Ulcerative colitis (UC) and Alzheimer's disease (AD) share a common etiology as inflammatory diseases characterized by barrier deterioration. The aim of this study is to elucidate how neutrophil extracellular traps (NETs), serving as a comorbid etiological factor, can trigger the dysfunction in both the intestinal barrier and blood-brain barrier (BBB). Integrated bioinformatics analysis revealed 14 overlapped NETs-related differential expressed genes in UC and AD, which strongly featured barrier dysfunction. The following verification experiments identified enriched NETs, as well as damaged intestinal epithelium and BBB permeability, in the colon and prefrontal cortex of colitis mice and APP/PS1 mice. By employing pharmacological interventions (Cl-amidine and Disulfiram), we disrupted the formation of NETs and discovered significantly restored barrier integrity and attenuated inflammation. Further enrichment and correlation analysis indicated, for the first time, DDIT4/IL-1β NETs might drive macrophage-mediated phagocytosis to induce barrier dysfunction in UC and AD. Our findings originally established the peripheral-central inflammation interactions of UC and AD from the perspective of NETs, highlighting the potential valuable roles in gut-brain interactions and future clinic translational therapeutics.