Salidroside mitigates experimental colitis through cyclic adenosine monophosphate pathway activation and suppression of enteric glial cell responses

BACKGROUND Inflammatory bowel disease, particularly ulcerative colitis (UC), represents a chronic relapsing intestinal disorder of complex pathogenesis. The inflammatory cascade characteristic of UC compromises both the architecture and physiological integrity of the enteric nervous system. Salidroside (Sal), a bioactive component with well-documented anti-inflammatory and tissue-protective properties, has emerged as a potential candidate for UC treatment, yet its specific effects on enteric glial cells (EGCs) behavior and the underlying mechanisms mediating its therapeutic potential in experimental colitis remain incompletely understood. AIM To investigate how Sal regulates EGCs activation and its therapeutic pathways in experimental colitis. METHODS Colitis severity was quantified through disease activity scores, histological examination, and colonic length measurements. Mucosal barrier function was evaluated using immunofluorescent detection of tight junction proteins, ultrastructural analysis via transmission electron microscopy, and fluorescein isothiocyanate-dextran permeability assay. EGCs activation status was characterized through immunofluorescence and Western blot analysis. Systemic inflammatory markers were quantified using enzyme-linked immunosorbent assays to measure circulating cytokine concentrations. Mechanistic insights were obtained by integrating network pharmacology predictions with whole-transcriptome profiling. RESULTS Sal treatment significantly reduced disease activity index scores by (P < 0.0001), preserved colon length by 11.80% compared to dextran sulfate sodium salt (DSS) group (5.23 ± 0.16 cm vs 5.93 ± 0.17 cm, P = 0.0268), and decreased serum interleukin (IL)-1β by 78.17% [from 61.09 ± 0.90 pg/mL to 13.33 ± 0.68 pg/mL, P < 0.0001, 95% confidence interval (CI): 45.10%-50.40%], IL-6 by 64.13% (from 85.96 ± 1.73 pg/mL to 30.83 ± 0.84 pg/mL, P < 0.0001, 95%CI: 50.39%-59.87%), and tumor necrosis factor-α by 11.40% (from 91.06 ± 1.92 pg/mL to 80.68 ± 0.02 pg/mL, P = 0.0054, 95%CI: 3.57%-17.19%) in the DSS-induced colitis model. These beneficial outcomes correlated with modulatory effects on EGCs within the enteric nervous system. Integrated network pharmacology and transcriptomic investigations revealed that Sal operates through stimulation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) cascade, which underlies its anti-colitic properties. Sal intervention suppressed EGCs reactivity across both myenteric and submucosal plexuses, evidenced by diminished glial fibrillary acidic protein expression and decreased levels of inflammatory mediators. Concurrently, Sal augmented glial cell line-derived neurotrophic factor production, reconstituted epithelial tight junction complexes, normalized intestinal permeability parameters, and promoted comprehensive restoration of mucosal barrier architecture and function. CONCLUSION Through activation of the cAMP/PKA/CREB signaling cascade, Sal suppresses pathological EGCs activation, consequently attenuating intestinal inflammatory processes, preserving mucosal barrier integrity, and ameliorating experimental colitis.