Background & Aims

Fibromyalgia (FM) is a chronic pain syndrome with an unknown cause. FM subjects (FMS) exhibit an altered composition of gut microbiota and heightened gut permeability compared to healthy controls (HC)[3,7–9]. We have previously suggested that an autoimmune component contributes to pain in FM by immunoglobulin G binding to satellite glial cells (anti-SGC IgG)[4,5]. Short-chain fatty acids (SCFAs) are gut microbiota-derived metabolites linked to neuropathic pain in mice[11]. Primary bile acids (BAs) are derived from cholesterol and transformed by the gut microbiota into secondary BAs. Bile acids can have neuropathic pain-resolving functions[2,10] and induce itch and pain in mice[1]. Bile acids can also cause visceral hypersensitivity in diarrhea-predominant irritable bowel syndrome (IBS-D)[6]. Secondary muricholic acid (MCA) was recently shown to be increased in FMS[8]. However, the associations between BAs/SCFAs with anti-SGC IgG levels and FM symptomology have never been investigated.

Methods

The cohort consisted of 88 FMS and 39 HC, all well characterized regarding symptoms with validated questionnaires. Immunocytochemistry was used to assess the anti-SGC IgG levels by determining the percentage of murine SGC in culture binding human IgG [5]. Serum concentrations of 24 BAs and 11 SCFAs were determined using liquid chromatography coupled with high-resolution mass spectrometry. The individuals were analyzed as the whole group, as well as non-overweight (BMI < 25) and overweight/obese (BMI ? 25) groups. The FMS were divided into severe (FMS severe) and mild symptomatology (FMS mild) groups, based on pain intensity (visual analogue scale (VAS) ratings) and disease severity (fibromyalgia impact questionnaire (FIQ) scores). The FMS were also divided into groups of high (? 50%) and low (< 50%) anti-SGC IgG level groups. Linear regression was used to compare all groups, adjusting for age and BMI. The BA and SCFA concentrations were correlated to the demographic and clinical data.

Results

FMS, as a group, had higher (P < 0.05) total concentrations of secondary BAs, while the total BA concentrations were unchanged. The secondary deoxycholic acid (DCA) was increased, and SCFA isovaleric acid decreased in FMS compared to HC (P < 0.05). Interestingly, non-overweight FMS with high anti-SGC IgG levels showed significantly (P < 0.05) increased concentrations of eleven BAs (CDCA, CA, DCA, HCA, MCA, UDCA, Gly-HDCA, Gly-DCA, Gly-CDCA, Gly-CA, and Gly-LCA-3-S), compared to FMS with low anti-SGC IgG. Additionally, there was a strong association in non-overweight FMS, between conjugated bile acids (glycine-conjugated CA, DCA, HCA, LCA-3-S and taurine-conjugated CDCA, CA, DCA, HCA, HDCA) and anti-SGC IgG levels, worse mental well-being (the mental component of SF36 and Hospital anxiety and depression scale), and higher FIQ. No significant positive associations existed between BAs and pain ratings (VAS) in FMS, regardless of grouping.

Conclusions

Fibromyalgia subjects have higher serum concentrations of gut microbiota-derived BAs than HC, which could be related to a dysregulated gut microbiome. Interestingly, in non-overweight FMS, there is a strong association between the concentrations of conjugated bile acids, anti-SGC IgG levels, and reduced mental well-being.

The increase of DCA in FMS may be connected to IBS, where DCA and CDCA have been found to induce visceral hypersensitivity. As such, these findings suggest a new link between anti-SGC IgG levels, gut-microbiota-derived changes, and IBS-related comorbidities typically found in FMS. The differences between non-overweight and overweight/obese FMS are interesting and should be further explored.

References

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[2] Fiore NT, Debs SR, Hayes JP, Duffy SS, Moalem-Taylor G. Pain-resolving immune mechanisms in neuropathic pain. Nat Rev Neurol 2023;19:199–220.
[3] Goebel A, Buhner S, Schedel R, Lochs H, Sprotte G. Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome. Rheumatology 2008;47:1223–1227.
[4] Goebel A, Krock E, Gentry C, Israel MR, Jurczak A, Urbina CM, Sandor K, Vastani N, Maurer M, Cuhadar U, Sensi S, Nomura Y, Menezes J, Baharpoor A, Brieskorn L, Sandström A, Tour J, Kadetoff D, Haglund L, Kosek E, Bevan S, Svensson CI, Andersson DA. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest 2021;131. doi:10.1172/JCI144201.
[5] Krock E, Morado-Urbina CE, Menezes J, Hunt MA, Sandström A, Kadetoff D, Tour J, Verma V, Kultima K, Haglund L, Meloto CB, Diatchenko L, Kosek E, Svensson CI. Fibromyalgia patients with elevated levels of anti-satellite glia cell immunoglobulin G antibodies present with more severe symptoms. Pain 2023;164:1828–1840.
[6] Li W-T, Luo Q-Q, Wang B, Chen X, Yan X-J, Qiu H-Y, Chen S-L. Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis. FASEB J 2019;33:2435–2450.
[7] Martín F, Blanco-Suárez M, Zambrano P, Cáceres O, Almirall M, Alegre-Martín J, Lobo B, González-Castro AM, Santos J, Domingo JC, Jurek J, Castro-Marrero J. Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery. Front Immunol 2023;14:1253121.
[8] Minerbi A, Gonzalez E, Brereton N, Fitzcharles M-A, Chevalier S, Shir Y. Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity. Pain 2023;164:e66–e76.
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[10] Wu Y, Qiu Y, Su M, Wang L, Gong Q, Wei X. Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain. CNS Neurosci Ther 2023. doi:10.1111/cns.14154.
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Presenting Author

Jenny Jakobsson

Poster Authors

Jenny Jakobsson

MS

Uppsala university

Lead Author

E-mail

Ida Erngren

PhD

Uppsala University

Lead Author

E-mail

Henrik Carlsson

PhD

Uppsala University

Lead Author

E-mail

Joana Menezes

MS

Karolinska Institutet

Lead Author

E-mail

Emerson Krock

PhD

Karolinska Institutet, McGill University

Lead Author

E-mail

Katalin Sandor

PhD

Karolinska Institutet

Lead Author

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Jeanette Tour

MD

Karolinska Institutet

Lead Author

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Angelica Sandström

PhD

Karolinska Institutet

Lead Author

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Diana Kadetoff

MD PhD

Karolinska Institutet

Lead Author

E-mail

Camilla Svensson

Karolinska Institutet

Lead Author

E-mail

Eva Kosek

Karolinska Institutet, Stockholm, Sweden

Lead Author

E-mail

Kim Kultima

PhD

Uppsala University, Karolinska Institutet

Lead Author

E-mail

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Fibromyalgia