Vitamin D3 ameliorates inflammation and autonomic dysfunction in a rat model of reflux esophagitis via modulation of IL-6 and TNF-α

Gastroesophageal reflux disease (GERD) and its manifestation as reflux esophagitis (RE) involves mucosal inflammation and autonomic dysfunction. Vitamin D3 deficiency is increasingly implicated in gastrointestinal inflammation and immune imbalance. This study investigated the therapeutic and prophylactic effects of 1,25-dihydroxyvitamin D3 on esophageal inflammation and autonomic nervous system disruption in a non-surgical rat model of RE. RE was induced via intermittent fasting and refeeding. Rats received either no treatment, prophylactic vitamin D3 (1250 IU/day pre- and post-induction), or therapeutic vitamin D3 (post-induction only). We assessed esophageal histopathology, immunohistochemical expression of tumor necrosis factor α (TNF-α) and transforming growth factor β (TGF-β), serum interleukin 6 (IL-6) levels via ELISA, and heart rate variability (HRV) indices. RE rats exhibited characteristic mucosal damage, elevated IL-6 and TNF-α expression, and impaired HRV (reduced standard deviation of normal to normal intervals (SDNN), High frequency (HF); increased low frequency/high frequency ratio (LF/HF)). Vitamin D3 supplementation significantly reversed these alterations. Prophylactic administration showed superior efficacy in preserving mucosal integrity and autonomic function compared to therapeutic intervention. Notably, TNF-α expression was abolished and IL-6 was significantly reduced. 1,25-dihydroxyvitamin D3 exerts protective and therapeutic effects in RE through suppression of inflammatory cytokines and restoration of autonomic balance. These findings support its potential as a neuroimmune modulator in esophageal inflammatory diseases. Heart rate variability (HRV) was assessed as an autonomic marker, and correlations with cytokine levels were explored. Scale bars and schematic workflow diagrams were included for clarity. A Limitations section was added to acknowledge constraints such as absence of a DMSO control.