Disrupting intestinal cell pyroptosis-NETs crosstalk reverse mucosal damage and restore Treg/Th17 equilibrium in ulcerative colitis via a calcium pectate microsphere composite hydrogel

The crosstalk between dysregulated intestinal epithelial cells (IECs) death and hyperactivated immune cells is crucial to maintain the intestinal barrier integrity in ulcerative colitis (UC), but remains seldom explored for the anti-inflammatory therapies reported so far. For this purpose, this study first identifies the crucial role of the crosstalk between Gasdermin D (GSDMD)-dependent intestinal cell pyroptosis and neutrophil extracellular traps (NETs) in exacerbating intestinal barrier damage. An orally administrable inulin gel composite (BCPD@gel) was further developed, encapsulating calcium pectate-based microspheres that are loaded simultaneously with berberine (BBR) and Deoxyribonuclease I (DNase I) via hydrophobic and electrostatic interactions, respectively. BCPD@gel breaks the crosstalk between GSDMD-dependent intestinal cell pyroptosis and NETs to modulate gut microbiota composition and restore Th17/Treg equilibrium, collectively leading to compromised inflammation cascade for dextran sulfate sodium (DSS)-induced colitis treatment. BCPD@gel administration greatly restored epithelium barriers by alleviating the vicious cycle between GSDMD-dependent IEC pyroptosis and NETs in a DSS-induced colitis model, which was evidenced by a mouse colon length of 6.76 ± 0.4 cm. This improved value is close to that of the normal group and 1.4-fold longer than that of the DSS group. Overall, this study highlights the leverage of IEC-neutrophil interactions as a potent strategy to circumvent ongoing inflammation and maintain the intestinal barrier integrity for effective DSS-induced colitis treatment.