Background: Fibromyalgia (FM) is a chronic disorder characterized by widespread pain and immune dysregulation. Emerging evidence suggests that gut microbiota and inflammatory proteins may contribute to the development of FM. Objective: The aim of this study was to investigate the causal relationships between gut microbiota, inflammatory proteins (cytokines/chemokines), and FM using bidirectional Mendelian randomization (MR) and meta-analysis approaches. Methods: MR analyses were conducted using genetic data from European populations, employing methods such as MR-IVW, MR-Egger, and MR-weighted median. Reverse MR was also performed, with FM treated as the exposure. A meta-analysis was conducted to consolidate the findings. Results: Ruminococcus gauvreauii was identified as a risk factor for FM, while Enterorhabdus, Parabacteroides, Butyricicoccus, and Prevotella 9 were found to be protective. Five inflammatory proteins C-X-C motif chemokine 5 (CXCL5), S100-A12, Leukemia inhibitory factor receptor (LIFR), Monocyte chemoattractant protein 2 (MCP-2/CCL8), and Tumor necrosis factor (TNF-α) exhibited protective associations, while Natural killer cell receptor 2B4 (NKCR-2B4/CD244) and Interleukin-12 subunit beta (IL-12β) were associated with an increased risk of FM. Conclusion: This study highlights the role of gut microbiota and inflammatory proteins (cytokines/chemokines) in the pathogenesis of FM. Through Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the findings suggest their involvement in immune regulation, inflammatory responses, and viral pathways. These findings provide new insights into potential therapeutic targets for modulating gut health and immune responses, opening new avenues for future research and clinical interventions.

The authors have declared no competing interest.

There was no specific funding for this specific study.

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Our analyses were based on publicly available data that had been approved by relevant review boards. Therefore, no additional ethical approval is required.

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The datasets used and/or analyzed during the current study are presented in the manuscript. Summary statistics for GWAS are publicly available.