Quercetin Alleviates Intestinal and Liver Dysfunction Induced by Hypoxia in a Microphysiological System

Pathological hypoxia such as high-altitude exposure is harmful to the human body system and multiply organs. However, the systemic damage effects of hypoxia on the intestine and liver tissue remain unclear due to the limitations of traditional 2D cell cultures and animal models. Here, we establish a biomimetic gut-liver microphysiological system (GLMPS) as a human model of the gut–liver axis by coculturing human gut and liver cell lines interconnected under circulating fluid flow, for investigating the mechanisms of hypoxia-induced injury in the intestine and liver. By treatment with 1% O 2 for 48 h, cocultured Caco-2/HT29 gut cells and HepG2 hepatocyte-like cells exhibit increased intestinal barrier permeability, inflammatory responses, and cellular apoptosis. Transcriptomic analysis reveals similar activated pathways associated with endoplasmic reticulum stress and apoptosis in the gut and liver cells. Furthermore, quercetin effectively attenuates hypoxia-induced oxidative stress and apoptosis by enhancing autophagy. The GLMPS provides a biomimetic in vitro platform for studying hypoxia-related pathologies of gut and liver and facilitating the exploration of therapeutic targets.