cGAS/STING is associated with brain-gut-liver axis disturbance and systemic inflammation in cerebral ischemia.

Cerebral ischemia triggers a cascade of systemic inflammatory responses closely associated with brain-gut-liver axis disturbance, yet the underlying molecular mechanism remains incompletely understood. This study aimed to elucidate the mechanistic role of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway in disrupting gut-liver axis homeostasis following cerebral ischemia. Using a middle cerebral artery occlusion (MCAO) rat model, we employed a multidisciplinary approach combining behavioral, histological, molecular, and biochemical assays. We demonstrated that MCAO-induced cerebral infarction led to significant neurological deficits and behavioral impairment. Concurrently, Western blot analysis confirmed a significant upregulation of caspase-3, STING, cGAS, and phosphorylated IRF3 in the hippocampus. Consistent with these central changes, protein levels of caspase-3, STING, cGAS, and IRF3 were also elevated in both colonic and hepatic tissues, while the expression of tight junction proteins ZO-1 and Occludin was downregulated in the colon. H&E staining and electron microscopy of MCAO colon revealed mucosal disruption, crypt atrophy, and inflammatory infiltration, accompanied by reduced and deformed microvilli with impaired tight junctions. These changes coincided with elevated IL-12 and IL-18 levels in both the colon and liver. Immunofluorescence confirmed cGAS upregulation in MCAO colon. RT-qPCR analysis demonstrated a consistent pro-inflammatory response, with significant upregulation of cGAS, STING, IL-12, and IL-18 mRNA in the colon; elevated IL-12, IL-18, IFN-γ, and IL-1β mRNA in the liver; and increased IFN-γ, IL-1β, IL-18, and IL-12 mRNA in the hippocampus. Our findings suggest cerebral ischemia-induced systemic inflammation and gut-liver axis dysfunction may be associated with the activation of the cGAS/STING pathway.