Toll-like receptor 2 impacts small intestinal villus capillarization through epithelial dual oxidase 2

The microbiota shapes postnatal gut development and physiology. In the small intestine, epithelial-to-endothelial crosstalk governs the microbiota-induced remodeling of villus capillary networks essential for nutrient transport. The intestinal epithelial enzyme dual oxidase-2 (DUOX2), an established regulator of the microbiome-host interaction, exerts microbicidal functions through the generation of reactive oxygen species. However, its role in intestinal vascular development remains poorly understood. Here, we demonstrate a Toll-like receptor-2 (TLR2)-dependent regulatory pathway controlling DUOX2 expression that influences villus vascularization in the small intestine. Mice globally lacking DUOX2 activity exhibited a notable reduction in vascularization in the small intestine, accompanied by alterations in gut microbial community structure. Conversely, mice with an intestinal epithelial-specific deficiency of TLR2 displayed an increase in villus vascularization along with elevated expression levels of DUOX2. Notably, DUOX2 expression was strongly upregulated in intestinal epithelial biopsies from patients with Crohn’s disease. Similarly, inflammatory conditions induced by dextran sulfate sodium (DSS) treatment in mice resulted in increased epithelial Duox2 expression accompanied by enhanced villus vascularization. Together, our findings suggest a microbiota–TLR2–DUOX2 signaling axis in intestinal epithelial cells that promotes villus vascularization. This mechanism links microbial sensing in the intestinal epithelium to structural remodeling of the villus microvasculature during homeostasis and inflammation. • Epithelial TLR2 regulates DUOX2 expression and mucosal vascularization. • Intestinal epithelial Duox2-deficiency is linked to reduced blood capillaries in the small intestinal mucosa. • Acute intestinal inflammation is associated with increased Duox2 expression and elevated small intestinal villus vascularization.