Chenodeoxycholic acid redirects the bile acid synthetic pathway to limit pro-inflammatory neutrophil infiltration and alleviate colitis.

Patients with inflammatory bowel disease (IBD) exhibit a dysregulated bile acid pool, characterized by increased primary and decreased secondary bile acids, largely due to gut microbiota dysfunction. However, the impact of colitis on hepatic bile acid synthesis remains poorly understood. In this study, analyses of public datasets, in-house patient samples, and an animal model revealed that colitis enhances flux through the classical bile acid synthesis pathway while suppressing the alternative pathway. Oral administration of chenodeoxycholic acid (CDCA) redirected bile acid synthesis toward the alternative pathway and alleviated colitis in mice. Single-cell RNA sequencing and adoptive transfer experiments demonstrated that CDCA administration reduced pro-inflammatory neutrophil accumulation in the colon by downregulating epithelial-derived CXCL2, a finding validated by in vitro assays and a transgenic mouse model. Mechanistic studies further demonstrated that lithocholic acid, a CDCA metabolite in the gut, activates colonic epithelial vitamin D receptor, thereby suppressing CXCL2 via NF-κB inhibition. Clinical sample analyses supported these findings, showing that a higher cholic acid to CDCA ratio positively correlates with neutrophil counts and CXCL2 levels in IBD patients. Together, these findings suggest a critical role of hepatic bile acid synthesis pathways in IBD pathogenesis and highlight CDCA as a potential therapeutic candidate.