Potential links between gut microbiota-derived propionate and succinate and CXCL8, IL1B, and IL6 in NMOSD: An integrated network pharmacology and mendelian randomization study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune demyelinating disease of the central nervous system. Gut microbiota metabolites may participate in NMOSD pathogenesis, but their biological relevance and underlying molecular links remain unclear. METHODS: Candidate key targets of gut microbiota metabolites in NMOSD were obtained from the intersection of public database targets (human gut, NMOSD, and metabolite targets). Functional enrichment and regulatory network analyses were conducted. Microbiota-metabolite-target-signaling pathway (MMTS) network, Mendelian randomization (MR) analysis, and metabolite evaluations (drug-likeness, toxicology, and molecular docking) were performed. RESULTS: CXCL8, IL1B, and IL6 were identified as candidate key targets. Notably, they were enriched in pathways related to immune regulation and inflammatory responses, such as "NOD-like receptor signaling pathway", "Toll-like receptor signaling pathway", and "IL-17 signaling pathway". Predicted regulatory factors included hsa-miR-191-5p and hsa-let-7c-5p. Additionally, Barnesiella intestinihominis, Ruminococcus bromii, and Ruminococcus champanellensis were identified as key microbiota. Their associated key metabolites, including propionate and succinate, exhibited favorable drug-likeness, low toxicity, and promising binding affinities to the candidate key targets. CONCLUSION: This study suggests that gut microbiota metabolites may affect NMOSD through CXCL8, IL1B, IL6, and immune-inflammatory pathways. Propionate and succinate were identified as candidate metabolites requiring experimental validation of their effects on these targets.