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Life sciences · Journal article
Microbiome · October 10, 2026
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Obesity is closely associated with gut microbial dysbiosis and chronic low-grade inflammation, yet how microbial signals orchestrate systemic immune-metabolic dysfunction remains unclear. In adiposity-prone Ningxiang pigs (NF), we observed an expansion of Gram-negative bacteria, elevated circulating lipopolysaccharide (LPS), and reduced abundance of Clostridium butyricum and its metabolite butyrate. Fecal microbiota transplantation (FMT) from NF donors induced adiposity in lean Duroc-Landrace-Yorkshire (CF) recipients, accompanied by a significant decrease in C. butyricum colonization. In high-fat diet (HFD)-fed mice, supplementation with C. butyricum and butyrate effectively restored gut microbial homeostasis and ameliorated obesity. Integrated multi-organ transcriptomic analyses across pigs and long-tailed macaques revealed that early growth response 1 ( EGR1 ) is a central regulator of obesity-associated inflammation, with consistent enrichment of PI3K-Akt signaling. Single-cell RNA sequencing further demonstrated that EGR1 -high macrophages adopt a pro-inflammatory M1 phenotype, whereas EGR1 -low macrophages exhibit an anti-inflammatory M2 profile. Leveraging EGR1 macrophage-specific differentially expressed genes, both in silico knockout of EGR1 and pharmacological inhibition (EGR1i; IT25) confirmed the functional involvement of PI3K-Akt signaling downstream of EGR1. Integrating metagenomic and single-cell data, we propose a conserved LPS- EGR1 axis that governs macrophage polarization in obesity. To experimentally validate this model, we established an LPS-potentiated HFD-induced obesity model in mice and an LPS-induced M1 polarization model in RAW264.7 macrophages. Treatment with C. butyricum, butyrate, arginine, or EGR1i significantly attenuated weight gain, downregulated EGR1 expression, and effectively suppressed M1 macrophage polarization, thereby restoring the M1/M2 balance. Notably, this process is accompanied by significant alterations in genes related to the PI3K-Akt signaling pathway, suggesting that this pathway may act in concert with EGR1 within this regulatory network. In summary, these cross-species experiments elucidate a fundamental mechanism whereby gut-derived LPS regulates macrophage polarization via EGR1, thereby linking microbial dysbiosis to metabolic inflammation in mammals. Video Abstract CB and BA break the LPS-EGR1-M1 loop to combat obesity. CB: Clostridium butyricum. BA: Butyric acid. LPS: Lipopolysaccharide. GNB: Gram-negative bacteria. EGR1: Early Growth Response 1.