Dietary Fiber Improves High-Fat Diet-Induced Hyperglycemia by Modulating Intestinal ILC3-Mediated Immunity through the SCFA-FFAR2 Pathway

Abstract Dietary fiber intake is associated with improved glycemic control in high-fat diet-induced hyperglycemia, yet the immunological mechanisms linking gut microbiota-derived metabolites to host defense remain poorly defined. Here, we investigated whether dietary fiber ameliorates these metabolic disorders by modulating intestinal group 3 innate lymphoid cells (ILC3s) via short-chain fatty acids (SCFAs) and their receptor FFAR2. In a 12-week fiber-supplemented high-fat diet mouse model, fiber alleviated hyperglycemia, insulin resistance, and intestinal barrier dysfunction. Mechanistically, fiber increased cecal SCFAs (especially propionate), which activated colonic ILC3s in an FFAR2-dependent manner. FFAR2 triggered ERK and STAT3 phosphorylation and directly bound STAT3 to facilitate its phosphorylation, boosting IL-22 transcription. SCFA-activated ILC3s strengthened epithelial barrier integrity via elevated tight-junction proteins. Collectively, our findings demonstrate that dietary fiber restores gut barrier function through the SCFA-FFAR2-ERK/STAT3-IL-22 axis in ILC 3s, highlighting ILC3-expressed FFAR2 as a potential therapeutic target for high-fat diet-related metabolic disorders.