Gut microbiota derived L-ornithine promotes resistance to obesity through metabolites mediated immunosuppressive macrophages

Gut microbiota can affect the occurrence and development of obesity. But the exact mechanism(s) by which obesity is prevented is still not fully understood. In this study, we found that L-ornithine (L-orn) from the gut microbiota lactobacillus helps mice to resist to high-fat diet (HFD) mediated obesity through its metabolite spermine (SPM) and spermindine (SPD) in the macrophages. SPM reduced inflammatory cytokines in the macrophages by inhibiting NF-κB and AKT (protein kinase B) signal pathways, while SPD activated Src and induced indoleamine 2, 3-dioxygenase 1 (IDO-1) to promote immunosuppressive IDO-1 macrophages. Notably, L-orn was inversely associated with body mass index (BMI) in obese patients. Sc-RNA sequencing data also showed that the NF-κB and AKT pathways were significantly up-regulated and the Src signaling pathway was significantly down-regulated in the inflammatory macrophages of adipose tissues. Thus, our results suggest that gut microbiota derived L-orn can control the occurrence and development of obesity through metabolites mediated anti-inflammatory macrophages.