawley (SD) rats, with gut microbiota modulation, particularly targeting the Ruminococcaceae NK4A214 group to ameliorate symptom. In addition to the blank control and the untreated group, the researchers installed a finasteride-treated group, the outcome showed that PPs could target different genera compared to the finasteride group, thus exerting therapeutic effects. Research thereafter clarified that PPs may modulate several key bacteria and metabolic outputs, including 7-keto-deoxycholic acid and haloperidol glucuronide, resulting in palliative effects (Yu et al., 2022).

Astaxanthin (AST), a compound with potent antioxidant, anti-inflammatory, and immunomodulatory properties (Chen Z. et al., 2020), has recently been the subject of related studies that have demonstrated its value in upregulating the relative abundance of Akkermansia muciniphila, which in turn ameliorating CP/CPPS symptoms. NOD mice were stratified into four groups: control, EAP, EAP + AST 50 mg/kg group, and EAP + AST 100 mg/kg group. All mice excluding the control group received oral AST administration every other day for 6 weeks starting from the first subcutaneous immunization until the end of the experiment, following a second immunization to obtain the EAP model at the fourth week. Feces from CP/CPPS patients exhibited a reduction of A. muciniphila in the gut microbiota compared to the healthy population the same as in EAP mice versus the normal mice, whereas AST treatment restored A. muciniphila levels in EAP models. A. muciniphila transplantation to EAP mice mirrored similar benefits of AST intervention in elevating the concentration of SCFAs, especially acetic acid which ultimately eases prostate inflammation (Liu et al., 2024).

Berberine hydrochloride is known to work in the therapeutic area across various diseases. In EAP models, daily administration of berberine hydrochloride 200 mg/kg for 4 weeks restored the α- and β-diversity of the gut microbiota, reduced prostate inflammation, and mitigated alterations in the relative abundance of the bacterial species at the genus and species level. Strikingly, Clostridium butyricum increased SCFA production in the course that berberine hydrochloride regulates the intestinal microbiota, representing a candidate target of the berberine hydrochloride effect. Fecal microbiome transplantation (FMT) based on pseudo-germ-free mice (PGFR) revealed that recipient mice receiving microbiota from berberine hydrochloride-treated EAP donors exhibited more severe inflammatory reactions than those receiving untreated EAP microbiota, reaffirming the mitigating effect of berberine hydrochloride (Tian et al., 2024).

In the work of Yu et al. (2024), prostate inflammation was significantly alleviated in EAP mice receiving daily oral gavage of EriB 10 mg/kg for 14 consecutive days, as well as altered gut microbiota α- and β-diversity in EAP mice compared to untreated controls. Such changes in microbiota composition altered the metabolic pathway of vitamin D3, promoting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2. Subsequent FMT in PGFR confirmed these findings, showing reduced M1/M2 ratios in recipients of EriB-treated donor microbiota compared to the EAP group without EriB, further substantiating the above mechanism.

While promising, the mutual deficiency of these studies is the boundedness of murine models. Their pharmaceutical validity and safety for human application are unverified, necessitating human-appropriate formulations and large-scale clinical trials. Nevertheless, these compounds represent promising candidates to help develop rational alternative treatment scheme regimens of CP/CPPS at this stage.