Ligilactobacillus Murinus and Lactobacillus Johnsonii Suppress Macrophage Pyroptosis in Atherosclerosis through Butyrate‐GPR109A‐GSDMD Axis

Abstract Gut microbiota and their metabolites are remarkable regulators in atherosclerosis. Oral drugs such as aspirin have recently been found to modulate the gut microbiome. However, the roles of drug‐microbiota‐metabolite interactions in atherosclerosis have not been explored. Herein, two gut probiotics, Ligilactobacillus murinus ( L. murinus ) and Lactobacillus johnsonii ( L. johnsonii ), are identified from mouse models and human cohorts, which are positively correlated with aspirin usage. Specifically, the eradication of these two species eliminated aspirin's anti‐atherosclerotic effects, while their transplantation exhibited therapeutic effects against atherosclerosis. Integrative analysis of metagenomic and metabolomic data showed that elevated levels of butyrate are associated with these two species. Mechanically, L. murinus and L. johnsonii form symbiotic networks with butyrate‐producing bacteria such as Allobaculum . This study confirmed that gut microbes produce butyrate, which helps preserve the gut barrier and prevents the leakage of lipopolysaccharides. By integrating molecular biology and single‐cell sequencing data, G protein‐coupled receptor 109A (GPR109A) is confirmed as the direct target of butyrate. Through the activation of GPR109A, butyrate produced by L. murinus and L. johnsonii suppressed the expression of Gasdermin D (GSDMD) in the pyroptosis of macrophages during atherosclerosis. These findings offer novel insights into the drug‐microbiota axis that can be targeted to improve the treatment of atherosclerosis.