A severe gastrointestinal disease in premature infants, necrotizing enterocolitis (NEC), is known for its high mortality and intestinal damage. However, a comprehensive new review published in the World Journal of Pediatric Surgery on July 13, 2026, reveals that NEC also causes significant, lasting neurodevelopmental impairment (NDI) in up to 40% of survivors. The study, led by Augusto Zani and colleagues from Washington University in St. Louis, synthesizes decades of research to show that NEC itself drives brain injury through an inflammatory cascade originating in the gut, independent of prematurity.
NEC affects premature infants with mortality rates of 15% to 30%. While neonatal intensive care has improved survival, survivors face higher risks of cerebral palsy, vision and hearing loss, and cognitive delays compared to premature infants without NEC. Historically, these deficits were attributed to prematurity, but the review indicates that severe systemic inflammation from a necrotic bowel inflicts specific damage on the developing brain. The severity of intestinal disease correlates with brain injury: surgically treated infants show higher rates of cerebral palsy, lower IQ scores, and greater cognitive deficits. Neuroimaging confirms reduced brain volume, delayed cortical folding, and white matter injury linked to intestinal inflammation.
The mechanism involves a breakdown of the blood-brain barrier, allowing gut-derived immune cells and inflammatory proteins to infiltrate the brain. A key driver is high-mobility group box 1 (HMGB1), a protein released from dying gut cells. Preclinical studies show that blocking HMGB1-Toll-like receptor 4 (TLR4) signaling or preventing immune cell infiltration reduces brain injury in animal models. The review also identifies hyponatremia and thrombocytopenia as potential early warning signs for NDI, emphasizing the importance of rapid surgical intervention to remove necrotic tissue.
These findings have profound implications for clinical practice. They reinforce the need for structured, long-term neurodevelopmental follow-up for all NEC survivors, from the neonatal period through school age, to enable early intervention. Clinical decisions, such as the timing of surgery, have significant neurological consequences, and the review advocates for early laparotomy to limit inflammatory burden. Moreover, the mechanistic insights open doors for testing novel therapies in clinical trials, including antioxidants like N-acetylcysteine, human milk oligosaccharides, and HMGB1 inhibitors like glycyrrhizin, which have shown promise in preclinical models.
Ultimately, this research shifts the paradigm from treating only the gut to protecting the brain, paving the way for a dual-pronged approach that aims to save both the intestines and the mind. For the medical community, it underscores the urgency of translating these biological insights into real-world therapies to improve the quality of life for these fragile infants. The full review is available at https://doi.org/10.1136/wjps-2026-001199.
