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Background <p>Uncontrolled pneumonia induced by influenza virus infection results in severe lung pathology. Timely and proper tissue self-repair is critical to improve survival. This study aimed to identify probiotic strains that confer protection against acute lung injury induced by influenza virus infection and to elucidate the underlying molecular mechanisms.</p> Results <p>Significant structural alterations in the gut microbiota were observed in influenza patients, characterized by a marked depletion in <i>Faecalibacterium prausnitzii</i>, whose abundance was negatively correlated with disease severity. In a murine model of influenza infection, oral administration of <i>Faecalibacterium prausnitzii</i> and its culture supernatant markedly alleviated lung injury. Targeted metabolomic analysis identified butyrate as the principal metabolite produced by <i>Faecalibacterium prausnitzii</i> that mediates lung tissue protection. Single-cell RNA sequencing further revealed that butyrate promotes the differentiation of pulmonary CD4⁺T cells into a reparative phenotype with enhanced interleukin-22 (IL-22) production. Mechanistically, butyrate facilitates IL-22 secretion through monounsaturated fatty acid biosynthesis via a histone-acetylation-dependent NR4A1-SCD1 axis. Accumulated monounsaturated fatty acids further enhance mitochondrial activities, which are essential for robust IL-22 production. Utilizing an IL-22 knockout mouse model, we confirmed the indispensable protective role of IL-22 in this gut-lung axis during influenza infection.</p> Conclusion <p>Our findings demonstrate that butyrate, derived from intestinal commensal <i>Faecalibacterium prausnitzii</i>, plays a crucial role in maintaining pulmonary tissue homeostasis during influenza infection by modulating intrinsic lipid metabolism in CD4<sup>+</sup>T cells. This study underscores the promising translational potential of <i>Faecalibacterium prausnitzii</i> supplementation as an innovative therapeutic strategy for severe influenza-associated lung injury.</p> <p><MediaObject ID="MOESM9"><VideoObject FileRef="MediaObjects/40168_2026_2486_MOESM9_ESM.mp4" VideoID="BqJtoNEADfNEu9ir3Te7Bo"><Caption Language="En" xml:lang="en"><CaptionContent><p>Video Abstract</p></CaptionContent></Caption></VideoObject></MediaObject></p> Graphical Abstract <p></p>

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Faecalibacterium prausnitzii in the gut protects against acute lung injury in influenza through butyrate educated reparative CD4+T cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Zheying Mao,
  • Liqian Wang,
  • Chenyue Zhuo,
  • Mingzhu Huang,
  • Jili Ni,
  • Chang Liu,
  • Weizhen Chen,
  • Jiaqi Bao,
  • Bin Lou,
  • Haiying Yu,
  • Shufa Zheng,
  • Yu Chen

摘要

Background

Uncontrolled pneumonia induced by influenza virus infection results in severe lung pathology. Timely and proper tissue self-repair is critical to improve survival. This study aimed to identify probiotic strains that confer protection against acute lung injury induced by influenza virus infection and to elucidate the underlying molecular mechanisms.

Results

Significant structural alterations in the gut microbiota were observed in influenza patients, characterized by a marked depletion in Faecalibacterium prausnitzii, whose abundance was negatively correlated with disease severity. In a murine model of influenza infection, oral administration of Faecalibacterium prausnitzii and its culture supernatant markedly alleviated lung injury. Targeted metabolomic analysis identified butyrate as the principal metabolite produced by Faecalibacterium prausnitzii that mediates lung tissue protection. Single-cell RNA sequencing further revealed that butyrate promotes the differentiation of pulmonary CD4⁺T cells into a reparative phenotype with enhanced interleukin-22 (IL-22) production. Mechanistically, butyrate facilitates IL-22 secretion through monounsaturated fatty acid biosynthesis via a histone-acetylation-dependent NR4A1-SCD1 axis. Accumulated monounsaturated fatty acids further enhance mitochondrial activities, which are essential for robust IL-22 production. Utilizing an IL-22 knockout mouse model, we confirmed the indispensable protective role of IL-22 in this gut-lung axis during influenza infection.

Conclusion

Our findings demonstrate that butyrate, derived from intestinal commensal Faecalibacterium prausnitzii, plays a crucial role in maintaining pulmonary tissue homeostasis during influenza infection by modulating intrinsic lipid metabolism in CD4+T cells. This study underscores the promising translational potential of Faecalibacterium prausnitzii supplementation as an innovative therapeutic strategy for severe influenza-associated lung injury.

Video Abstract

Graphical Abstract