Akkermansia muciniphila and Its Extracellular Vesicles Alleviate LPS-Induced Acute Respiratory Distress Syndrome in Rats: Integrated Microbiome, Metabolomic, and Transcriptomic Analyses.

Abstract

Purpose: Akkermansia muciniphila (AKK) and its extracellular vesicles (EVs) have immunomodulatory and metabolic effects, but their protective effects in acute respiratory distress syndrome (ARDS) remain unclear. This study compared live AKK with AKK-EVs and investigated their effects on LPS-induced ARDS using integrated microbiome, metabolome, and lung transcriptome analyses.

Methods: An ARDS rat model was established by intratracheal instillation of lipopolysaccharide (LPS). Rats were randomly allocated to the control, ARDS, AKK, and EVs groups. Following model establishment, AKK or AKK-EVs were administered orally once daily for 7 consecutive days. Lung injury was evaluated by body weight, hematoxylin and eosin staining, lung wet/dry weight ratio, and bronchoalveolar lavage fluid (BALF) analysis. Fecal 16S rRNA sequencing, untargeted metabolomics, lung transcriptomics, and integrated multi-omics analyses were performed. The pulmonary expression of Il17a, Cxcl1, Tnf, and Il6 was validated by qRT-PCR.

Results: Compared with the ARDS group, AKK and AKK-EVs attenuated weight loss and lung histopathological injury and reduced the lung wet/dry weight ratio, BALF total cell count and protein concentration, and BALF IL-17A and TNF-α levels. Both interventions partially remodeled the gut microbial community, including changes in Lachnospiraceae_NK4A136_group, norank_f_Muribaculaceae, Bacteroides, and Escherichia-Shigella. Metabolomic changes mainly involved lipid, amino acid, and bile acid metabolism. Lung transcriptomic analysis identified differential enrichment of the IL-17, TNF, chemokine, and cytokine-cytokine receptor interaction pathways. qRT-PCR further showed increased Il17a, Cxcl1, Tnf, and Il6 expression in the ARDS group and reduced expression following AKK or AKK-EVs intervention. Integrated analyses identified associations among alterations in gut microbiota, metabolites, and pulmonary gene expression.

Conclusion: AKK and AKK-EVs alleviated LPS-induced ARDS, accompanied by remodeling of gut microbial and metabolic profiles and attenuation of pulmonary IL-17- and TNF-related inflammatory signaling. AKK-EVs may represent a potential cell-free intervention for ARDS.