Researchers at the San Francesco Hospital in Telese Terme conducted a case‑control study of 12 patients with Long‑COVID‑19 and eight control subjects who underwent routine gastroscopy. Biopsies from the gastric mucosa were stained for the pan‑neuronal marker PGP 9.5 and the cholinergic marker vasoactive intestinal peptide (VIP) and analyzed with confocal microscopy to quantify nerve fiber density in the fundus and antrum.

Long‑COVID‑19 patients showed a median nerve density of 2.1 nm/µm³ in the fundus and 1.9 nm/µm³ in the antrum, compared with 3.9 nm/µm³ and 3.9 nm/µm³ in controls, respectively (p<0.01 and p=0.01). The reduction in VIP‑positive cholinergic fibers was more pronounced in the fundus (p<0.01) and also present in the antrum (p=0.01).

Heart rate variability analysis revealed a higher LF/HF ratio of 1.7 in patients versus 1.1 in controls (p<0.01) and elevated levels of NT‑proBNP (646 ng/L vs 259 ng/L) and D‑dimer (797 ng/mL vs 349 ng/mL) (both p<0.01). Nerve density correlated with LF/HF ratio (R=0.50, p<0.05) and with NT‑proBNP (R=0.52, p<0.01).

These findings provide the first in vivo evidence of selective cholinergic denervation in the gastric mucosa of Long‑COVID‑19 patients and indicate a structural component to the autonomic dysfunction observed in this population. Further studies are needed to evaluate whether restoration of vagal function can mitigate the associated symptoms.