Necrotizing enterocolitis-induced systemic immune suppression in neonatal preterm pigs

Objectives Preterm infants are at high risks of sepsis and necrotising enterocolitis (NEC). Some develop sepsis shortly after suspected or confirmed NEC, implying that NEC may predispose to sepsis but the underlying mechanisms are unknown. Using NEC-sensitive preterm pigs as models, we investigated the immune status in animals with and without NEC. Methods Preterm pigs (n=113, caesarean delivered at day 106) were reared until day 5 or 9. Blood was analyzed for T cell subsets, neutrophil phagocytosis, trans criptomics and immune responses to LPS challenge. Gut tissues were used for histology and cytokine analyses. Pigs with/without macroscopic NEC lesions were scored as healthy, mild or severe NEC. Results Overall NEC incidence was similar on days 5 and 9 (61-62%) with less severe lesions on day 9, implying gradual mucosal repair following the early phase of NEC on day 5. Pigs with NEC, especially severe NEC, showed decreased goblet cell density and increased MPO + and CD3 + cell density in the distal intestine or colon. Circulating parameters were minimally affected by NEC on day 5, but widely altered on day 9 in pigs with NEC, especially severe NEC, to the direction of immune suppression. These included elevated Treg frequency, impaired neutrophil phagocytosis, diminished LPS-induced cytokine secretions and immune gene responses, and consistently low expressions of genes related to innate immune signalling and Th1 polarization. Conclusion We shows evidence for NEC-induced systemic immune suppression, even with mild and sub-clinical NEC lesions, thereby suggesting mechanisms for increased secondary infections in infants with previous NEC diagnosis.