From homeostasis to dysregulation: human milk, microbial metabolites, and the preterm intestinal microenvironment in...

Preterm birth disrupts normal intestinal and immune development, leading to preterm neonates increased vulnerability to necrotizing enterocolitis (NEC). The immature gut is characterized by impaired epithelial barrier formation, altered intestinal epithelial cell function, and underdeveloped mucosal immune responses, all of which disrupt intestinal homeostasis. In addition, microbial colonization in preterm neonates differs substantially from that in term neonates, with reduced abundance of beneficial taxa, delayed establishment of a stable microbiota, and altered production of microbial metabolites. These early-life disturbances are closely associated with NEC pathogenesis. Human milk is increasingly recognized as more than a source of nutrition in preterm neonates. Its bioactive components contribute to intestinal protection by strengthening epithelial integrity, regulating immune responses, and limiting excessive inflammation. In parallel, human milk shapes gut microbial colonization and promotes the generation of functional microbial metabolites, which further influence barrier maturation and mucosal immune homeostasis. This review summarizes the ontogeny of the preterm gut, with a focus on epithelial and immune development, and discusses human milk-driven microbiota and their major metabolites in preterm neonates. It further highlights the mechanisms by which human milk bioactive components and microbiota-derived metabolites protect against NEC. Understanding the interplay among immature intestinal development, human milk, and microbial metabolism may provide new insights into NEC pathogenesis and support the development of targeted preventive strategies for preterm neonates.