Combined effects of ozone and heat on intestinal barrier integrity and epithelial renewal: mediating roles of gut microbiota and tryptophan metabolism

The increasing frequency of heat waves, combined with elevating ozone levels, constitutes an increasingly significant threat to public health. In this study, 8-week-old male C57BL/6J mice were subjected to individual or combined exposure of ozone (1 ppm) and heat (34°C) for 4 weeks. Both ozone and heat exposure disrupted intestinal barrier integrity and intestinal stem cell (ISC) function, with the most severe effects observed under combined exposure. Notably, co-exposure to ozone and heat resulted in the largest increase in Alistipes finegoldii (A. finegoldii) abundance, accompanied by enhanced tryptophan metabolism activity. Gut microbiota depletion and vertical microbiota transfer, together with intestinal content gavage, demonstrated the critical role of gut microbiota and their metabolites in mediating intestinal disruption. Colonization by A. finegoldii impaired ISC proliferation and differentiation, with elevated levels of indole and its derivatives, including indole-3-acetic acid (IAA) and tryptamine. Moreover, inhibition of aryl hydrocarbon receptor (AhR) signaling alleviated co-exposure-induced of intestinal injury. Mechanistically, AhR activation contributed to mitochondrial dysfunction. Interaction analysis indicated that ozone and heat primarily acted in an additive manner on gut integrity and microbiota dysbiosis. This study reveals that the A. finegoldii-tryptophan catabolite-AhR axis mediates the disruption of intestinal homeostasis induced by combined ozone and heat exposure.