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Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic condition with severe pelvic pain and urinary symptoms significantly impairing quality of life. This study investigated the clinical relevance of the metabotropic glutamate receptor (mGluR) family in IC/BPS. Bladder biopsy samples were taken from 61 patients, including 42 Hunner-type IC, 11 non-Hunner type IC, and 8 controls without IC. Gene expression analysis revealed that mGluR2, mGluR3, and mGluR5 were significantly elevated in patients with IC/BPS compared to controls. Among these, mGluR5 showed the strongest association with pain severity, fibrosis, and lymphoplasmacytic infiltration. Patients with Hunner-type IC also exhibited increased expression of p65 and interleukin-1β, suggesting activation of inflammatory response modulation in IC/BPS. These findings suggest that mGluR5 may contribute to pain through immune response modulation in IC/BPS. Targeting mGluR5 could represent a promising therapeutic strategy to alleviate symptoms and improve patient quality of life.

Interstitial cystitis (IC) was still a disease with the exclusive diagnosis and lacked an effective gold standard. It was of great significance to find diagnostic markers for IC. Our study was aimed to screen characteristic genes via machine learning algorithms, characterize the immune landscape of IC, and show correlations between characteristic genes and immune cell subtypes. RNA sequencing data sets on IC were downloaded from Gene Expression Omnibus (GEO) database, including GSE57560, GSE11783 and GSE621, whose corresponding platforms were GPL16699, GPL570 and GPL262 respectively. Three machine learning algorithms were applied for identification of characteristic gene for IC. Single sample Gene Set Enrichment Analysis (ssGSEA) was applied to figure out the immune cell infiltration (ICI) of IC and normal tissue samples. Correlation analysis was performed via Spearman test. Receiver operator characteristic curve (ROC) was used to evaluate diagnostic efficacy of key genes. CCL18, MMP10 and WIF1 were identified as characteristic gene via machine learning algorithms. MMP10 and CCL18 were with higher expression in IC tissues compared with normal bladder tissues, while WIF1 had lower expressionin IC tissues (P < 0.05). These three genes had good diagnostic efficacy for IC. Compared with normal bladder tissues, 18 immune cell subtypes were up-regulated in interstitial cystitis tissues (P < 0.05). MMP10 and CCL18 were positively correlated to immune scores in IC, while WIF1 was negatively correlated to immune scores (P > 0.05). We screened the feature genes, CCL18, MMP10 and WIF1, among the differentially expressed genes (DEGs) by three different machine learning algorithms. They showed good diagnostic performance in both training and testing cohorts and were potential diagnostic markers for IC. We paint the immune landscape of IC. In IC tissue, immune cell subtypes infiltrated extensively. Most immune cell subtypes were up-regulated in IC tissue, including mast cells, activated CD4 T cells, and regulatory T cells that suppress immune responses. MMP10 and CCL18 had positive correlation to ICI, while WIF was negatively correlated with ICI. MMP10 and CCL18 may be the driving factors of immune response or their expression levels may be increased by immune response. The effect of characteristic genes of IC on immune cell subtypes still needed to be further explored.

This study aimed to elucidate distinct cellular and immunological characteristics associated with chronic inflammatory conditions of the urinary bladder, including Hunner-type interstitial cystitis (HIC), bacillus Calmette–Guérin (BCG)-related cystitis, follicular cystitis (FC), and chronic bacterial cystitis (CBC). Transcriptomic analyses using next-generation RNA sequencing, along with quantitative polymerase chain reaction, were performed on mucosal bladder biopsies to assess the whole transcriptional and immune-response profiles. Furthermore, digital immunohistochemical quantification evaluated urothelial denudation and the densities of infiltrating immune cells, including T-lymphocytes, B-lymphocytes, mast cells, and plasma cells. HIC specimens exhibited a markedly distinct transcriptional profile, with 3,566 differentially expressed genes and enrichment of 116 biological processes particularly associated with microbial response and heightened autoimmunity with Th1/Th17 axis polarization. Histologically, HIC bladders demonstrated significant epithelial denudation, elevated IL-17-positive cell density, and increased plasma cell ratios compared to other cystitis types. No significant differences were observed in overall lymphoplasmacytic or mast cell densities, nor in B cell ratios among the groups. These findings underscore a unique immunopathological signature in HIC, characterized by plasma cell predominance within a Th1/17-polarized immune environment and epithelial denudation, offering new insights into its pathogenesis and therapeutic targeting.

