Necrotising enterocolitis (NEC) is one of the most devastating complications of prematurity. Despite advances in neonatal management for preterm very-low-birth-weight infants, NEC-associated morbidities and mortality remain high.1 NEC often manifests in a fulminant manner with minimal antecedent signs and symptoms; it is important to recognise the initial bowel injury early so that neonatologists can promptly initiate treatment to minimise further damages to the bowel. Acute-phase proteins, cell surface antigens, cytokines, and chemokines have been used to identify sepsis and NEC cases, but these mediators are unable to differentiate the two conditions.2,3 Proteins originated from the bowel such as intestinal-fatty acid binding protein, liver-fatty acid binding protein, trefoil factor-3 (TFF3), and claudin-3 can be used as biomarkers for diagnosing NEC.4 Nonetheless, these biomarkers are only useful in differentiating severe (surgical) cases from milder (medical) cases, and they are not clinically useful for detection of early bowel injury.4 Such biomarkers are also unable to differentiate mild NEC cases from septicaemic or control patients. Significant and extensive changes of gene expression are associated with multiple pathways involving inflammation, hypoxia and oxidative stress, cell adhesion and chemotaxis, extracellular matrix remodelling, angiogenesis, muscle contraction, and arginine metabolism.5 These molecular responses correspond closely with the pathophysiology of NEC.We therefore hypothesised that novel tissue-specific or NEC-specific biomarkers could be discovered through searching for (1) gut-specific genes with mRNA levels dysregulated in NEC tissues, (2) genes that were up-regulated in accordance to the pathophysiologic mechanisms (eg, microbial infection and hypoxic and oxidative stress), and (3) proteins that shared the same protein family with known NEC biomarkers. We used a systemic bioinformatic approach to discover novel biomarkers through mining of the global gene expression data in diseased small bowel tissues collected from NEC infants. The objective was to discover novel biomarkers with good diagnostic value (sensitivity and specificity >85%) for diagnosing both medical (mild) and surgical (severe) NEC at the early phase.