Formononetin: a promising therapeutic agent targeting the gut-lung axis in acute lung injury

Background: Acute lung injury (ALI) is a common acute inflammatory lung disease in critical clinical conditions, with a complex pathogenesis and limited available treatment options. Although the gut-lung axis has been identified as an emerging field of host-related microbiota in various chronic lung diseases, it remains unclear whether gut microbiota is associated with the development and progression of ALI. Objective: This study aims to investigate the therapeutic effects of formononetin on ALI mice and elucidate how formononetin ameliorates ALI by regulating the gut-lung axis. Methods: Pathological changes in lung and intestinal tissues of LPS-induced ALI mice were first examined using histopathological detection. Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blot (WB) were employed to assess lung/intestinal inflammation and intestinal barrier integrity. 16S rRNA sequencing was used to evaluate the intestinal microbial microenvironment, and metabolomics was applied to detect changes in serum metabolites. Results: Formononetin effectively ameliorated lung injury in ALI mice, reduced the expression of lung/intestinal inflammatory factors, and protected the integrity of the lung-intestinal barrier in ALI mice. Gut microbiota analysis revealed that the anti-ALI effect of formononetin may be associated with Parabacteroides. Metabolite pathway enrichment involved bile acid metabolism and ABC transporters. Conclusion: Formononetin reverses lung injury and repairs the gut-lung barrier in ALI mice. These effects are accompanied by changes in Parabacteroides abundance, as well as alterations in ABC transporters and bile secretion. This study provides new insights and potential applications for the clinical intervention of ALI.