Vagal cholinergic denervation of the gastric mucosa in Long-COVID-19: in vivo evidence of structural autonomic dysfunction

OBJECTIVES: Dysautonomia has been increasingly recognized as a key feature of Long-COVID-19, potentially contributing to persistent gastrointestinal and systemic symptoms. Reduced vagal activity observed in these patients may reflect structural damage to autonomic fibers. We hypothesized that dysautonomic manifestations in Long-COVID-19 are associated with impaired cholinergic innervation of the gastric mucosa. METHODS: We conducted a case-control study including 12 patients with Long-COVID-19 and 8 control subjects undergoing routine gastroscopy. Gastric mucosal biopsies were analyzed using immunohistochemistry with the pan-neuronal marker protein gene product 9.5 (PGP 9.5) and vasoactive intestinal peptide (VIP) as a marker of cholinergic fibers. Nerve fiber density was quantified in both fundus and antrum samples. RESULTS: Compared with controls, Long-COVID-19 patients exhibited a significant reduction in mucosal innervation density: 2.1 vs 3.9 nm/µm³ (p<0.01) in the fundus and 1.9 vs 3.9 nm/µm³ (p<0.05) in the antrum. The reduction in cholinergic innervation was more pronounced in the fundus (p<0.01) andalso evident in the antrum (p=0.01). Gastric nerve density correlated with HRV parameters (LF/HF ratio: R=0.50, p<0.05) and NT-proBNP levels (R=0.52, p<0.01). CONCLUSIONS: Patients with Long-COVID-19 exhibit reduced gastric mucosal cholinergic innervation. This structural autonomic impairment may represent an anatomical substrate underlying dysautonomia in Long-COVID-19.