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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 with body mass index (BMI) in obese individuals, underscoring its potential relevance in human obesity. Single-cell RNA sequencing (scRNA-seq) analysis further revealed dysregulated macrophage signaling in obese adipose tissue, characterized by hyperactivation of NF-κB and Akt pathways and downregulation of Src signaling in inflammatory macrophages. Collectively, our findings highlight a novel mechanism by which gut microbiota-derived L-orn mitigates obesity through metabolite-driven reprogramming of macrophages toward an anti-inflammatory phenotype, offering new therapeutic avenues for metabolic disord

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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