RESUMO
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a urinary disorder that affects youthful to middle-aged men most frequently. It has been revealed that Th17/Treg imbalance is a crucial factor in the pathophysiological mechanisms behind this disease. However, this imbalance's mechanisms are unknown. In the experimental autoimmune prostatitis (EAP) mouse model, the NLRP3 inflammasome was turned on, IL-1ß levels went up. Moreover, there exists a discernible positive association between the upsurge in IL-1ß and the perturbation of Th17/Treg equilibrium. Additionally, we have revealed that IL-1ß plays a vital role in promoting the differentiation of Naïve CD4+ T cells into the Th17 cells and enhances the conversion of Treg cells into Th17 cells. Further studies revealed that IL-1ß promotes STAT3 phosphorylation, which is what causes Treg cells to become Th17 cells. All data strongly suggest that the NLRP3 inflammatory influence Th17 cell development and the conversion of Treg cells into Th17 cells through IL-1ß, disrupting the Th17/Treg balance and exacerbating EAP inflammation. In this article, we provide new theories for the pathogenesis of CP/CPPS and propose new prevention and therapy methods.
Assuntos
Doenças Autoimunes , Modelos Animais de Doenças , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Prostatite , Linfócitos T Reguladores , Células Th17 , Animais , Masculino , Prostatite/imunologia , Prostatite/metabolismo , Prostatite/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Camundongos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Fator de Transcrição STAT3/metabolismo , Inflamassomos/metabolismo , Diferenciação Celular , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is very common worldwide, and alcohol consumption is a notable contributing factor. Researches have shown that gut microbiota can be influenced by alcohol consumption and is an important mediator in regulating Th17 cell immunity. However, it is still unclear the exact mechanism by which alcohol exacerbates the CP/CPPS and the role of gut microbiota in this process. METHOD: We first constructed the most-commonly used animal model for CP/CPPS, the experimental autoimmune prostatitis (EAP) model, through immunoassay. Based on this, mice were divided into EAP group and alcohol-consuming EAP group. By 16S rRNA sequencing and non-targeted metabolomics analysis, differential gut microbiota and their metabolites between the two groups were identified. Subsequently, metabolomics detection targeting cholesterols was carried out to identify the exact difference in cholesterol. Furthermore, multiple methods such as flow cytometry and immunohistochemistry were used to detect the differentiation status of Th17 cells and severity of prostatitis treated with 27-hydroxycholesterol (the differential cholesterol) and its upstream regulatory factor-sterol regulatory element-binding protein 2 (SREBP2). Lastly, fecal transplantation was conducted to preliminary study on whether alcohol intake exacerbates EAP in immune receptor mice. RESULTS: Alcohol intake increased the proportion of Th17 cells and levels of related inflammatory factors. It also led to an altered gut bacterial richness and increased gut permeability. Further metabolomic analysis showed that there were significant differences in a variety of metabolites between EAP and alcohol-fed EAP mice. Metabolic pathway enrichment analysis showed that the pathways related to cholesterol synthesis and metabolism were significantly enriched, which was subsequently confirmed by detecting the expression of metabolic enzymes. By targeting cholesterol synthesis, 27-hydroxycholesterol was significantly increased in alcohol-fed EAP mice. Subsequent mechanistic research showed that supplementation with 27-hydroxycholesterol could aggravate EAP and promote Th17 cell differentiation both in vivo and in vitro, which is regulated by SREBP2. In addition, we observed that fecal transplantation from mice with alcohol intake aggravated EAP in immunized recipient mice fed a normal diet. CONCLUSION: Our study is the first to show that alcohol intake promotes Th17 cell differentiation and exacerbates EAP through microbiota-derived cholesterol biosynthesis.
