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<p>HIV infection disrupts gut epithelial barrier integrity and mucosal immunity, driving chronic inflammation and disease progression which are not fully resolved despite anti-retroviral therapy. Here we identify the microbiota-derived octadecanoid-hydroxy-fatty-acid metabolite 10-hydroxystearic acid (10-HSA), produced by <i>Lactiplantibacillus plantarum</i>, as a key mediator of gut epithelial barrier repair in human intestinal epithelial cells in vitro, ex vivo and in the non-human primate model of HIV/AIDS. X-ray crystallography and transcriptomics combined with functional analyses revealed that 10-HSA directly binds PPARα, inducing lipid metabolism, mitochondrial regeneration and subsequent epigenetic histone crotonylation, thereby promoting gut epithelial renewal. Co-administration of 10-HSA with anti-retroviral therapy in SIV-infected macaques accelerated viral suppression, resolved systemic inflammation, repaired gut epithelial integrity and recovered the gut microbiota. These findings identify a microbiota-derived lipid metabolite–PPARα–histone crotonylation axis that activates gut epithelial regeneration. This study defines a host–microbiome metabolic pathway that restores epithelial–immune homeostasis and enhances the efficacy of anti-retroviral therapy.</p>

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Microbiota-derived 10-hydroxystearic acid activates PPARα to restore gut epithelial barrier integrity and enhance anti-retroviral therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月30日

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  • Dylan Kramer,
  • Clarissa Santos Rocha,
  • Christopher A. Gaulke,
  • Marie Nearing,
  • Sumathi Sankaran-Walters,
  • Ikaika Loque,
  • Anugraha Kidigannappa,
  • Eric Pham,
  • Shuang Hu,
  • Patrawin Wanakumjorn,
  • Ramona Abbattista,
  • Abhaya Dandekar,
  • Roland Faller,
  • Satya Dandekar

摘要

HIV infection disrupts gut epithelial barrier integrity and mucosal immunity, driving chronic inflammation and disease progression which are not fully resolved despite anti-retroviral therapy. Here we identify the microbiota-derived octadecanoid-hydroxy-fatty-acid metabolite 10-hydroxystearic acid (10-HSA), produced by Lactiplantibacillus plantarum, as a key mediator of gut epithelial barrier repair in human intestinal epithelial cells in vitro, ex vivo and in the non-human primate model of HIV/AIDS. X-ray crystallography and transcriptomics combined with functional analyses revealed that 10-HSA directly binds PPARα, inducing lipid metabolism, mitochondrial regeneration and subsequent epigenetic histone crotonylation, thereby promoting gut epithelial renewal. Co-administration of 10-HSA with anti-retroviral therapy in SIV-infected macaques accelerated viral suppression, resolved systemic inflammation, repaired gut epithelial integrity and recovered the gut microbiota. These findings identify a microbiota-derived lipid metabolite–PPARα–histone crotonylation axis that activates gut epithelial regeneration. This study defines a host–microbiome metabolic pathway that restores epithelial–immune homeostasis and enhances the efficacy of anti-retroviral therapy.