Background: Fibromyalgia (FM) is a complex disease characterized by chronic musculoskeletal pain, affecting about 2% to 4% worldwide middle-aged women [1]. Currently, there is no molecular analysis to diagnose FM and its complex pathophysiology complicates both diagnosis and treatment despite EULAR recommendations for the disease [2]. Previous studies have suggested an association between the disease and oxidative stress, mitochondrial metabolism, intestinal microbiota and inflammation, supporting the multifactorial origin of FM [3, 4]. However, these studies are designed in small cohorts and, consequently, obtain inconclusive results. To solve these limitations, this project represents the first low-interventional investigation with more than 200 participants focused on exploring the pathways and triggers of FM and monitoring these during the development of the disease.

Objectives: The objective of this randomized, prospective, low-interventional, double-blinded and placebo-controlled clinical trial (NCT05921409) is the development of a specific panel of FM biomarkers and the evaluation of their response to a six-month nutritional intervention.

Methods: A group of 210 FM patients and 40 age-matched healthy women were selected according to ACR. Both groups were involved in placebo (olive oil) and extra virgin olive oil- treatment group (EVOO), during a 6 months nutritional intervention. Both groups provided stool and blood samples at the beginning, after 3 months, at the end of the nutritional intervention, and 6 months after the six-month treatment. The composition of the intestinal microbiota was identified by 16S rRNA gene sequencing using Illumina technology, the plasma proteome was analyzed using an nLC-MS/MS proteomics approach, and clinical data were collected through health questionnaires such as SF-36 and FIQ-R. The impact of treatment was analyzed over time using bioinformatics and machine learning tools.

Results: The longitudinal analysis allowed us to discover how the EVOO-treated group compared to the placebo group had differential effects on the gut microbiome and plasma proteome. Surprisingly, it was identified different groups of bacteria and proteins that were interesting for patient follow-up, such as those that had a positive impact during the intervention and continued the same trend after treatment was discontinued. However, others were only influenced during EVOO intervention and reversed the effect once treatment was discontinued, highlighting the importance of its continued consumption in patients. The vast majority of the identified biomarkers, with statistically significant differences ( p <0.05), are related to neurotransmitter signaling and loss of beneficial taxa in gut microbiome in addition to oxidative stress and inflammation related proteins in peripheral blood samples. Clinical data collected through the SF36 and FIQ.R questionnaires showed interesting correlations that provide a valuable resource for the relief of FM symptoms through diet therapy.

Conclusion: This study represents the first low-interventional clinical trial with more than 200 participants focused on exploring diet therapy and EVOO treatment impact on FM patients gut microbiome and plasma proteome. The results of this study contribute to a better understanding of FM and to the development of a robust panel of diagnostic and monitoring biomarkers that shed light on the modulation of the disease with non-pharmacological therapies that act on the proposed biomarkers. The early diagnosis of FM patients and their ongoing follow-up over time are critical aspects that could be significantly enhanced with this innovative approach to the disease.

REFERENCES: [1] Sarzi-Puttini P, Giorgi V, Marotto D, Atzeni F. Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat Rev Rheumatol. 2020;16(11):645-60.

[2] Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Fluß E, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis. 2017;76(2):318-28.

[3] Martínez-Lara A, Moreno-Fernández AM, Jiménez-Guerrero M, Díaz-López C, De-Miguel M, Cotán D, Sánchez-Alcázar JA. Mitochondrial Imbalance as a New Approach to the Study of Fibromyalgia. Open Access Rheumatol. 2020 Aug 24;12:175-185.

[4] Erdrich S, Hawrelak JA, Myers SP, Harnett JE. Determining the association between fibromyalgia, the gut microbiome and its biomarkers: A systematic review. BMC Musculoskelet Disord. 2020 Mar 20;21(1):181.

Acknowledgements: This project will be fully completed with the kind collaboration of healthy volunteers and FM patients, with a crucial role being played by several FM associations that will help to study coordination. These associations, in alphabetical order, are: ACEF (Asociación Cántabra de Fibromialgia; Santander, Spain), ACOFI (Asociación Cordobesa de Fibromialgia; Córdoba, Spain), AENFIPA (Asociación de Enfermos de Fibromialgia y Síndrome de Fatiga Crónica del Principado de Asturias; Oviedo, Spain), AFIAL (Asociación de Fibromialgia y Síndrome de Fatiga Crónica; Almería, Spain), AFIBRODON (Asociación de Enfermos de FM de Don Benito; Don Benito, Badajoz, Spain), AFIBROL (Asociación de Fibromialgia y Fatiga Crónica de Olivenza; Olivenza, Badajoz, Spain).

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.