Gut microbial and metabolomic alterations associated with herpetic trigeminal neuralgia: an exploratory multi-omics study

Background: Herpetic trigeminal neuralgia (HTN) is a neuropathic pain disorder caused by varicella-zoster virus invasion of the trigeminal nerve, but its mechanisms remain poorly elucidated. Accumulating evidence implicates gut microbiota dysbiosis and metabolic perturbations in modulating chronic pain via the gut–brain axis, yet their roles in HTN have not been systematically explored. Methods: Integrated multi-omics analysis was performed on 19 patients with HTN and 18 healthy controls. Fecal metagenomic sequencing characterized gut microbial composition and function. Untargeted metabolomics profiled metabolic signatures in fecal and circulating samples. Weighted gene co-expression network analysis (WGCNA) and random forest modeling screened pivotal microbial and metabolic features associated with HTN. Correlation analysis between differential metabolites and clinical pain scores validated the translational potential of identified alterations. Results: HTN patients showed significantly reduced gut microbial diversity, with enriched Proteobacteria, depleted butyrate-producing bacteria (including Faecalibacterium, Roseburia, and Lachnospira), and expanded opportunistic pathogens (Escherichia coli and [Ruminococcus] gnavus). Microbial pathways for pH homeostasis and oxidative stress defense were downregulated. Metabolomic analysis identified differential metabolites, primarily involving nicotinate/nicotinamide metabolism and retrograde endocannabinoid signaling. WGCNA and random forest analyses suggested fecal metabolites as potential candidate features, with associations between gut microbial dysregulation and systemic metabolic changes. Furthermore, screened metabolites correlated significantly with pain scores. Conclusions: This study provides multi-omics evidence of gut microbial and metabolic dysregulation in HTN, generating hypotheses for further mechanistic research. Large-scale, multicenter prospective cohorts with standardized metadata collection are needed to validate these findings.

Herpetic trigeminal neuralgia; Gut microbiota; Metagenomics; Metabolomics; Gut–brain axis

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