Activation of GABAR alleviates DSS-induced colitis in mice by rebalancing inflammatory responses and antioxidant capacity through IRAK-M.

Abstract

The pathogenesis of inflammatory bowel disease is complex, involving key contributors such as inflammatory factors and oxidative stress. While the gamma-aminobutyric acid B receptor (GABAR) is recognized for its potential anti-inflammatory and antioxidant capabilities, its specific role in colitis requires further elucidation. This study aimed to determine whether GABAR activation could alleviate colitis by modulating these interconnected pathways. Our findings demonstrate that dextran sulfate sodium-induced colitis significantly downregulates GABAR expression in colonic tissues, a finding confirmed in lipopolysaccharide-stimulated Caco-2 cells. Pharmacological activation of GABAR with baclofen effectively mitigated overall disease severity by ameliorating clinical symptoms and preventing colon shortening; it also preserved mucosal architecture while restoring goblet cell numbers and modulating mast cell populations. Mechanistically, experiments across both in vivo and in vitro models demonstrated that these multifaceted protective effects were primarily mediated through the upregulation of interleukin-1 receptor-associated kinase M (IRAK-M). Specifically, GABAR activation produced coordinated effects by significantly suppressing pro-inflammatory cytokines including IL-1β, IL-6, IL-17A, IL-22, and TNF-α, while potently countering oxidative stress via elevation of key antioxidants including HO-1, NRF2, and GPX4 and simultaneous inhibition of iNOS. Most importantly, genetic knockout of IRAK-M completely exacerbated all pathological aspects of colitis, encompassing clinical severity, histological damage, inflammatory cytokine storm, and oxidative imbalance, thereby definitively confirming IRAK-M as the essential downstream mediator. Consequently, these results establish that GABAR alleviates colitis by targeting IRAK-M to coordinately enhance antioxidant responses and inhibit inflammation, highlighting the GABAR signaling as a promising therapeutic target.