AbstractInflammatory bowel disease (IBD) is a chronic inflammatory condition caused by multiple genetic and environmental factors. Numerous genes are implicated in the etiology of IBD, but the diagnosis of IBD is challenging. Here, XGBoost, a machine learning prediction model, has been used to distinguish IBD from healthy cases following elaborative feature selection. Using combined unsupervised clustering analysis and the XGBoost feature selection method, we successfully identified a 32-gene signature that can predict IBD occurrence in new cohorts with 0.8651 accuracy. The signature shows enrichment in neutrophil extracellular trap formation and cytokine signaling in the immune system. The probability threshold of the XGBoost-based classification model can be adjusted to fit personalized lifestyle and health status. Therefore, this study reveals potential IBD-related biomarkers that facilitate an effective personalized diagnosis of IBD.