OC 35.4 - The role of DUOX2 and intestinal epithelial TLR2 in villus vascularization

Background: The commensal microbiota influences postnatal gut development and physiology. This microbial ecosystem significantly impacts the remodeling of capillary networks in small intestinal villus structures, a process crucial for nutrient uptake and facilitated through an epithelial-to-endothelial crosstalk. Exerting microbicidal functions, the dual oxidase-2 (DUOX2) serves as a key regulator of microbiome-host interaction. Toll-like receptor-2 (TLR2), influencing epithelial cell renewal and angiogenesis, also mediates microbiota-host interplay. Understanding these interactions provides insights into the intricate mechanisms governing gut morphogenesis and vascular network regulation.

Aims: This study was aimed to investigate the role of DUOX2 and small intestinal epithelial TLR2 on villus vascularization.

Methods: This study investigated two mouse models: one with a global Duox2-deficiency and another with an intestinal epithelial-specific Tlr2-deficiency. We evaluated villus vessel density through immunofluorescence staining of vascular markers in the mid small intestine. Additionally, quantitative real-time PCR (qRT-PCR) analyses were employed to measure the expression of vascular markers, Duox2, and its maturation factor Duoxa2. Microbial abundances in the small intestinal content were determined by 16S rDNA gene sequencing.

Results: Mice lacking DUOX2 activity exhibited a notable reduction in vascularization in the small intestine, accompanied by an altered microbial community and decreased Duox2 and Duoxa2 mRNA expression. In contrast, mice lacking TLR2 in the intestinal epithelium displayed increased villus vascularization along with elevated expression levels of the vascular marker platelet endothelial cell adhesion molecule-1 (Pecam1). Notably, this heightened vascularization was accompanied by an increase in Duox2 expression in the small intestine, suggesting a complex interplay between TLR2, DUOX2, and mucosal vascularization.

Conclusion(s): We propose that small intestinal epithelial DUOX2, a known regulator of microbial colonization, is involved in the epithelial-to-endothelial crosstalk, influencing villus vascularization in a microbiota-dependent fashion. Furthermore, we identified intestinal epithelial TLR2 as a potential modifier of small intestinal vascular remodeling.