Procyanidin B2 Promotes Intestinal Injury Repair and Attenuates Colitis-Associated Tumorigenesis <i>via</i> Suppression of Oxidative Stress in Mice

Abstract

<b><i>Aims:</i></b> Intact intestinal epithelium is essential to maintain normal intestinal physiological function. Irradiation-induced gastrointestinal syndrome or inflammatory bowel disease occurred when epithelial integrity was impaired. This study aims at exploring the mechanism of procyanidin B2 (PB2) administration to promote intestinal injury repair in mice. <b><i>Results:</i></b> PB2 treatment reduces reactive oxygen species (ROS) accumulation and protects the intestine damage from irradiation. Mechanistic studies reveal that PB2 could effectively slow down the degradation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and it significantly triggers Nrf2 into the nucleus, which leads to subsequent antioxidant enzyme expression. However, knockdown of Nrf2 attenuates PB2-induced protection in the intestine. More importantly, PB2 also promotes leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive intestinal stem cells (Lgr5⁺ ISCs) driven regeneration <i>via</i> enhancing Wnt/β-catenin signaling, which depends on, at least in part, activation of the Nrf2 signal. Evidence from an injury model of intestinal organoids is similar with <i>in vivo</i> results. Correspondingly, results from flow cytometric analysis and luciferase reporter assay reveal that PB2 also inhibits the level of ROS and promotes Lgr5 expression <i>in vitro</i>. Finally, PB2 alleviates the severity of experimental colitis and colitis-associated cancer in a long-term inflammatory model <i>via</i> inhibiting nuclear localization of p65. <b><i>Innovation:</i></b> This study, for the first time, reveals a role of PB2 for intestinal regeneration and repair after radiation or dextran sulfate sodium-induced injury in mice. <b><i>Conclusion:</i></b> Our results indicate that PB2 can repress oxidative stress <i>via</i> Nrf2/ARE signaling and then promote intestinal injury repair.