A Dual Action of Everolimus in Ulcerative Colitis: Blocking CLEC4E‐Driven Inflammation and Remodeling the Gut Microbiota‐Metabolite Axis

ABSTRACT Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options. This study investigated the therapeutic potential and mechanisms of Everolimus (Eve), a selective mTORC1 inhibitor, in experimental UC. Dextran sulfate sodium (DSS)‐induced colitis mice were used to assess Eve's effects on clinical outcomes, histopathology, inflammation, barrier integrity, and signaling pathways. CLEC4E agonist rescue and antibiotic‐mediated microbiota depletion clarified mechanistic roles. Fecal microbiota transplantation (FMT), 16S rRNA sequencing, and untargeted metabolomics evaluated microbiota‐ and metabolite‐driven effects. A Caco‐2/THP‐1 coculture model was applied to validate the functions of CLEC4E and propionic acid. Eve alleviated DSS‐induced colitis by reducing weight loss, colon shortening, tissue injury, cytokine overproduction, and barrier disruption. Mechanistically, Eve suppressed macrophage CLEC4E/Syk/NF‐κB signaling, while CLEC4E activation abolished these benefits. Eve reshaped gut microbiota, enriching Bacteroides_acidifaciens and elevating propionic acid. FMT confirmed transferable protection, whereas microbiota depletion negated Eve's efficacy. In vitro , propionic acid reproduced Eve's anti‐inflammatory and barrier‐protective effects. Eve protects against UC via a dual mechanism: inhibiting CLEC4E‐driven inflammation and remodeling the gut microbiota‐metabolite axis, notably propionic acid. These findings highlight Eve's therapeutic promise and potential for clinical translation in UC.