Clostridium_butyricum and butyrate ameliorate obesity by reprogramming macrophage polarization and suppressing inflammation through downregulation of EGR1

Obesity is closely associated with gut microbial dysbiosis and chronic low-grade inflammation, yet how microbial signals orchestrate systemic immune-metabolic dysfunction remains unclear. By comparing lean and obese pig breeds, we found that obesity correlates with expansion of Gram-negative bacteria (GNB), elevated circulating lipopolysaccharide (LPS), and reduced abundance of the butyrate-producing bacterium Clostridium_butyricum and its metabolite butyrate. Integrated multi-organ transcriptomic analyses across pigs and Macaca fasciculariss revealed evolutionarily conserved inflammatory signatures. Single-cell RNA sequencing further showed that in tissue macrophages, high EGR1 expression strongly associates with a pro-inflammatory M1 phenotype, whereas EGR1-low cells exhibit an anti-inflammatory M2 profile-suggesting a potential GNB-LPS-EGR1-macrophage polarization axis in obesity. To assess the functional relevance of this axis, we first performed fecal microbiota transplantation (FMT) from obese Ningxiang pigs into lean crossbred pigs. Recipient pigs exhibited a significant increase in body fat percentage, supporting a causal role for obesity-associated gut microbiota in adiposity. Separately, in diet-induced obese mice, we tested multiple therapeutic approaches: oral administration of Clostridium_butyricum, supplementation with butyrate or arginine, and pharmacological inhibition of EGR1. All interventions consistently attenuated multi-organ inflammation, promoted polarization of macrophages toward the anti-inflammatory M2 phenotype, and ameliorated obesity-related pathologies-including excessive weight gain, adipocyte hypertrophy, and hepatic steatosis. Together, these cross-species experiments reveal a conserved mechanism by which gut-derived LPS modulates macrophage function via EGR1, thereby linking microbial dysbiosis to metabolic inflammation across mammals. Our findings provide preclinical evidence supporting microbiota-, metabolite-, and EGR1-targeted strategies for the treatment of obesity.