Abstract
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) and also 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.
Keywords: Autonomic dysfunction; Gastric innervations; HRV; Long-COVID-19; Vagus nerve.
Conflict of interest statement
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.