Current Evidence, Controversies, and the Future of Biotics in the Prevention of Necrotizing Enterocolitis: A...

Necrotizing enterocolitis (NEC) remains one of the most devastating gastrointestinal disorders affecting preterm infants, with substantial mortality and long-term morbidity despite advances in neonatal care. Increasing evidence implicates intestinal dysbiosis, impaired intestinal barrier function, and dysregulated immune responses as central drivers of NEC pathogenesis, making microbiome-targeted interventions a promising preventive strategy. Collectively termed "biotics," these interventions include probiotics, prebiotics, synbiotics, and postbiotics, each aimed at modulating the developing gut ecosystem. This narrative review summarizes current evidence on the efficacy, safety, and clinical applicability of biotics for NEC prevention in very preterm and very-low-birth-weight infants. Randomized controlled trials and meta-analyses involving more than 10,000 infants demonstrate that specific multi-strain probiotic formulations, particularly those combining Lactobacillus and Bifidobacterium species, reduce NEC incidence and all-cause mortality, although benefits are less consistent in extremely low-birth-weight infants. Prebiotics alone showed a limited impact on NEC prevention, while emerging evidence suggests synbiotics may offer additive or superior protection compared with probiotics alone. Postbiotics represent a novel and potentially safer alternative, especially for the most vulnerable infants, though clinical data remain limited. Despite favorable effectiveness in meta-analyses, probiotics adoption remains variable due to strain heterogeneity, variable product quality, regulatory challenges, and rare but serious safety concerns. Precision microbiome approaches, pharmaceutical-grade formulations, personalized therapies informed by multi-omics profiling, and next-generation delivery systems may drive the future in this field.