Related Experiment Video
Updated: Mar 2, 2026
A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Gut microbiota immaturity with DL-endopeptidase deficiency links antibiotic use to preterm late-onset sepsis
Wei Shen1, Huidi Wang2, Jiaxuan Wang2
1Department 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.
Insights
Early antibiotic exposure in preterm infants elevates sepsis risk by disrupting gut microbiota development. Restoring bacterial DL-endopeptidase activity may mitigate this risk and protect infants.
Area of Science:
- Microbiology
- Neonatal Medicine
- Immunology
Background:
- Early antibiotic exposure is a significant risk factor for late-onset sepsis (LOS) in preterm infants.
- Gut dysbiosis, or an imbalance in gut bacteria, is a suspected mechanism linking antibiotics to increased LOS risk.
- The specific microbial factors and host responses involved remain incompletely understood.
Purpose of the Study:
- To investigate the relationship between gut microbiota development and LOS risk in preterm infants exposed to early antibiotics.
- To identify microbial biomarkers associated with delayed gut maturation and increased LOS.
- To explore potential therapeutic interventions targeting gut microbiota to prevent LOS.
Main Methods:
- Analysis of 4,938 longitudinal fecal samples from preterm infants across China, the US, and the UK.
- Correlation of gut microbiota development pace with LOS risk and antibiotic exposure.
- In vitro and in vivo studies using bacterial supplementation (Enterococcus faecium, Limosilactobacillus reuteri) and NOD2 receptor activation in neonatal mice.
- Pilot randomized controlled trial assessing L. reuteri supplementation in preterm infants.
Main Results:
- Preterm infants exhibited differential rates of gut microbiota development, with delayed maturation linked to over one-third of LOS risk from early antibiotics.
- A deficiency in bacterial DL-endopeptidase was a hallmark of delayed microbiota development and correlated with higher LOS risk.
- Supplementation with DL-endopeptidase-producing bacteria activated the NOD2 receptor, modulated macrophage responses, reduced hyperinflammation, and protected mice from LOS.
- L. reuteri supplementation enhanced fecal NOD2 activation in a pilot trial with preterm infants.
Conclusions:
- Microbiota immaturity and reduced DL-endopeptidase activity are linked to antibiotic exposure and increased LOS risk in preterm infants.
- Bacterial DL-endopeptidase, via NOD2 activation, represents a potential therapeutic target and biomarker for LOS prevention.
- Further clinical validation is warranted for the translation of these findings into clinical practice.
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.
