An early post-birth immune-microbiota landscape predicts the development of necrotizing enterocolitis in term newborns with congenital heart defects.

The pathogenesis of NEC in term infants with critical congenital heart defects (CHD) is mainly associated with hypoxic-ischemic events that initiate an exaggerated systemic inflammatory response. Herein, we investigated the cumulative impact of the cytokine landscape and gut microbiota on the pathobiology leading to NEC onset in term newborns with CHD. This study involved 36 newborns who underwent surgical correction of CHD during the first two weeks of life; eight of them developed NEC within one week after cardiac surgery. Blood and fecal samples were collected at two time points: before and after surgery. Newborns without NEC exhibited significant changes in the levels of 22 cytokines, whereas newborns with NEC had changes in only 4 cytokines during the perioperative period. A panel including IL-1RA, IL-5, IL-18, and MCP-1 showed impressive test performance characteristics for diagnosing NEC at the preclinical stage with an AUC of 0.938, a sensitivity of 100.0%, and a specificity of 85.7%. Fifteen bacterial taxa were differentially abundant between feces samples of newborn groups. The pathobionts Collinsella and Mediterraneibacter gnavus group, known to be associated with increased intestinal permeability, were enriched in NEC newborns' feces before cardiac surgery. Our study demonstrated that the gut microbiota mediates the equilibrium of cytokine network dynamics under a broad spectrum of "friend or foe" conditions, effectively suppressing excessive inflammatory responses during early postnatal adaptation. In contrast, under conditions of low microbial diversity, a strong imbalanced cytokine feedback loop formed, resulting in deviations from normal immune response maturation. These findings offer new insights into understanding the fine-tuning of gut microbiota-immune system interactions in the first days of life.