Assuntos
Consumo de Bebidas Alcoólicas , Doenças Autoimunes , Diferenciação Celular , Colesterol , Modelos Animais de Doenças , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Prostatite , Células Th17 , Animais , Masculino , Células Th17/imunologia , Prostatite/imunologia , Prostatite/microbiologia , Prostatite/metabolismo , Prostatite/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/induzido quimicamente , Camundongos , Diferenciação Celular/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/efeitos adversos , Colesterol/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genéticaRESUMO
Chronic prostatitis is one of the most common urologic diseases that troubles young men, with unclear etiology and ineffective treatment approach. Pyroptosis is a novel model of cell death, and its roles in chronic prostatitis are unknown. In this study, P2X7R, NEK7, and GSDMD-NT expression levels were detected in prostate tissues from benign prostate hyperplasia (BPH) patients and experiment autoimmune prostatitis (EAP) mice. P2X7R agonist, antagonist, NLRP3 inhibitor, and disulfiram were used to explore the roles of the P2X7R-NEK7-NLRP3 axis in prostate epithelial cell pyroptosis and chronic prostatitis development. We found that P2X7R, NEK7, and GSDMD-NT were highly expressed in the prostate epithelial cells of BPH patients with prostatic inflammation and EAP mice. Activation of P2X7R exacerbated prostatic inflammation and increased NLRP3 inflammasome component expressions and T helper 17 (Th17) cell proportion. Moreover, P2X7R-mediated potassium efflux promoted NEK7-NLRP3 interaction, and NLRP3 assembly and activation, which caused GSDMD-NT-mediated prostate epithelial cell pyroptosis to exacerbate EAP development. Disulfiram could effectively improve EAP by inhibiting GSDMD-NT-mediated prostate epithelial cell pyroptosis. In conclusion, the P2X7R-NEK7-NLRP3 axis could promote GSDMD-NT-mediated prostate epithelial cell pyroptosis and chronic prostatitis development, and disulfiram may be an effective drug to treat chronic prostatitis.
Assuntos
Células Epiteliais , Quinases Relacionadas a NIMA , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Ligação a Fosfato , Próstata , Prostatite , Piroptose , Animais , Humanos , Masculino , Camundongos , Doenças Autoimunes/metabolismo , Células Epiteliais/metabolismo , Gasderminas , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Próstata/metabolismo , Prostatite/metabolismo , Piroptose/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismoRESUMO
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.
Assuntos
Doenças Autoimunes , Quimiocina CCL20 , Quimiotaxia , Interleucina-17 , Prostatite , Células Th17 , Masculino , Prostatite/imunologia , Prostatite/patologia , Prostatite/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Animais , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Macrófagos/metabolismo , Macrófagos/imunologia , Modelos Animais de Doenças , NF-kappa B/metabolismo , Transdução de Sinais , Humanos , Camundongos Endogâmicos C57BL , Próstata/patologia , Próstata/metabolismo , Próstata/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , AutoimunidadeRESUMO
PURPOSE: Prostatitis is a highly prevalent condition that seriously affects men's physical and mental health. Although epidemiological investigations have provided evidence of a correlation between insufficient sleep and prostatitis, the pathogenesis of prostatitis remains unclear. We sought to identify the underlying mechanism involved and identify a promising therapeutic target. METHODS: Sleep deprivation (SD) was utilized to establish a mouse model of insufficient sleep in a special device. Prostatitis was observed at different time points post-SD. The degree of prostatitis was evaluated by pathological section and behavioural tests. Using immunofluorescence, western blot, and proteomic analyses, the underlying mechanism of SD-related prostatitis was investigated, and the development and therapeutic target of prostatitis were elucidated. RESULTS: SD, as an initial pathological trigger, resulted in a reduction in dihydrotestosterone and melatonin levels. Proteomic analysis revealed that the cGAS-STING pathway may play a significant role in inducing prostatitis. The subsequent results illustrated that the dual reduction in dihydrotestosterone and melatonin led to an accumulation of reactive oxygen species and the release of mitochondrial DNA (mt-DNA). The accumulation of mt-DNA activated the cGAS-STING pathway, which recruited inflammatory cells into the prostatic stroma through the secretion of interferon-ß. Consequently, an inflammatory microenvironment was formed, ultimately promoting the development of prostatitis. Notably, mice with SD-induced prostatitis gradually recovered to a normal state within 7 days of recovery sleep. However, after being subjected to SD again, these mice tended to have a more pronounced manifestation of prostatitis within a shorter timeframe, which suggested that prostatitis is prone to relapse. CONCLUSIONS: The cGAS-STING pathway activated by dual deficiency of dihydrotestosterone and melatonin plays a comprehensive inflammatory role in SD-related prostatitis. This research provides valuable insights into the pathogenesis, therapeutic targets, and prevention strategies of prostatitis.
