Lung microbiota metabolite L-malic acid attenuates the airway inflammation in asthma by inhibiting ferroptosis

Abstract

Inhaled environmental allergens, such as house dust mites (HDM), have been shown to induce an inflammatory reaction, tissue injury, and increased airway sensitivity in the lungs, ultimately leading to the development of allergic asthma. The imbalance of respiratory microbiota and metabolites plays a crucial role in the progression of allergic asthma. However, there is limited knowledge available regarding the alterations in respiratory microbiota and metabolites and their impact on the host in the context of asthma. The aim of this study was to investigate the potential pathways involved in the development of asthma through the analysis of lung flora and metabolites. A mouse model of house dust mite (HDM)-induced asthma was established, and alveolar lavage samples were collected for microbiome 16S rRNA sequencing and untargeted metabolic analysis. Microbiological analyses indicated a significant alteration in the microbiota after 4 and 6 weeks of HDM nebulisation stimulation. This was characterized by a decrease in microbial diversity, as well as reductions in the relative proportion of Gallionella and Lactobacillus. Conversely, the abundance of Flavobacterium and Ralstonia increased in the HDM4W and HDM6W groups, respectively. Metabolomic analyses revealed seven distinct metabolites, among them L-malic acid, which were linked to signaling pathways in a mouse model of HDM-induced asthma. The correlation analysis demonstrated a positive association between L-malic acid and Rhodanobacter and Nocardioides. L-malic acid was discovered to be efficacious in reducing airway inflammation in mice with house dust mite-induced asthma. Further analysis revealed that this change was linked to lipid peroxidation and changes in ferroptosis markers, namely GPX4 and FTH. These findings suggest that L-malate inhibits ferroptosis. However, the introduction of ferroptosis inducers, such as Erastin, was observed to negate the beneficial effect of butyrate. In summary, this research implies that the respiratory microbiota metabolite L-malic acid lessens airway inflammation in asthma by inhibiting ferroptosis, offering a potential approach for managing asthma.