Intestinal Microbiota-derived Propionic Acid Protects Against Zinc Oxide Nanoparticles-induced Lung Injury

Am J Respir Cell Mol Biol. 2022 Sep 23. doi: 10.1165/rcmb.2021-0515OC. Online ahead of print.

ABSTRACT

With 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 intestinal microbiota are considered important modulators of various diseases, the role and mechanism of intestinal microbiota in the pathology of ZnONPs-induced ALI are unclear. Herein, we established an intratracheal instillation of ZnONPs-induced ALI mice model and found that ZnONPs inhalation caused ALI along with a perturbation of intestinal flora. Antibiotic cocktail treatment (ABX)-mediated depletion of intestinal microbiota aggravated ZnONPs-induced ALI, and in contrast, faecal microbiota transplantation (FMT)-mediated restoration of intestinal microbiota exerted the opposite effects. A decrease in the intestinal microbiota-derived metabolites short-chain fatty acids (SCFAs) in the plasma, in particular acetate acid and propionic acid, occurred after ZnONPs exposure. Importantly, supplementation with propionic acid, but not acetate acid, ameliorated ZnONPs-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 ZnONPs-induced inflammatory response and oxidative stress in both primary alveolar macrophages and RAW 264.7 macrophage cell lines. Altogether, we reveal a novel gut-lung axis mechanism in which intestinal microbiota and their derived metabolite propionic acid play protective roles against ZnONPs-induced ALI and suggest that FMT and supplementation with propionic acid are potential remedy strategies.

PMID:36150095 | DOI:10.1165/rcmb.2021-0515OC

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