Interstitial cystitis/painful bladder syndrome (IC) is a chronic pelvic pain condition which has high comorbidity with other nociplastic, or unexplained, pain disorders [e.g. fibromyalgia (FM), irritable bowel syndrome (IBS), and myalgic encephalomyelitis/chronic fatigue (ME/CFS)] and some psychiatric conditions [major depressive disorder (MDD) and panic disorder (PD)]. Here we investigated the shared familiality of IC and these other nociplastic and psychiatric conditions. Subjects were identified in the Utah Population Database, which links genealogy data back to the 1800s to medical record diagnosis billing code data back to 1995. We computed the relative risk of each of these disorders among first (FDR), second (SDR), and third-degree relatives (TDR) of six proband groups: IC, FM, IBS, ME/CFS, PD, and MDD. Given the known familial aggregation of each of these disorders, we conducted our analyses to test for heritable interrelationships using proband subgroups whose members did not have the diagnosis assessed in their relatives. We observed strong evidence for heritable interrelationships among all six disorders. Most analyses indicated significantly increased risk for each of the six disorders in FDR, SDR, and TDR of all or most proband groups. Out of 30 possible bidirectional disorder interrelationships, 26 were significant among FDR, 23 were significant among SDR, and 7 were significant among TDR. Clustering was observed in both close and distant relatives. Our results support a common, heritable component to IC and other nociplastic and psychiatric conditions.

Bladder Pain Syndrome/Interstitial Cystitis encompasses Hunner lesion and non-Hunner lesion (NHIC) subtypes, characterized by chronic pelvic pain and urinary symptoms. The two subtypes show distinct clinical presentations, yet their underlying mechanisms remain poorly understood. Advancements in biological detection technologies allow for deeper insights into disease pathogenesis through integrated multi-omics approaches. This study aims to delineate the differences between NHIC and HIC using multi-omics analysis to uncover distinct microbiome, metabolome, and transcriptome profiles, thereby elucidating their unique pathogenic mechanisms. We conducted a comprehensive analysis involving bladder tissue samples and urine specimens from NHIC and HIC patients. Genomic, metabolomic, and transcriptomic data were obtained using high-throughput sequencing techniques. Differentially expressed genes, metabolites, and microbial communities were identified and subjected to pathway enrichment analysis to explore their associations with disease subtypes. Our findings revealed significant differences in the urinary microbiota, with NHIC showing a predominance of Lactobacillus and Enterococcus, while HIC exhibited higher levels of Pseudomonas and Gardnerella. Metabolomic analysis identified altered pathways, such as arginine and proline metabolism in NHIC and steroid hormone biosynthesis in HIC. Transcriptomic profiling highlighted upregulation of immune response genes in HIC, particularly those involved in mast cell degranulation and viral infection pathways. In contrast, NHIC was associated with increased expression of metabolic and energy-related pathways. This multi-omics analysis revealed distinct pathogenic signatures between NHIC and HIC, indicating that HIC may be driven by chronic immune dysregulation and past infections, while NHIC is more closely associated with metabolic disturbances. These insights suggest potential avenues for tailored therapeutic interventions based on the molecular characteristics of each subtype. Further research is warranted to confirm these findings and explore their clinical implications.

