Intestinal Microbiota-derived Propionic Acid Protects against Zinc Oxide Nanoparticle-induced Lung Injury

With the rapid development of nanotechnology, the risks of accidental and/or occupational exposure to zinc oxide nanoparticles (ZnONPs) are increasing. Inhalation of ZnONPs induces metal fume fever in humans and acute lung injury (ALI) in animal models. Although the intestinal microbiota is considered an important modulator of various diseases, the role and mechanism of intestinal microbiota in the pathology of ZnONP-induced ALI are unclear. Herein, we established an intratracheal instillation of a ZnONP-induced ALI mouse model and found that the inhalation of ZnONPs caused ALI along with a perturbation of intestinal flora. Antibiotic cocktail treatment-mediated depletion of intestinal microbiota aggravated ZnONP-induced ALI, and in contrast, fecal microbiota transplantation-mediated restoration of intestinal microbiota exerted the opposite effects. A decrease in short-chain fatty acids, the intestinal microbiota-derived metabolites in the plasma-in particular, acetic acid and propionic acid-occurred after exposure to ZnONPs. It is important to note that supplementation with propionic acid, but not acetic acid, ameliorated ZnONP-induced ALI. We also showed that the source of inflammatory cytokines might partially be the infiltration of macrophages. Supplementation with propionic acid was found to act on macrophages through the receptor GPR43, because knockdown of GPR43 sharply reversed the protective effects of propionic acid during the ZnONP-induced inflammatory response and oxidative stress in both primary alveolar macrophages and RAW 264.7 macrophage cell lines. Altogether, a novel gut-lung axis mechanism is revealed in which intestinal microbiota and their derived metabolite propionic acid play protective roles against ZnONP-induced ALI and suggest that fecal microbiota transplantation and supplementation with propionic acid are potential remedy strategies.