Mangiferin Protects Gut Barrier Integrity by Remodeling the Gut Microbiota–Sphingolipid–S1PR4 Signaling Axis

Abstract Mangiferin, a poorly absorbed C-glycosyl xanthone derived from mango, exerts intestinal protective effects through unclear mechanisms. This study investigated whether mangiferin mitigates high-fat diet (HFD)-induced gut barrier dysfunction via the gut microbiota–sphingolipid signaling axis. In HFD-fed mice, mangiferin ameliorated gut barrier injury by strengthening the mucus layer and upregulating tight junction proteins. Integrated multiomics revealed that mangiferin remodeled the gut microbiota and enriched fecal bioactive sphingolipids. Fecal microbiota transplantation from mangiferin-treated donors substantially recapitulated both the sphingolipidomic signature and the barrier-protective phenotype, suggesting a contributory role of gut microbiota. Furthermore, pharmacological inhibition of sphingosine-1-phosphate receptor 4 (S1PR4) with CYM50358 attenuated mangiferin-induced barrier protection, supporting the functional contribution of S1PR4 activation. These findings propose a novel gut microbiota–sphingolipid–S1PR4 signaling axis through which mangiferin protects the intestinal barrier, at least in part, providing a mechanistic framework for dietary xanthone-host communication and identifying S1PR4 as a promising target for developing gut barrier-protective nutraceuticals.