Obstructive sleep apnea (OSA) and interstitial cystitis/bladder pain syndrome (IC/BPS) are chronic conditions that significantly impact patients' quality of life. OSA involves recurrent upper airway obstruction during sleep, causing hypoxia and fragmented sleep linked to cardiovascular and metabolic issues. IC/BPS is defined by chronic pelvic pain and urinary symptoms; its pathophysiology is complex and poorly understood. The overlap in the prevalence of OSA and IC/BPS suggests a possible shared pathophysiological link. This study aimed to identify shared molecular mechanisms and diagnostic biomarkers between OSA and IC/BPS through integrated bioinformatics approaches. This study used bioinformatics and machine learning to analyze transcriptomic data for OSA and IC/BPS, identifying differential expressed genes (DEGs) and enriched pathways from Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) constructed gene co-expression networks and identified hub genes, while immune infiltration analysis characterized the immune microenvironment. Four machine learning algorithms developed diagnostic models and also identified key markers. A total of 2,233 DEGs were identified in OSA and 1,183 in IC/BPS, with 93 overlapping genes. Among these, machine learning algorithms identified DUSP9 as the single common gene linking both disorders, forming two-gene signatures for each condition (DUSP9/CCDC68 for OSA and DUSP9/KPNA2 for IC/BPS). Key pathways for OSA included RIG-I-like and NOD-like receptor signaling. In contrast, IC/BPS was linked to cytokine interactions and JAK-STAT signaling. Immune infiltration analysis showed that DUSP9 expression was correlated with CD56dim natural killer cells in OSA and with activated CD4 T cells in IC/BPS, further supporting its role in the immune response associated with these disorders. This study established DUSP9 as a pivotal shared biomarker and central regulator linking OSA and IC/BPS through integrated bioinformatics analysis.

Interstitial cystitis (IC) is an aseptic chronic bladder inflammation of unknown etiology and poorly understood pathophysiology with symptoms resembling bacterial cystitis (BC). There is limited data about the contribution of regulatory microRNAs (miRNAs) in IC. The study aimed to identify differences in miRNA expression between mouse models of IC and BC to find potential miRNAs that would distinguish between the two types of cystitis and to evaluate the use of the mouse model of IC as a tool to study the pathogenic mechanisms of IC in humans. Two mouse models were utilized: cyclophosphamide was used for induction of chronic aseptic cystitis, and uropathogenic E.coli for induction of acute bacterial cystitis. Potential regulatory miRNAs were selected based on publicly available human IC datasets and validated in mice. Quantitative PCR and RNA isolated from formalin-fixed, paraffin-embedded mouse bladder tissue were used. An enrichment analysis of the target mRNAs of the validated miRNAs was performed to suggest the differences in the possible mechanisms of inflammation between the IC and BC. We observed differential expression of 20 of the 33 selected miRNAs in IC and BC compared to the control group, with 11 miRNAs showing the same trend of expression between mouse and human IC. There are 8 common reporter-assay (RA) validated targets (performed by others) of these miRNAs in mouse and human. Histopathological analysis of mouse IC and BC urinary bladders, miRNA expression analysis, and expression of their validated targets revealed significant differences between the urinary bladders of BC and IC mouse models. We identified as a possible marker of discrimination between two types of cystitis and its target gene, nuclear factor-κB (NF-κB) suppressing factor ( ). Our results show that miRNA expression and its RA-validated targets, and enriched signaling pathways, differ between the two types of cystitis and might depend on the type of bladder inflammation. The mouse model of IC has some similarities with human IC, confirming that it is a useful tool to identify novel potentially discriminatory biomarkers between BC and IC, such as , and also potential therapeutic targets for IC (e.g., and NF-κB).

