High-Fat Diet Enhances Stemness and Compromises Intestinal Permeability in A Translational Canine Intestinal Organoid Model

Abstract

Abstract Background: Emerging evidence underscores the responsiveness of the mammalian intestine to dietary cues, notably through the involvement of LGR5+ intestinal stem cells in orchestrating responses to diet-driven signals. However, the effects of high-fat diet (HFD) on these cellular dynamics and their impact on gut integrity remain insufficiently understood. Our study aims to assess the multifaceted interactions between lipotoxicity, stemness, and the intestinal epithelial barrier using a canine colonoid model. Canine models, due to their relevance in simulating human intestinal diseases, offer a unique platform to explore the molecular mechanisms underlying HFD derived intestinal dysfunction. Results: Canine colonoids were subjected to palmitic acid (PA) exposure, a surrogate for the effects of HFD. This intervention revealed a remarkable augmentation of stemness characteristics. Furthermore, we observed a parallel reduction in transepithelial electrical resistance (TEER), indicating altered epithelium barrier integrity. While E-cadherin exhibited consistency, ZO-1 displayed a noteworthy reduction in fluorescence intensity within the PA-exposed group. Conclusions: By employing canine intestinal organoid systems, we provide compelling insights into the impact of lipotoxicity on intestinal physiology. These findings underscore the importance of considering both stemness and epithelial integrity in comprehending the repercussions of HFDs on intestinal health. Our study contributes to a deeper understanding of the consequences of HFD on intestinal homeostasis, utilizing valuable translational in vitro models derived from dogs.