biostudies-literatureLi YNational Outstanding Youth Science Fund Project of National Natural Science Foundation of China426https://www.ebi.ac.uk/biostudies/studies/S-EPMC12647480biostudies-literatureUnknown82(1)The gut microbiota plays a pivotal role in modulating obesity pathogenesis, yet the molecular mechanisms underlying its protective effects remain elusive. In this study, we demonstrate that L-ornithine (L-orn), a metabolite produced by Lactobacillus, confers resistance against high-fat diet (HFD)-induced obesity in mice by modulating macrophage function through its downstream metabolites spermine (SPM) and spermidine (SPD). Mechanistically, SPM suppressed pro-inflammatory cytokine production in macrophages by inhibiting the NF-κB and Akt signaling pathways, while SPD activated Src kinase and upregulated indoleamine 2,3-dioxygenase 1 (IDO-1), thereby promoting the polarization of immunosuppressive IDO-1⁺ macrophages. Clinically, circulating L-orn levels were inversely correlated Cellular and molecular life sciences : CMLSGut microbiota L-ornithine promotes resistance to obesity through metabolites mediated immunosuppressive macrophages.PMC1264748091842302Liu YLi YZhang YGao YYang RWang JfalseGut microbiota L-ornithine promotes resistance to obesity through metabolites mediated immunosuppressive macrophages.The gut microbiota plays a pivotal role in modulating obesity pathogenesis, yet the molecular mechanisms underlying its protective effects remain elusive. In this study, we demonstrate that L-ornithine (L-orn), a metabolite produced by Lactobacillus, confers resistance against high-fat diet (HFD)-induced obesity in mice by modulating macrophage function through its downstream metabolites spermine (SPM) and spermidine (SPD). Mechanistically, SPM suppressed pro-inflammatory cytokine production in macrophages by inhibiting the NF-κB and Akt signaling pathways, while SPD activated Src kinase and upregulated indoleamine 2,3-dioxygenase 1 (IDO-1), thereby promoting the polarization of immunosuppressive IDO-1⁺ macrophages. Clinically, circulating L-orn levels were inversely correlated 2025-01-01T00:00:00Z2025 Nov2026-06-05T16:45:54.46Z2026-05-18T03:13:13.265ZS-EPMC126474804129131710.1007/s00018-025-05882-8