Intestinal IL-25 prevents high-fat diet-induced obesity by modulating the cholesterol transporter NPC1L1 expression in the intestinal epithelial cells

The intestine is essential for digestion and nutrient absorption, and its altered function contributes to metabolic dysregulation and obesity-induced intestinal inflammation. Intestinal immune responses have been associated with the regulation of metabolic dysfunction during obesity. Given that the epithelial cell-derived cytokine IL-25 has been demonstrated to regulate metabolic disorders, we sought to examine the role of intestinal IL-25 in modulating a high-fat diet (HFD)-induced obesity. We found that mice on a high-fat diet exhibited decreased IL-25 expression in the small intestine. Intestinal IL-25 mRNA levels displayed an inverse association with plasma triglycerides, total cholesterol, glucose levels, and the expression of the cholesterol transporter Npc1l1 in the intestine. In HFD-induced obesity, transgenic mice overexpressing IL-25 in the intestinal epithelial cells demonstrated diminished mRNA expression of intestinal genes related to glucose, cholesterol, and fat absorption, along with chylomicron production, while also systemically decreasing plasma glucose, total cholesterol, and triglyceride levels, fat accumulation, and weight gain. In vitro, IL-25 treatment of human intestinal Caco-2 cells directly decreased cholesterol uptake and downregulated the expression of NPC1L1 and its transcriptional regulator, SREBP2. These findings highlight IL-25 as a potential modulator in the intestine that regulates intestinal cholesterol absorption and systemic metabolism in obesity.