Propionic acid protects ZnONPs-induced lung injury

Inhalation zinc oxide fumes results in the development of the clinical syndrome known as metal fume fever, the severe cases of which may develop to diffuse alveolar damage. However, the link between inhaled zinc oxide at nano-size (zinc oxide nanoparticles, ZnONPs)-induced acute lung injury (ALI) and intestinal microbiota remains largely unknown.To investigate the role and mechanism of intestinal microbiota and its metabolites short chain fatty acids (SCFAs) in the pathology of ZnONPs-induced ALI and the therapeutic potential of modulating intestinal microbiota in ZnONPs-induced ALI.Intratracheal instillation of ZnONPs was used to establish a ALI mice model; antibiotic cocktail treatment (ABX) and fecal microbiota transplantation (FMT) were used to modulate intestinal microbiota; 16S rRNA sequencing and LC-MS/MS were applied to evaluate the change of intestinal microbiota and SCFAs.Intratracheal instillation of ZnONPs caused macrophage-mediated ALI in mice. ABX-mediated depletion of intestinal microbiota aggravated ZnONPs-induced ALI; in contrast, FMT-mediated restoration of intestinal microbiota exerted opposite effects; ZnONPs inhalation resulted in the perturbation of intestinal flora and consequently the decrease of SCFAs (especial acetate acid or propionate acid) in the plasma; supplementation of sodium propionate, but not sodium acetate, remarkably ameliorated ZnONPs-induced ALI; GPR43 was the major receptor of propionate acid in RAW 264.7 macrophage cell lines. We illuminates a novel gut-lung axis mechanism that intestinal microbiota and its-derived metabolite propionate acid plays protective role against ZnONPs-induced ALI through repressing macrophage-mediated inflammation and oxidative stress via GPR43 receptor. FMT and supplementation of propionate acid are potential remedy strategies吸入氧化锌烟尘可引发被称为金属烟尘热（metal fume fever）的临床综合征，重症病例可进展为弥漫性肺泡损伤。然而，纳米级吸入氧化锌（氧化锌纳米颗粒，zinc oxide nanoparticles, ZnONPs）诱发的急性肺损伤（acute lung injury, ALI）与肠道菌群之间的关联仍尚未明确。为探讨肠道菌群及其代谢产物短链脂肪酸（short chain fatty acids, SCFAs）在ZnONPs诱发ALI的病理机制中的作用，以及调控肠道菌群在ZnONPs诱发ALI中的治疗潜力，本研究采用气管内滴注ZnONPs构建ALI小鼠模型；通过抗生素联合处理（antibiotic cocktail treatment, ABX）与粪便菌群移植（fecal microbiota transplantation, FMT）调控肠道菌群；运用16S rRNA测序与液相色谱-串联质谱（LC-MS/MS）评估肠道菌群与SCFAs的变化。气管内滴注ZnONPs可诱发小鼠巨噬细胞介导的ALI。ABX介导的肠道菌群耗竭会加重ZnONPs诱发的ALI；与之相反，FMT介导的肠道菌群重建则发挥相反的保护作用；吸入ZnONPs会导致肠道菌群紊乱，进而使血浆中SCFAs（尤其是乙酸与丙酸）水平降低；补充丙酸钠而非乙酸钠可显著改善ZnONPs诱发的ALI；GPR43是RAW 264.7巨噬细胞系中丙酸的主要受体。本研究阐明了一种全新的肠-肺轴机制：肠道菌群及其代谢产物丙酸可通过GPR43受体抑制巨噬细胞介导的炎症与氧化应激，从而对ZnONPs诱发的ALI发挥保护作用。粪便菌群移植与丙酸补充均为潜在的治疗策略。