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

Summary

Across multi-country preterm cohorts, delayed gut microbiota maturation—marked by loss of a bacterial DL-endopeptidase—mediated a substantial portion of antibiotic-associated LOS risk. Mechanistic work showed DL-endopeptidase-producing probiotics activate NOD2 via MDP, modulate macrophages via CYLD, and protect neonatal mice; a pilot RCT indicated L. reuteri enhances fecal NOD2 activation in preterm infants.

Key Findings

• In 4,938 longitudinal fecal samples, delayed microbiota maturation explained over one-third of early-antibiotic-associated LOS risk in preterm infants.
• Deficiency of a bacterial DL-endopeptidase marked immature microbiota and correlated with higher LOS risk.
• DL-endopeptidase-producing E. faecium or L. reuteri activated NOD2 via MDP, induced CYLD, modulated macrophage polarization, and protected neonatal mice from LOS.
• A pilot randomized trial showed L. reuteri increased fecal NOD2 activation in preterm infants.

Clinical Implications

In NICUs, selecting or developing probiotics with DL-endopeptidase activity could be prioritized for LOS prevention, and fecal NOD2 activation may serve as a pharmacodynamic biomarker. Findings also support cautious antibiotic use to avoid microbiota immaturity.

Limitations

• Pilot RCT was small and focused on biomarker activation, not powered for clinical LOS outcomes.
• Causality and generalizability of specific strains and enzyme activity require larger, controlled clinical trials.

Future Directions

Conduct adequately powered RCTs testing DL-endopeptidase-producing probiotics on LOS incidence, validate fecal NOD2 activation as a surrogate, and develop rapid assays for DL-endopeptidase activity to guide NICU probiotic selection.