Modeling diabetic intestinal organoids: Aspects of rapid gut barrier disruption

Abstract

Increased intestinal permeability can occur in patients with diabetes mellitus. Previous studies demonstrated a correlation between impaired intestinal barrier function, elevated blood glucose levels, and diminished protective capacity of intestinal epithelial cells. However, few studies have explored gut-barrier disruption using three-dimensional (3D) in vitro models. In this study, we developed and optimized a 3D intestinal organoid model that mimics diabetic conditions by exposing the organoids to high glucose (HG) and palmitic acid (PA) levels. Human intestinal organoids derived from samples of both healthy individuals and patients with diabetes mellitus were analyzed. We evaluated the transcript levels of tight junction proteins and inflammation-related genes in ex vivo mouse intestinal organoids cultured under HG and PA conditions for 48 h. Human intestinal organoids from patients with diabetes mellitus exhibited reduced expression of genes associated with intestinal function and barrier integrity compared with those from healthy individuals. In mouse intestinal organoids, PA treatment induced cytotoxicity and significantly reduced the expression of intestinal stem cells and tight junction proteins, including zonula occludens-1 and occludin, compared with the control and HG-treated groups. Furthermore, treatment with HG and PA resulted in increased levels of inflammatory factors compared with those in the control group. Our in vitro model using 3D intestinal organoids can be used to investigate the impact of diabetic conditions and provide insights into gut barrier disruption.