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<p>Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease typically managed with broad-spectrum immunosuppressants that carry significant systemic side effects and often provide incomplete efficacy. While gut-microbiota-derived metabolites are known to influence AIH progression, the specific microbial drivers that maintain hepatic immune homeostasis remain poorly defined. Here, we show that <i>Bacteroides acidifaciens</i> (BA) and its metabolite 1-oleoyl-sn-glycero-3-phosphoethanolamine (O-LysoPE) are enriched in self-healing mouse models of hepatitis but markedly depleted in AIH patients. We demonstrate that O-LysoPE induces a ‘hepatocyte-driven active immunosuppression’ by targeting the Qa-1b (HLA-E): NKG2A immune checkpoint. Mechanistically, O-LysoPE selectively redirects the transcription factor Creb1 to the <i>H2T23</i> promoter under inflammatory conditions, thereby upregulating hepatocytic Qa-1b expression. This elevation of Qa-1b engages the inhibitory receptor NKG2A on T cells, suppressing their overactivation and restoring a quiescent phenotype. Genetic disruption of <i>H2T23</i> abrogates the hepatoprotective effects of O-LysoPE, confirming the central role of this metabolic-immune axis. Our findings reveal that the BA–O-LysoPE axis mobilizes the liver’s intrinsic self-rescue mechanisms to restore immune quiescence. This study establishes a robust biological framework for liver-specific, targeted immunotherapy in AIH, offering a precision alternative to current systemic immunosuppression.</p>

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The bacteroidal metabolite O-LysoPE facilitates hepatocyte-mediated immunosuppression in autoimmune hepatitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Mengyi Xu,
  • Kangkang Luo,
  • Zhou Zhou,
  • Junjie Li,
  • Shiyao Zhang,
  • Lingdong Kong,
  • Longfeng Jiang,
  • Yuxuan Zhang,
  • Yu Li,
  • Fuyu Xiao,
  • Chuanlong Zhu,
  • Qiang Xu,
  • Hongwei Yi,
  • Xudong Wu

摘要

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease typically managed with broad-spectrum immunosuppressants that carry significant systemic side effects and often provide incomplete efficacy. While gut-microbiota-derived metabolites are known to influence AIH progression, the specific microbial drivers that maintain hepatic immune homeostasis remain poorly defined. Here, we show that Bacteroides acidifaciens (BA) and its metabolite 1-oleoyl-sn-glycero-3-phosphoethanolamine (O-LysoPE) are enriched in self-healing mouse models of hepatitis but markedly depleted in AIH patients. We demonstrate that O-LysoPE induces a ‘hepatocyte-driven active immunosuppression’ by targeting the Qa-1b (HLA-E): NKG2A immune checkpoint. Mechanistically, O-LysoPE selectively redirects the transcription factor Creb1 to the H2T23 promoter under inflammatory conditions, thereby upregulating hepatocytic Qa-1b expression. This elevation of Qa-1b engages the inhibitory receptor NKG2A on T cells, suppressing their overactivation and restoring a quiescent phenotype. Genetic disruption of H2T23 abrogates the hepatoprotective effects of O-LysoPE, confirming the central role of this metabolic-immune axis. Our findings reveal that the BA–O-LysoPE axis mobilizes the liver’s intrinsic self-rescue mechanisms to restore immune quiescence. This study establishes a robust biological framework for liver-specific, targeted immunotherapy in AIH, offering a precision alternative to current systemic immunosuppression.