The etiology of Interstitial cystitis/bladder pain syndrome (IC/BPS) remains largely unknown, though recent evidence implicates the gut microbiota (GM) and immune microenvironment. We hypothesize that specific immune cells act as crucial mediators in the pathway from the gut microbiota to IC/BPS. This original study aims to investigate the causal relationships between GM, immune cells, and IC/BPS, and to quantify the mediating role of immune cells within the gut-bladder axis.

We conducted a two-sample Mendelian randomization (MR) study utilizing publicly available genome-wide association study (GWAS) data. Genetic instruments were robustly selected for 473 GM taxa and 731 immune cell traits. The inverse variance weighting (IVW) method was employed as the primary statistical approach to assess causality. Furthermore, mediation analyses were executed to quantify the proportion of the GM's effect on IC/BPS that is mediated through specific immune cell traits. Sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy.

The MR analysis identified significant causal relationships linking 14 GM subtypes and 32 immune cell traits to the risk of IC/BPS. For instance, genetically predicted Bacteroides faecis was associated with an elevated risk of IC/BPS (OR = 1.801, 95% CI: 1.022 - 3.173) , whereas Pandoraea demonstrated a protective effect (OR = 0.056, 95% CI: 0.004 - 0.646). Reverse MR analysis did not support a causal effect of IC/BPS on either GM or immune cells. Crucially, the mediation analysis revealed that 16 immune cell traits could mediate the effects of 6 GM subtypes on IC/BPS. Notably, CD25 on activated CD4 regulatory T cells exhibited the highest mediating role, accounting for 19.39% of the effect of Bacteroides faecis on IC/BPS.

These findings provide robust genetic evidence for a causal network involving the gut microbiota, systemic immune cells, and IC/BPS. The identification of specific immune traits, particularly CD25+ regulatory T cells, as key mediators highlights the intricate crosstalk within the gut-immune-bladder axis. The results suggest that GM dysbiosis can significantly influence IC/BPS pathogenesis by reprogramming the immune microenvironment.

This study systematically establishes a causal link between gut microbiota, immune cell modulation, and the development of IC/BPS. By identifying specific immune mediators in the gut-bladder pathway, these findings provide valuable insights into novel, microbiota-targeted therapeutic strategies for managing IC/BPS.

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Continence 19S (2026) 102755
DOI: 10.1016/j.cont.2026.102755