Assuntos
Melatonina , Prostatite , Humanos , Masculino , Animais , Camundongos , Privação do Sono/complicações , Di-Hidrotestosterona/farmacologia , Proteômica , Sono , DNA Mitocondrial , NucleotidiltransferasesRESUMO
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common inflammatory immune disease of the urogenital system. High glucose intake is considered to be a potential promoter of autoimmune diseases. However, the influence of high glucose intake on CP/CPPS is unknown. This research aimed to explore the influences of high glucose intake on experimental autoimmune prostatitis (EAP), a valid animal model of CP/CPPS, and the underlying mechanism. NOD mice received 20% glucose water or normal water treatment during EAP induction. EAP severity and Th17 cell responses were evaluated. Then, we explored the effects of an IL-17A neutralizing antibody, an inhibitor of TGF-ß, the reactive oxygen species (ROS) inhibitor NAC, and the mitochondrial ROS (mtROS) antioxidant MitoQ on glucose-fed EAP mice. The results demonstrated that high glucose intake aggravated EAP severity and promoted Th17 cell generation, which could be ameliorated by the neutralization of IL-17A. In vitro experiments showed that high dextrose concentrations promoted Th17 cell differentiation through mtROS-dependent TGF-ß activation. Treatment with TGF-ß blockade, NAC, or MitoQ suppressed Th17 cell generation both in vivo and in vitro, resulting in the amelioration of EAP manifestations caused by high glucose intake. This study revealed that high glucose intake exacerbates EAP through mtROS-dependent TGF-ß activation-mediated Th17 differentiation. Our results may provide insights into the molecular mechanisms underlying the detrimental effects of an environmental factor, such as high glucose intake, on CP/CPPS.
Assuntos
Doenças Autoimunes , Prostatite , Masculino , Humanos , Camundongos , Animais , Prostatite/induzido quimicamente , Prostatite/tratamento farmacológico , Espécies Reativas de Oxigênio , Interleucina-17 , Células Th17 , Camundongos Endogâmicos NOD , Diferenciação Celular , Fator de Crescimento Transformador beta , Glucose , Modelos Animais de DoençasRESUMO
BACKGROUND: Premature ejaculation (PE) is the most prevalent sexual dysfunction among men. Eejaculation involves a complex nervous mechanism in which the ejaculatory centers play a key role in modulating sperm emission. Although treatment possibilities span from psychotherapy to pharmacological approaches, results show inconsistent efficacy. In this context, the emergence of repetitive transcranial magnetic stimulation (rTMS) as a non-invasive neuromodulatory approach represents a compelling avenue for potential therapeutic exploration. OBJECTIVE: To investigate whether high-frequency transcranial magnetic stimulation can modulate the ejaculatory behavior of rats with rapid ejaculation by altering neurotransmitter levels and neuroplasticity in the hippocampus. METHODS: Rats have been screened for rapid ejaculation by observing behavioral indices of mating, and subsequently divided into two groups. The intervention group was administered with a 10 Hz rTMS stimulation, whereas the control group received a sham procedure. Upon the delivery of rTMS, we investigated ejaculation latency (EL), the hippocampal 5-hydroxytryptamine (5-HT) concentration, brain-derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95) expressions, as well as BDNF-receptor tyrosine kinase receptor B (TrkB) pathway upregulation. RESULTS: After 14 days, EL was increased in the intervention group compared with the control group. 5-HT concentration in the hippocampal region was increased, and high-frequency rTMS activated the BDNF and TrkB pathways, including phosphorylation of cAMP response element-binding protein (CREB), and upregulated the transcription and protein expression of SYN, and PSD95. CONCLUSION: RTMS upregulates BDNF, SYN, and PSD95 expression through activation of the BDNF-TrkB pathway and increases brain 5-hydroxytryptamine thereby regulating neuroplasticity and improving ejaculation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Ejaculação , Hipocampo , Plasticidade Neuronal , Receptor trkB , Comportamento Sexual Animal , Estimulação Magnética Transcraniana , Animais , Estimulação Magnética Transcraniana/métodos , Plasticidade Neuronal/fisiologia , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Ratos , Ejaculação/fisiologia , Receptor trkB/metabolismo , Comportamento Sexual Animal/fisiologia , Serotonina/metabolismo , Sinaptofisina/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Ejaculação Precoce/metabolismo , Ejaculação Precoce/fisiopatologiaRESUMO
