Innovative Butyric Acid Nanoparticle Therapy Restores Gut–Lung Axis and Suppresses <scp>PTPN1</scp> ‐Mediated Inflammation in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a severe respiratory disorder characterized by systemic inflammation, pulmonary endothelial damage, and high mortality rates. Dysbiosis of gut microbiota has been identified as a key factor in the progression of ARDS, but effective therapies targeting this axis are still lacking. This study evaluates the efficacy of lipid nanoparticle-encapsulated butyric acid in modulating gut microbiota and reducing inflammation in ARDS. 16S Ribosomal RNA (16S rRNA) sequencing revealed that ARDS models exhibited reduced microbial diversity and Blautia abundance, alongside decreased butyric acid levels. We profiled fecal metabolites from lipopolysaccharide (LPS)-induced ARDS mice using untargeted liquid chromatography-mass spectrometry (LC-MS/MS) and identified differential metabolites via OPLS-DA modeling coupled with KEGG pathway enrichment analysis. Metabolomic analysis revealed a significant decrease in fecal butyrate in the LPS group compared with the PBS group. Transcriptomic analysis identified protein tyrosine phosphatase nonreceptor type 1 (PTPN1) as a critical inflammatory regulator associated with butyric acid pathways. Lipid nanoparticles encapsulating butyric acid were developed for targeted delivery. In vitro studies showed that these nanoparticles reduced inflammatory cytokines, improved endothelial barrier integrity, and enhanced cell viability under LPS-induced stress. In vivo experiments confirmed these results, demonstrating improved respiratory function, reduced lung inflammation, and restored gut microbiota balance in ARDS mice. This study provides strong evidence for the therapeutic potential of butyric acid-loaded nanoparticles. It offers a novel approach for treating ARDS by targeting both gut microbiota and molecular pathways. The findings highlight the importance of the gut-lung axis in developing more effective, integrated therapeutic strategies.