cis-Aconitic Acid Derived from Clostridium sporogenes Attenuates Colitis via Targeting of Neutrophil TREM1

Inflammatory bowel disease (IBD) remains a significant therapeutic challenge, with current agents plagued by suboptimal efficacy and safety issues. While gut microbiota dysbiosis is increasingly acknowledged as a key driver of IBD pathogenesis, the identification of functionally characterized, translationally applicable microbial-metabolic axes remains an unmet need. Here, we demonstrate that Clostridium sporogenes (C. sporogenes) is significantly decreased in both IBD patients and experimental colitis models. Notably, supplementation with this commensal bacterium markedly alleviates disease severity in both DSS-induced chemical colitis and Il10-/- spontaneous genetic colitis, thereby validating its therapeutic potential. Critically, we reveal that the protective effects of C. sporogenes are mediated by its secretion of the bioactive metabolite cis-aconitic acid (CAA). We further establish that aconitate hydratase A (AcnA) is essential for CAA biosynthesis: an acnA-knockout C. sporogenes strain fails to produce CAA and loses therapeutic efficacy, whereas engineered Escherichia coli overexpressing acnA recapitulates both CAA production and colitis protection. Mechanistically, CAA directly binds to the neutrophil receptor triggering receptor expressed on myeloid cells-1 (TREM1), thereby inhibiting neutrophil release of pro-inflammatory mediators and NETosis—pathological processes central to IBD progression. Finally, the therapeutic effect of CAA is completely abolished in neutrophil-specific Trem1 knockout (Trem1NeutKO) mice, confirming TREM1 as the critical target of CAA. This work establishes the C. sporogenes-CAA-TREM1 pathway as a promising therapeutic strategy for IBD.