OBJECTIVE: To investigate the mechanism of the CXCL10/CXCR3 axis regulating Th1 cell differentiation and migration through the PI3K/AKT pathway in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: Experimental autoimmune prostatitis (EAP) model, a well-described and validated animal model of CP/CPPS, was used in our study. After treatment with CXCL10, the severity of EAP and Th1 cell proportion were respectively measured by HE stains, immunohistochemistry, and flow cytometry. Then, the protein expression of the PI3K/AKT pathway in CXCL10/CXCR3-regulated Th1 cell differentiation and migration was evaluated by western blotting. Additionally, by the CXCR3 antagonist AMG487 and the PI3K inhibitor LY294002 applications, the effects of CXCL10/CXCR3 through PI3K/AKT pathway on the Th1 cell differentiation and migration were further assessed. RESULTS: The EAP model was successfully built. CXCL10 increased the proportion of Th1 cells in EAP mice, accompanied by upregulation of the PI3K/AKT pathway. Additionally, the PI3K/AKT pathway was found to be involved in CXCL10/CXCR3 axis-mediated Th1 cell differentiation and migration. CONCLUSIONS: Our investigations indicate that the CXCL10/CXCR3 axis regulates Th1 cell differentiation and migration in EAP through the PI3K/AKT pathway, which provides a new perspective on the immunological mechanisms of CP/CPPS.
RESUMO
BACKGROUND: Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. METHODS: Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. RESULTS: We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. CONCLUSIONS: The model in our work is a novel assessment tool to measure immunotherapy's effectiveness and anticipate BLCA patients' prognosis, offering new avenues for immunological biomarkers and targeted treatments.
RESUMO
Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS-STING pathway inhibition-related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese-zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously-injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS-STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer-associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS-STING pathway further amplifies the efficacy of ICD by generating interferon-ß. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.
Assuntos
Nanopartículas , Neoplasias , Neoplasias da Próstata , Masculino , Humanos , Próstata , Morte Celular Imunogênica , Neoplasias da Próstata/tratamento farmacológico , Imunoterapia , PolietilenoglicóisRESUMO
Adrenocortical carcinoma (ACC) is a malignancy of the endocrine system. We collected clinical and pathological features, genomic mutations, DNA methylation profiles, and mRNA, lncRNA, microRNA, and somatic mutations in ACC patients from the TCGA, GSE19750, GSE33371, and GSE49278 cohorts. Based on the MOVICS algorithm, the patients were divided into ACC1-3 subtypes by comprehensive multi-omics data analysis. We found that immune-related pathways were more activated, and drug metabolism pathways were enriched in ACC1 subtype patients. Furthermore, ACC1 patients were sensitive to PD-1 immunotherapy and had the lowest sensitivity to chemotherapeutic drugs. Patients with the ACC2 subtype had the worst survival prognosis and the highest tumor-mutation rate. Meanwhile, cell-cycle-related pathways, amino-acid-synthesis pathways, and immunosuppressive cells were enriched in ACC2 patients. Steroid and cholesterol biosynthetic pathways were enriched in patients with the ACC3 subtype. DNA-repair-related pathways were enriched in subtypes ACC2 and ACC3. The sensitivity of the ACC2 subtype to cisplatin, doxorubicin, gemcitabine, and etoposide was better than that of the other two subtypes. For 5-fluorouracil, there was no significant difference in sensitivity to paclitaxel between the three groups. A comprehensive analysis of multi-omics data will provide new clues for the prognosis and treatment of patients with ACC.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Multiômica , Cisplatino/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Análise de DadosRESUMO
Environmental pollution sources may play a key role in the pathogenesis of nephrolithiasis, although the link between environmental aldehyde exposure and the incidence of nephrolithiasis is unclear. The researchers in this study set out to see whether adult kidney stone formation was linked to environmental aldehydes. We examined data from 10,175 adult participants over the age of 20 who took part in the 2013-2014 National Health and Nutrition Examination Survey (NHANES), which was a cross-sectional research. A logistic regression model was employed in this work to examine the relationship between aldehyde exposure and kidney stones, machine learning was utilized to predict the connection of different parameters with the development of kidney stones, and a subgroup analysis was performed to identify sensitive groups. After controlling for all confounding variables, the results revealed that isopentanaldehyde, benzaldehyde, and hexanaldehyde were risk factors for kidney stone formation, with odds ratio (OR) of 2.47, 1.12, and 1.17, respectively, and 95 percent confidence intervals (95% CI) of 1.15-5.34, 1.02-1.22, and 1.00-1.36. Kidney stones may be a result of long-term exposure to aldehydes, which may cause them to form. Environmental pollution-related aldehyde exposure might give a novel notion and direction for future study into the process of kidney stone production, even if the cause is yet unknown.
