Nicotinamide adenine dinucleotide phosphate alleviates intestinal ischemia/reperfusion injury via Nrf2/HO-1 pathway

Intestinal ischemia-reperfusion (I/R) injury is a critical condition in the abdomen that has significant morbidity and fatality rates. Prior studies have noted the defensive role of the coenzymatic antioxidant reduced nicotinamide adenine dinucleotide phosphate (NADPH) in heart and brain I/R damage, yet its impact on intestinal I/R trauma required further exploration. Through the application of an in vitro oxygen-glucose deprivation-reoxygenation model and a mouse model of short-term intestinal I/R, this study clarified the defensive mechanisms of NADPH against intestinal I/R injury. We demonstrated that intraperitoneal NADPH administration markedly reduced interleukin-1β (IL-1β) levels and blocked NLRP3 inflammasome activation, hence reducing inflammation. The antioxidative properties of NADPH were established by the reduction of oxidative stress markers and enhancement of glutathione levels. Importantly, NADPH improved intestinal barrier integrity, indicated by an upregulation of zonula occludens-1 and the promotion of a balanced gut microbiome profile. Furthermore, we identified the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1(HO-1) pathway as a crucial conduit for NADPH's beneficence. When this pathway was inhibited by ML385, the favorable outcomes conferred by NADPH were significantly abrogated. These results demonstrate that NADPH functions as an antioxidative, anti-inflammatory, microbiota-balancing, barrier-strengthening, and anti-inflammatory agent against intestinal I/R damage through activation of the Nrf2/HO-1 signaling pathway.