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

Summary

Across three countries, delayed microbiome maturation marked by DL-endopeptidase deficiency explained a substantial fraction of LOS risk attributable to early antibiotics. DL-endopeptidase–producing commensals activated NOD2 via MDP, induced CYLD, tuned macrophage responses, and protected neonatal mice; a pilot RCT showed L. reuteri enhanced fecal NOD2 activation in preterm infants.

Key Findings

• Analyzed 4,938 longitudinal fecal samples across China, US, and UK to chart preterm microbiome maturation.
• Delayed microbiota maturation accounted for over one-third of LOS risk linked to early antibiotics.
• DL-endopeptidase deficiency was a hallmark of delayed maturation and associated with higher LOS risk.
• DL-endopeptidase–producing E. faecium or L. reuteri activated NOD2 via MDP, induced CYLD, modulated macrophages, and protected neonatal mice from LOS.
• A pilot RCT showed L. reuteri increased fecal NOD2 activation in preterm infants.

Clinical Implications

Supports antibiotic stewardship in preterm infants, motivates development of DL-endopeptidase-based diagnostics, and justifies larger efficacy trials of NOD2-activating probiotics to prevent LOS.

Limitations

• Pilot RCT assessed biomarker activation rather than clinical endpoints
• Residual confounding in observational components cannot be fully excluded

Future Directions

Validate DL-endopeptidase deficiency as a clinical biomarker, test efficacy and safety of NOD2-activating probiotics in larger multicenter RCTs, and define dosing/timing relative to antibiotic exposure.