Assuntos
Benzaldeídos , Cálculos Renais , Adulto , Humanos , Inquéritos Nutricionais , Estudos Transversais , Cálculos Renais/epidemiologia , Cálculos Renais/etiologia , Aldeídos/efeitos adversosRESUMO
Our study intended to investigate five cytokine gene single nucleotide polymorphisms (SNPs) and their associations with prostate cancer risk. Genotypes of five cytokine gene SNPs were detected by MassARRAY for blood samples from a group of patients with prostate cancer (n = 90) and a control group (n = 140) in central China. The differences in tumor clinical stages, Gleason scores, and PSA values in patients with prostate cancer were also investigated. The frequencies of the five cytokine gene SNPs (L-1ß rs16944, IL-4 rs2070874, IL-4rs2227284, IL-16 rs7175701, and IL-16 rs11556218) genotypes were not found to be significantly mutated in prostate cancer patients compared with the control group. In addition, for five cytokine gene SNPs genotypic comparisons, patients with different Gleason scores, clinical stages, and PSA values were grouped into two subgroups. There was also no statistically significant association in all these subgroups. Our study suggests that cytokine gene polymorphisms may not be a risk factor for prostate cancer in a central Chinese population. Nevertheless, more large-scale studies on the Chinese population are necessary to examine our conclusions. The discovery of cytokine gene polymorphisms related to prostate cancer could update our understanding of the etiology and improve our knowledge of the early detection, diagnosis, and treatment of prostate cancer.
Assuntos
Predisposição Genética para Doença , Neoplasias da Próstata , Estudos de Casos e Controles , Humanos , Interleucina-16 , Masculino , Polimorfismo de Nucleotídeo Único , Antígeno Prostático EspecíficoRESUMO
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a very common urological disorder and has been gradually regarded as an immune-mediated disease. Multiple studies have indicated that the gut microflora plays a pivotal part in immune homeostasis and autoimmune disorder development. However, whether the gut microflora affects the CP/CPPS, and the underlying mechanism behind them remain unclear. Here, we built an experimental autoimmune prostatitis (EAP) mouse model by subcutaneous immunity and identified that its Th17/Treg frequency was imbalanced. Using fecal 16s rRNA sequencing and untargeted/targeted metabolomics, we discovered that the diversity and relative abundance of gut microflora and their metabolites were obviously different between the control and the EAP group. Propionic acid, a kind of short-chain fatty acid (SCFA), was decreased in EAP mice compared to that in controls, and supplementation with propionic acid reduced susceptibility to EAP and corrected the imbalance of Th17/Treg cell differentiation in vivo and in vitro. Furthermore, SCFA receptor G-protein-coupled receptor 43 and intracellular histone deacetylase 6 regulated by propionic acid in Th17 and Treg cells were also evaluated. Lastly, we observed that fecal transplantation from EAP mice induced the decrease of Treg cell frequency in recipient mice. Our data showed that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP via the decrease of metabolite propionic acid and provided valuable immunological groundwork for further intervention in immunologic derangement of CP/CPPS by targeting propionic acid.