Sphingosine-1-phosphate ameliorates necrotizing enterocolitis by regulating mitochondrial redox homeostasis and gut microbiota

Sphingolipid metabolism critically links intestinal barrier integrity to inflammatory responses, and its role in necrotizing enterocolitis (NEC) pathogenesis may inform strategies for prevention and treatment. To investigate this association, metabolomic profiling of serum samples from preterm infants was performed, and the findings were validated in independent cohorts. The effects of sphingosine-1-phosphate (S1P) were evaluated in LPS-induced IEC-6 cells and experimental NEC models. Mechanistic studies were performed using pharmacological inhibitors, and microbiota-dependent effects were assessed through bacterial intervention experiments. Serum S1P levels were reduced prior to NEC diagnosis and correlated with disease severity. Opaganib reduced S1P levels and exacerbated NEC pathology, while S1P supplementation reversed these effects. Mechanistic investigations revealed that S1P exerted a protective effect against NEC by modulating mitochondrial oxidative respiration and redox balance, as well as by reshaping the gut microbiota to attenuate inflammation, apoptosis, and intestinal barrier disruption. The protective effects of S1P were partially attenuated by S1PR1 blockade. In addition, supplementation with Bacteroides thetaiotaomicron improved sphingolipid metabolic profiles in NEC intestinal tissues and upregulated S1P levels. These findings suggest that dysregulation of sphingolipid metabolism is associated with NEC and intestinal barrier dysfunction. S1P may alleviate NEC-related injury in experimental models, potentially involving S1PR1 signaling, mitochondrial redox balance, and interactions with the gut microbiota.