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Background <p>The mechanisms by which microbiota from disease-resistant populations or animals improve intestinal immune defense remain incompletely elucidated. Tibetan pig, a renowned disease-resistant breed, serve as a valuable research subject for the health of humans and economic animals.</p> Results <p>In this study, fecal microbiota transplantation from Tibetan piglets into mice conferred enhanced resistance to <i>C. rodentium</i> DBS100. Further microbiota profiling and metabolomics analysis showed this protection may be partly ascribed to <i>C. butyricum</i> SLZX19-05 in recipients’ colon. Administration of <i>C. butyricum</i> SLZX19-05 to germ-free mice resulted in the significantly increased lysozyme expression within colonic macrophages, subsequently bolstering the resistance to <i>C. rodentium</i> infection. In mice and piglets, this <i>C. butyricum</i> similarly elevated the lysozyme level in colon and decreased diarrhea incidence. Conversely, lyz1-knockout heightened mice's susceptibility to <i>C. rodentium</i>, highlighting lysozyme’s critical role in immune defense. Mechanistically, this study systematically revealed that <i>C. butyricum</i> enhanced lysozyme expression by inhibiting mTORC1-HDAC3/8 pathway, leading to the increased H4K31 Crotonylation (H4K31Cr) and openness of an upstream region of <i>lyz1</i> promoter via butyrate in macrophages. Additionally, H4K31-mutant mice showed the leukopenia, further validating the significance of H4K31Cr in immune regulation.</p> Conclusions <p>Collectively, mTORC1-HDAC3/8-H4K31Cr pathway is a key mechanism by which butyrate-producing commensal bacteria enhance immune defense in gut. This discovery provides a novel foundation for the screening and application of the next generation of butyrate-producing probiotics.</p> <p><MediaObject ID="MOESM3"> <VideoObject FileRef="MediaObjects/40168_2025_2234_MOESM3_ESM.mp4" VideoID="ExudCwSVL4HD5NKcnUPE8W"> <Caption Language="En" xml:lang="en"> <CaptionContent> <p>Video Abstract</p> </CaptionContent> </Caption> </VideoObject> </MediaObject></p>

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Butyrate-producing commensal bacteria confers colon immune defense function via enhancing H4K31 Crotonylation of macrophages

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月1日

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  • Jianmin Wu,
  • Pingting Guo,
  • Minghui Wang,
  • Zhaoyue Men,
  • Zishen Lin,
  • Jinping Wang,
  • Shumin Zhang,
  • Min Zhou,
  • Jinbiao Zhao,
  • Hu Liu,
  • Xi Ma

摘要

Background

The mechanisms by which microbiota from disease-resistant populations or animals improve intestinal immune defense remain incompletely elucidated. Tibetan pig, a renowned disease-resistant breed, serve as a valuable research subject for the health of humans and economic animals.

Results

In this study, fecal microbiota transplantation from Tibetan piglets into mice conferred enhanced resistance to C. rodentium DBS100. Further microbiota profiling and metabolomics analysis showed this protection may be partly ascribed to C. butyricum SLZX19-05 in recipients’ colon. Administration of C. butyricum SLZX19-05 to germ-free mice resulted in the significantly increased lysozyme expression within colonic macrophages, subsequently bolstering the resistance to C. rodentium infection. In mice and piglets, this C. butyricum similarly elevated the lysozyme level in colon and decreased diarrhea incidence. Conversely, lyz1-knockout heightened mice's susceptibility to C. rodentium, highlighting lysozyme’s critical role in immune defense. Mechanistically, this study systematically revealed that C. butyricum enhanced lysozyme expression by inhibiting mTORC1-HDAC3/8 pathway, leading to the increased H4K31 Crotonylation (H4K31Cr) and openness of an upstream region of lyz1 promoter via butyrate in macrophages. Additionally, H4K31-mutant mice showed the leukopenia, further validating the significance of H4K31Cr in immune regulation.

Conclusions

Collectively, mTORC1-HDAC3/8-H4K31Cr pathway is a key mechanism by which butyrate-producing commensal bacteria enhance immune defense in gut. This discovery provides a novel foundation for the screening and application of the next generation of butyrate-producing probiotics.

Video Abstract