Synergy between HMOs and Postbiotics: A New Strategy in Preventing Intestinal Inflammation in Preterm and Surgical Neonates

Background Early modulation of the neonatal gut microbiota is emerging as a strategy to mitigate late-onset sepsis (LOS) and enhance enteral feeding tolerance in high-risk infants. Postbiotics—non-viable microbial preparations with immunomodulatory metabolites—may offer probiotic-like benefits while avoiding the risks associated with live organisms. We compared a daily postbiotic–synbiotic blend with bovine lactoferrin, another milk-derived bioactive, in preterm and surgical neonates. Methods In a single-centre, randomised (1:1), open-label trial conducted in a tertiary NICU (January 2022–March 2024), 130 infants (mean gestational age 34 ± 3 weeks; 44 with major surgical conditions) received either (i) 1 mL·day⁻¹ of a preparation containing 2′-fucosyllactose, lactase, and heat-inactivated Lactobacillus acidophilus (10⁹ cells) or (ii) bovine lactoferrin 100 mg·day⁻¹. Primary endpoint was culture-proven sepsis; secondary endpoints included time to full enteral feeds, days of parenteral nutrition, length of stay (LOS), discharge weight, and colonisation rates. Categorical data were analysed with χ²/Fisher’s exact test; continuous variables with Mann–Whitney U or t -test as appropriate (α = 0.05). Results Overall sepsis incidence was low (7.7%) and did not differ significantly between groups (postbiotic 3/65 vs lactoferrin 7/65, P  = 0.39). The postbiotic cohort achieved complete enteral feeding markedly earlier (median 8.3 ± 4.7 days vs 30 ± 8.3 days; P  < 0.001), required fewer parenteral-nutrition days, and had a shorter LOS (20.6 ± 17 vs 29 ± 20 days; P  = 0.01). Discharge weight was higher in the postbiotic group (2872 ± 632 g vs 2695 ± 335 g; P  = 0.04). Colonisation rates were comparable. Conclusions A synbiotic postbiotic formulation accelerated transition to full enteral nutrition, reduced hospital stay, and improved growth without increasing colonisation or sepsis risk relative to lactoferrin. Larger, multi-centre trials are warranted to confirm potential infection-protective effects and to explore synergistic combinations of postbiotics with lactoferrin in vulnerable neonatal populations.