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<p>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 <i>Lactobacillus</i>, 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<sup>+</sup> 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 disorders.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Yuanyuan Li,
  • Yuqing Liu,
  • Juanjuan Wang,
  • Yuanhuan Gao,
  • Yuan Zhang,
  • Rongcun Yang

摘要

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 disorders.