Unraveling the Role of Gut Microbiota and Plasma Metabolites in Fibromyalgia: Insights from Mendelian Randomization and Dietary Interventions

Background Fibromyalgia (FM) is a complex disorder characterized by chronic pain, fatigue, and functional impairments, with unclear pathological mechanisms. Gut microbiota and plasma metabolites have been implicated in FM, but their causal relationships remain unexplored.

This study aims to assess the causal relationships between gut microbiota, plasma metabolites, and FM using Mendelian randomization (MR) analysis and to explore potential mediating mechanisms.

Public genome-wide association study data were analyzed using bidirectional MR. Associations between gut microbiota, plasma metabolites, and FM were evaluated, and multivariable MR identified mediating metabolites. Results were validated with inverse variance weighted, MR-Egger, and weighted median methods, with metabolic pathway enrichment analysis for further insights.

MR identified protective associations between FM and four taxa (family Enterobacteriaceae, genus Butyricicoccus, genus Coprococcus1, and order Enterobacteriales) and risk associations with genus Eggerthella and genus Ruminococcaceae UCG005. Additionally, 82 plasma metabolites linked to pathways such as caffeine metabolism, α-linolenic acid metabolism, GLP-1, and incretin regulation were associated with FM. Mediation analysis revealed Enterobacteriaceae and Enterobacteriales influenced FM risk through 2,3-dihydroxypyridine and palmitoylcholine.

Personalized dietary interventions, such as limiting caffeine intake, increasing omega-3 fatty acid consumption, adopting a low glycemic index diet, and reducing the intake of high-oxalate foods, may effectively alleviate FM-related symptoms by modulating metabolic pathways, reducing inflammation, and mitigating oxidative stress. This study highlights the intricate interactions between the gut microbiota and metabolic pathways, providing critical scientific evidence and actionable targets for clinical interventions, dietary management, and precision medicine approaches in FM treatment. Competing Interest Statement The authors have declared no competing interest. Funding Statement There was no specific funding for this specific study. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Our analyses were based on publicly available data that had been approved by relevant review boards. Therefore, no additional ethical approval is required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The datasets used and/or analyzed during the current study are presented in the manuscript. Summary statistics for GWAS are publicly available.