SUMMARY Preterm infants face a unique trajectory of gut microbiome assembly, shaped by the convergence of physiological immaturity, necessary clinical interventions, and the neonatal intensive care unit environment. This dysbiotic ecosystem—characterized by low diversity, depletion of beneficial commensals such as Bifidobacterium , and expansion of pathobionts, including Enterobacteriaceae—is increasingly recognized as a central mediator of neonatal morbidity. This review synthesizes current evidence on preterm microbiome development, its role in necrotizing enterocolitis through mechanisms involving Toll-like receptor 4 signaling, bile acid dysmetabolism, and immune dysregulation, and its systemic impact via gut-organ axes linking the intestine to the brain, lung, eye, and systemic circulation. We critically evaluate microbiome-targeted interventions across the translational spectrum, from foundational practices such as human milk feeding and antibiotic stewardship to active modulation with probiotics and prebiotics, and emerging precision strategies, including postbiotics, phage therapy, and fecal microbiota transplantation. Methodological advances in multi-omics, machine learning, and digital twin modeling are paving the way for personalized, predictive microbiome-mediated care. We also address the hidden burden of antimicrobial resistance in the preterm gut and the challenges of translating mechanistic insights into clinical practice. Looking forward, embracing the complexity of the preterm microbiome as a dynamic, multi-kingdom ecosystem is essential for developing holistic interventions that improve both short-term survival and long-term neurodevelopmental, respiratory, and metabolic outcomes.
Tao et al. (Mon,) studied this question.