Dysregulated autophagy, neural signaling pathways and gut-brain axis in a novel vestibular migraine-like rat model:...

Vestibular migraine (VM) pathophysiology remains incompletely understood, partly due to lacking validated animal models replicating its dual vestibular-nociceptive phenotype. This study aimed to establish a VM-like rat model and investigate associated mechanisms and gut microbiota/Serum metabolomics alterations.

Male Sprague‒Dawley (SD) rats were used to establish a VM-like rat model via cervical subcutaneous nitroglycerin injections combined with variable-speed rotational stimulation. Behavioral tests, including tests for mechanical and thermal thresholds, balance beam traversal, and motion sickness (MS) index, were conducted to assess vestibular and nociceptive phenotypes. Molecular analyses included ELISA/WB/IF for TRP channels, CGRP, NMDAR1-CaMKII-CREB pathway, and autophagy markers in blood or brain tissues (trigeminocervical complex (TCC), vestibular nuclei (VN), thalamus, and cerebellum). Gut microbiota (16 S rRNA sequencing) and serum metabolomics (untargeted LC-MS) were profiled. Bioinformatics utilized OMIM, GeneCards, and GSE157495 datasets.

VM-like rats presented significant mechanical/thermal hyperalgesia, prolonged balance beam traversal, and elevated MS index scores (p < 0.05). Molecular analyses revealed upregulated TRPA1/TRPV1/TRPM8 in blood, increased CGRP in TCC/VN (p < 0.05), activated NMDAR1-CaMKII-CREB pathway in VN, and impaired autophagic flux (↑LC3-II, ↑P62; p < 0.05) in both VM patients and VM-like rats. Gut microbiota showed reduced evenness, increased Lactobacillus, HT002, and Bifidobacterium; and decreased Lachnospiraceae_NK4A136_group, Lachnospiraceae_unclassified, and Ligilactobacillus. Serum metabolomics revealed decreased SMs/PCs/PEs, increased 2-ketobutyric acid/GABA, and enrichment in amino acid metabolism, sphingolipid signaling, and vitamin pathways.

This validated VM-like rat model recapitulates core clinical and molecular features of VM. Gut dysbiosis and serum metabolic perturbations provide novel insights into the gut-brain axis in VM pathogenesis, suggesting potential therapeutic targets.