Objective: Chronic sleep disturbance aggravates peptic ulcer disease, yet the temporal ordering of vagal, secretory, inflammatory and mucosal events, and the role of the vagus nerve, remain unclear. We tested a time-ordered cascade (vagal hyperactivity to acid hypersecretion to mucosal inflammation to ulceration) and whether early versus late sleep restoration or subdiaphragmatic gastric vagotomy interrupts it.

Methods: 288 male Sprague-Dawley rats were allocated to six groups (control; ulcer alone; sleep deprivation with ulcer; early restoration, day 7; late restoration, day 21; vagotomy) and killed on days 3, 7, 14 or 28 (n = 12 per subgroup). Ulcers were induced by acetic acid injection; sleep deprivation used the modified multiple-platform method. Vagal firing, basal acid output, gastric pH and volume, IL-1β, IL-6, IL-8/CINC-1, TNF-α mRNA, ulcer index and histology were measured serially; day-28 data were analyzed by animal-level serial-mediation SEM with Monte Carlo intervals.

Results: Vagal firing rose first, on day 3, when acid had not yet risen (P = 0.62); acid increased on day 7, cytokines on day 14, and ulceration peaked on day 28 (65.8 ± 5.6 vs 4.3 ± 3.8 mm² control; P < 0.001). Early restoration reduced the ulcer index to near ulcer-alone levels (15.0 ± 8.8), late restoration only partially (36.7 ± 4.3; P < 0.001), and vagotomy returned ulcers to ulcer-alone levels (11.6 ± 4.2 vs 12.8 ± 8.2; equivalence P = 0.019). The model fitted well (CFI = 0.996, RMSEA = 0.074) with a significant serial indirect path (β = 0.81; 95% CI 5.47-8.64) and non-significant direct paths, indicating full mediation.

Conclusion: Sleep disturbance aggravates peptic ulcer through a vagus-initiated, time-ordered acid-inflammation cascade, identifying the vagus as an upstream, time-sensitive therapeutic target.

Keywords: Sleep Deprivation; Peptic Ulcer; Vagus Nerve; Gastric Acid; Inflammatory Mediators; Rats

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