2. Academic Validation
  3. Gut microbiota immaturity with DL-endopeptidase deficiency links antibiotic use to preterm late-onset sepsis

Gut microbiota immaturity with DL-endopeptidase deficiency links antibiotic use to preterm late-onset sepsis

  • Cell Host Microbe. 2026 Apr 8;34(4):672-691.e13. doi: 10.1016/j.chom.2026.02.004.
Wei Shen 1,  Huidi Wang 2,  Jiaxuan Wang 2,  Yuan Yuan 3,  Ying Luo 4,  Xirao Chen 2,  Jingyi Li 2,  Yuting Liu 5,  Ya Yin 2,  Mengjia Wang 5,  Lisha Lin 5,  Lepeng Zhou 2,  Jie Li 2,  Rihua Xie 6,  Yiheng Dai 4,  Fan Wu 7,  Zhenhe Huang 2,  Yifan Zhou 2,  Fangbo Xia 2,  Fan Wu 2,  Peihua Cao 8,  Jie Gao 9,  Xiaolong He 2,  Jose C Clemente 10,  Hongwu Chen 5,  Jie Yang 5,  Weimin Huang 11,  Hongwei Zhou 12,  Yan He 13
Affiliations

Affiliations

  • 1 Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China; Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Neonatology, Shenzhen Hospital, Southern Medical University, Shenzhen, China. Electronic address: [email protected].
  • 2 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Guangzhou Women and Children's Medical Center, Guangzhou, China.
  • 4 Foshan Women and Children Hospital, Foshan, China.
  • 5 Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 6 Foshan Women and Children Hospital, Foshan, China; School of Nursing, Southern Medical University, Guangzhou, China.
  • 7 Department of Neonatology, Guangzhou Key Laboratory of Neonatal Intestinal Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 8 Department of Biostatistics, School of Public Health, Southern Medical University, Guangzhou, China; Clinical Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 9 Department of Gastroenterology, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
  • 10 Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China. Electronic address: [email protected].
  • 12 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Neonatology, Shenzhen Hospital, Southern Medical University, Shenzhen, China; Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 13 Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Guangzhou 510515, Guangdong, China. Electronic address: [email protected].
PMID: 41763213 DOI: 10.1016/j.chom.2026.02.004
Abstract

Early Antibiotic exposure increases late-onset sepsis (LOS) risk in preterm infants, potentially via gut dysbiosis. Analyzing 4,938 longitudinal fecal samples from preterm infants in China, the US, and the UK, we identified a differential pace of gut microbiota development among preterm infants. Delayed maturation correlated with over one-third of LOS risk associated with early Antibiotic exposure. Deficiency of a Bacterial DL-endopeptidase represented a hallmark of delayed microbiota development and correlated with elevated LOS risk. Supplementation with DL-endopeptidase-producing Enterococcus faecium or Limosilactobacillus reuteri activated the NOD2 receptor via muramyl dipeptide (MDP), regulated macrophage differentiation and polarization, restrained hyperinflammation via cylindromatosis (CYLD) induction, and protected neonatal mice from LOS. A pilot randomized controlled trial showed that L. reuteri supplementation enhanced fecal NOD2 activation in preterm infants. These findings link microbiota immaturity and reduced DL-endopeptidase activity to Antibiotic exposure and LOS risk and highlight a candidate biomarker that warrants further validation for clinical translation.

Keywords

NOD2; gut microbiota; infant probiotics; late onset sepsis; preterm infants.

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