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Background Mucosal healing impairment represents a core pathological feature of ulcerative colitis (UC), strongly linked to disease recurrence. Parasutterella has been consistently observed to be enriched in UC patients, yet its specific contribution to mucosal injury remained enigmatic.Methods This study aims to investigate whether Parasutterella impairs mucosal healing by inducing HMGCS2 succinylation and inhibiting mitochondrial ketogenesis. This study integrates molecular, cellular, and animal approaches. Clinical samples from UC patients will be analyzed to assess correlations between Parasutterella abundance, HMGCS2 succinylation, and mucosal healing scores. Untargeted metabolomics was performed on intestinal tissues from Parasutterella-colonized colitis mice to identify alterations in ketone body and succinate metabolism. Protein modification proteomics was conducted on intestinal tissues from germ-free mice colonized with Parasutterella to profile global succinylation changes. Intestinal epithelial cell-specific Hmgcs2 knockout mice were generated and subjected to Parasutterella colonization and DSSinduced colitis. Mechanistically, CRISPR-Cas9 was used to generate HMGCS2 lysine mutants to determine the effects of succinylation on enzymatic activity, with SIRT5 evaluated as the primary desuccinylase. Gnotobiotic mouse models with isotope tracing were employed to distinguish microbial from host metabolism.Results Clinical data are expected to show positive correlations between Parasutterella abundance, HMGCS2 succinylation, and impaired mucosal healing. Untargeted metabolomics revealed that Parasutterella colonization significantly reduced β-hydroxybutyrate (BHB) levels and elevated succinate levels in intestinal tissues from colitis mice colonized with Parasutterella (IDDF2026-ABS-0533 Figure 1). Protein modification proteomics demonstrated increased global succinylation in intestinal tissues following Parasutterella colonization. In intestinal epithelial cell-specific Hmgcs2 knockout mice, deletion of Hmgcs2 abrogated the exacerbating effects of Parasutterella on mucosal healing impairment in DSSinduced colitis. Mechanistically, succinylation of HMGCS2 reduced its enzymatic activity and ketone body production, effects reversed by SIRT5.Conclusions This study establishes that Parasutterella impairs UC mucosal healing by inducing HMGCS2 succinylation, which reduces enzyme stability and activity, thereby inhibiting mitochondrial ketogenesis (IDDF2026-ABS-0533 Figure 2). This mechanism offers promising novel therapeutic targets for UC based on gut microbiota modulation.Abstract IDDF2026-ABS-0533 Figure 1Abstract IDDF2026-ABS-0533 Figure 2