Candidalysin drives pyroptosis of intestinal epithelium to exacerbate IBS by suppressing HDAC2-mediated deacetylation of GSDMD-K194.

Abstract

Introduction: Gut dysbiosis contributes to irritable bowel syndrome (IBS) pathogenesis and fungi exert independent effects on IBS patients, independent of bacterial influence. IBS patients exhibit elevated fecal Candida levels but the specific role of Candida in IBS remains unclear.

Objectives: This study investigated the contributions of Candida albicans (C. albicans) and its toxin candidalysin to IBS pathophysiology and elucidated the underlying mechanisms.

Methods: Fecal C. albicans in healthy controls and diarrhea-predominant IBS (IBS-D) patients were detected. Restraint stress murine models were gavaged with C. albicans, C. albicans mutant strains lacking candidalysin (ece1Δ/Δ) or PBS. RNA-seq of intestinal organoids treated with candidalysin and pyroptosis proteins were detected. Gsdmd^-/- mice were generated to evaluate the relationship of candidalysin and pyroptosis. Mass spectrometry, co-immunoprecipitation, and acetylome profiling were employed to characterize GSDMD post-translational modifications.

Results: C. albicans abundance was significantly higher in IBS-D patients than controls (31% vs 13%). C. albicans exacerbated barrier disruption, visceral sensitization and inflammation in restraint stress mice by candidalysin. While these pathophysiologic abnormalities were attenuated in Gsdmd^-/- mice. Mechanistically, candidalysin downregulated histone deacetylase 2 (HDAC2) in intestinal epithelial cells, which directly interacted with GSDMD. Acetylome profiling identified GSDMD-K194 as a critical acetylation site. Pharmacological HDAC2 inhibition exacerbated GSDMD-mediated pyroptosis, which was abolished by K194 mutagenesis.

Conclusion: Candidalysin exacerbates IBS by inducing pyroptosis in intestinal epithelial cells in vivo, specifically through the inhibition of HDAC2-mediated deacetylation of GSDMD-K194. These findings identify fungal toxins and HDAC2/GSDMD-mediated pyroptosis as pathophysiological mediators in IBS and propose mycobiota-directed therapeutic strategies.