Aucubin Restores Intestinal Mucosal Immunity and Barrier Integrity in Experimental Colitis via the Microbiota‐ SCFAs ‐ GPR41 / GPR43 Axis

ABSTRACT BackgroundInflammatory bowel disease (IBD) pathogenesis involves immune dysfunction and gut microbiota dysbiosis. Aucubin (AU), a naturally occurring iridoid glycoside known for its ability to alleviate inflammation and modulate intestinal flora, has not yet been investigated in the context of colitis MethodsThe effects of AU on DSS‐induced colitis in mice were evaluated, including disease severity, the balance of regulatory T cells (Tregs) and Th17 cells, intestinal barrier, inflammatory markers, fecal short‐chain fatty acids (SCFAs), and safety. The gut microbiota was assessed using 16S rRNA sequencing. GPR41/43 involvement was tested using receptor antagonists. The antibiotic‐treated mice and fecal transplantation were used to validate the microbiota‐dependent effects. ResultsAU treatment broadly ameliorated the DSS‐induced colitis and restored immune homeostasis by rebalancing Treg/Th17 cell populations. Meanwhile, intestinal barrier function was reinforced through upregulation of MUC2 and enhanced tight junction protein levels. Importantly, AU modulated gut microbiota composition, particularly enriching taxa associated with SCFA production, which indeed led to elevated fecal SCFA levels. Interestingly, the therapeutic effects of AU were absent in microbiota‐depleted mice but could be conferred to DSS‐induced recipients via fecal microbiota transplantation from AU‐treated donors. Furthermore, the protective benefits of AU were partially attenuated upon pharmacological inhibition of the SCFA receptors GPR41/GPR43. No treatment‐related toxicity was observed. ConclusionsAU safely alleviates colitis in mice by rebalancing the gut microbiota, activating SCFAs‐GPR41/GPR43 axis to support mucosal immune regulation and barrier repair.