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Probiotic interventions maintain intestinal barrier function and alleviate necrotizing enterocolitis by inhibiting

Meiqi Chen1,2, Qing Zhao2, Laiqin Peng3

  • 1Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.

Cell Death & Disease
|May 15, 2026
PubMed

Insights

Probiotic supplementation with Lactobacillus strains boosts intestinal polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and olfactomedin 4 (OLFM4) to combat necrotizing enterocolitis (NEC). This approach targets PMN-MDSC ferroptosis, offering a novel therapeutic strategy for NEC.

Area of Science:

  • Gastroenterology and Immunology
  • Microbiome Research
  • Cellular Mechanisms of Disease

Background:

  • Necrotizing enterocolitis (NEC) is a severe intestinal disease in neonates.
  • Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and gut probiotics are known to alleviate NEC.
  • The precise mechanisms linking intestinal PMN-MDSCs (iPMN-MDSCs) to specific gut microbiota in NEC remain largely undefined.

Purpose of the Study:

  • To elucidate the role of specific gut bacteria and iPMN-MDSCs in NEC pathogenesis.
  • To investigate the molecular mechanisms by which iPMN-MDSCs protect against NEC.
  • To identify potential therapeutic targets for NEC intervention.

Main Methods:

  • Identification of key Lactobacillus strains (L. reuteri, L. rhamnosus) reduced in NEC conditions.
  • Assessment of iPMN-MDSC abundance and OLFM4 expression following probiotic supplementation.
  • Investigation of OLFM4's role in iPMN-MDSC ferroptosis via ATF4, Slc7a11, and Gpx4 pathways.
  • Evaluation of indole-3-aldehyde, a probiotic metabolite, in alleviating NEC.
  • Analysis of PMN-MDSCs and anti-ferroptosis markers in NEC patient samples.

Main Results:

  • Combined supplementation of L. reuteri and L. rhamnosus increased iPMN-MDSC abundance and OLFM4 expression, improving intestinal epithelial cell function and attenuating NEC.
  • Olfm4 deficiency in neutrophils exacerbated NEC, impaired intestinal barrier integrity, and induced microbial dysbiosis.
  • OLFM4 was found to inhibit iPMN-MDSC ferroptosis by enhancing ATF4 activity and upregulating Slc7a11 and Gpx4.
  • Downregulation of Atf4 or Gpx4 mimicked the detrimental effects of Olfm4 deficiency.
  • Probiotic metabolite indole-3-aldehyde alleviated NEC by restoring the OLFM4-mediated anti-ferroptosis pathway.
  • Reduced intestinal LOX1+PMN-MDSCs and a weakened anti-ferroptosis pathway correlated with NEC progression in patients.

Conclusions:

  • Lactobacillus reuteri and L. rhamnosus play a protective role in NEC by modulating iPMN-MDSCs and OLFM4 expression.
  • OLFM4 is a critical regulator of iPMN-MDSC ferroptosis, crucial for maintaining intestinal barrier integrity during NEC.
  • Targeting the OLFM4-driven anti-ferroptosis axis in iPMN-MDSCs using probiotics or their metabolites represents a promising therapeutic strategy for NEC.

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