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<p>Circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and gut probiotics are crucial for alleviating experimental necrotizing enterocolitis (NEC) in mice, yet the mechanisms linking intestinal PMN-MDSCs (iPMN-MDSCs) to specific microbiota remain unclear. Herein, we identified <i>Lactobacillus</i> (<i>L</i>.) <i>reuteri</i> and <i>L. rhamnosus</i> as two key strains significantly reduced under NEC conditions; their combined supplementation increased iPMN-MDSC abundance and olfactomedin 4 (OLFM4) expression, thereby improving intestinal epithelial cell (IEC) function and attenuating NEC. <i>Olfm4</i> deficiency in neutrophils exacerbated NEC, disrupted intestinal barrier integrity, and induced microbial dysbiosis. Mechanistically, OLFM4 inhibited iPMN-MDSC ferroptosis by enhancing activating transcription factor 4 (ATF4) activity and upregulating its targets solute carrier family 7a member 11 (Slc7a11) and glutathione peroxidase 4 (Gpx4). Downregulation of Atf4 or Gpx4 recapitulated the phenotypic alterations observed in <i>Olfm4</i>-deficient mice, including aggravated NEC and impaired iPMN-MDSC function. Treatment with indole-3-aldehyde, an effector metabolite of probiotics, alleviated NEC by restoring the OLFM4-driven anti-ferroptosis axis in iPMN-MDSCs. In patients with NEC, reduced intestinal LOX1<sup>+</sup>PMN-MDSCs and a weakened anti-ferroptosis pathway were associated with disease progression. These findings offer a therapeutic strategy for NEC by targeting iPMN-MDSC ferroptosis via probiotic- or metabolite-based interventions.</p>

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Probiotic interventions maintain intestinal barrier function and alleviate necrotizing enterocolitis by inhibiting ferroptosis in intestinal PMN-MDSCs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月15日

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  • Meiqi Chen,
  • Qing Zhao,
  • Laiqin Peng,
  • Ziyang Chen,
  • Shuaijun Lv,
  • Zekai Zhuang,
  • Shudan Zheng,
  • Jiaxiu Ye,
  • Junyu He,
  • Yizhuang Lu,
  • Gang Xiao,
  • Yuxiong Guo,
  • Yumei He

摘要

Circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and gut probiotics are crucial for alleviating experimental necrotizing enterocolitis (NEC) in mice, yet the mechanisms linking intestinal PMN-MDSCs (iPMN-MDSCs) to specific microbiota remain unclear. Herein, we identified Lactobacillus (L.) reuteri and L. rhamnosus as two key strains significantly reduced under NEC conditions; their combined supplementation increased iPMN-MDSC abundance and olfactomedin 4 (OLFM4) expression, thereby improving intestinal epithelial cell (IEC) function and attenuating NEC. Olfm4 deficiency in neutrophils exacerbated NEC, disrupted intestinal barrier integrity, and induced microbial dysbiosis. Mechanistically, OLFM4 inhibited iPMN-MDSC ferroptosis by enhancing activating transcription factor 4 (ATF4) activity and upregulating its targets solute carrier family 7a member 11 (Slc7a11) and glutathione peroxidase 4 (Gpx4). Downregulation of Atf4 or Gpx4 recapitulated the phenotypic alterations observed in Olfm4-deficient mice, including aggravated NEC and impaired iPMN-MDSC function. Treatment with indole-3-aldehyde, an effector metabolite of probiotics, alleviated NEC by restoring the OLFM4-driven anti-ferroptosis axis in iPMN-MDSCs. In patients with NEC, reduced intestinal LOX1+PMN-MDSCs and a weakened anti-ferroptosis pathway were associated with disease progression. These findings offer a therapeutic strategy for NEC by targeting iPMN-MDSC ferroptosis via probiotic- or metabolite-based interventions.