Interstitial cystitis/bladder pain syndrome (IC/BPS), particularly the Hunner-type subtype (HIC), is a chronic inflammatory bladder disorder characterized by persistent inflammation and macrophage-driven immunometabolic dysregulation. CHI3L1, a secreted glycoprotein implicated in inflammation and tissue remodeling, is significantly upregulated in HIC and correlates with disease severity, but its mechanistic role in macrophage-mediated persistent inflammatory events (PIEs) remains poorly defined. This study integrated multi-omics analyses, including bioinformatics of IC/BPS transcriptomic datasets, a cyclophosphamide-induced IC/BPS mouse model for validation, and functional assays involving CHI3L1 overexpression in macrophages. Transcriptomic, metabolomic, and molecular biology techniques were employed to evaluate metabolic shifts, inflammatory pathways, and transcription factor correlations. CHI3L1 expression was significantly upregulated in HIC patients, especially those with reduced bladder capacity, and correlated with inflammatory markers (IL-6, TNFα). In macrophages, CHI3L1 overexpression drove pro-inflammatory activation via NF-κB and TNF pathways, promoted glycolysis, and suppressed mitochondrial oxidative phosphorylation (OXPHOS) and aspartate metabolism. Critically, CHI3L1 expression strongly correlated with the transcription factor MYC rather than STAT3 under inflammatory conditions, reinforcing M1 polarization. CHI3L1 exacerbates PIEs in HIC by reprogramming macrophage metabolism toward glycolysis and sustaining inflammation via MYC signaling. These findings establish CHI3L1 as a central regulator of chronic inflammation in HIC and highlight its potential as a therapeutic target for disrupting pathological immune-metabolic cycles.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a complex urological disorder characterized by chronic pelvic pain and urinary dysfunction, with limited diagnostic biomarkers and therapeutic options. Emerging evidence implicates immune microenvironment dysregulation in its pathogenesis, yet the identification of key driver genes and cross-omics integration remains underexplored. This study integrated three transcriptomic datasets to identify immune-related gene modules via weighted gene co-expression network analysis (WGCNA). A diagnostic model was constructed using 113 machine learning algorithms. Immune cell infiltration was assessed via CIBERSORT, and single cell sequencing elucidated cellular heterogeneity. Drug candidates were predicted using DSigdb and validated through molecular docking and dynamics simulations. A cyclophosphamide (CYP)/lipopolysaccharide (LPS)-induced IC/BPS murine model was established to evaluate therapeutic efficacy of prioritized compounds (Resiniferatoxin and Acetohexamide) via histopathology, ELISA, and immunohistochemistry. Eight core immune-related genes were identified. The machine learning model achieved AUC >0.9 in both training and validation cohorts. Single-cell analysis revealed IFI27 overexpression in epithelial and immune cells, correlating positively with M1 macrophages and activated CD4+ T cells (p<0.05). Molecular docking demonstrated strong binding affinity between IFI27 and Acetohexamide (-19.91 ± 0.98 kcal/mol) or Resiniferatoxin (-32.98 ± 1.74 kcal/mol), with dynamics simulations confirming structural stability. , both compounds significantly reduced bladder inflammation (p<0.05), with Acetohexamide showing superior efficacy in downregulating IFI27 expression and systemic pro-inflammatory cytokines. This multi-omics study deciphered immune dysregulation in IC/BPS and established a robust diagnostic framework. The validation of IFI27-targeting compounds in alleviating inflammation highlights translational potential for repurposed therapeutics. Our findings advance precision immunotherapy strategies for IC/BPS.

Evidence from previous studies have demonstrated that gut microbiota are closely associated with occurrence of interstitial cystitis/bladder pain syndrome (IC/BPS), yet the causal link between the two is not well known. In this study, we performed a two-sample Mendelian randomization (MR) analysis to determine the possible causal association between gut microbiota with IC/BPS. Gut microbiota summary level data were derived from the genome-wide association study (GWAS) conducted by MiBioGen and the IC/BPS GWAS summary level data were obtained from the GWAS Catalog. Next, we performed an MR study to investigate the causal link between gut microbiota and IC/BPS. The primary method for causal analysis was the inverse variance weighted (IVW), and the MR results were validated through multiple sensitivity analyses. A positive association was found between IC/BPS and eight gut microbial taxa, including genus Bacteroides , genus Haemophilus , genus Veillonella , genus Coprococcus1 , genus Butyricimonas , family Bacteroidaceae , family Christensenellaceae , and order Lactobacillales. Sensitivity analysis revealed lack of significant pleiotropy or heterogeneity in the obtained results. This MR analysis reveals that a causal association exists between some gut microbiota with IC/BPS. This finding may is expected to guide future research and development of IC/BPS preventions and treatments based on the bladder-gut axis. However, given the clinical complexity and diagnostic challenges of IC/BPS, along with the limitations of using large-scale GWAS summary data for analysis, our MR results require further validation through additional research.