Background: Emerging evidence highlights the pivotal role of the vagus nerve (VN) in rheumatoid arthritis (RA), with reduced VN activity preceding the disease onset and vagotomy identified as a potential risk factor for RA development. This phenomenon is linked to the VN’s immunomodulatory properties but may also integrate its role in the gut-brain axis. Both preclinical and clinical studies suggest that VN stimulation may alleviate chronic pain, including fibromyalgia, abdominal pain, and headaches. Despite achieving clinical and biological remission, approximately 30% of RA patients continue to experience persistent pain. Interestingly, dysbiosis—a disruption in gut microbiota composition—is present in RA and may even precede the development of articular symptoms. Using heart rate variability (HRV) analysis from telemetric electrocardiograms, our team demonstrated that fecal microbiota transplantation (FMT) from RA patients altered VN activity in recipient mice compared to FMT from healthy controls (HC), mimicking the VN dysfunction observed in RA. We hypothesize that chronic pain in RA may partly stem from dysbiosis and its effects on the VN and gut-brain axis.

Objectives: Here, we explore the interplay between gut microbiota, VN activity, and pain using a mouse model.

Methods: FMT was performed using gut microbiota from RA patients (RA-FMT) or HC (HC-FMT) in male C57/Bl6 mice. VN activity was assessed via calcium imaging of vagal afferent neurons isolated from nodose/jugular ganglia. Neurons were stimulated with pharmacological agents, including serotonin and nicotine, to evaluate their responses. Behavioral experiments were conducted to assess mechanical sensitivity (Von Frey Test) and anxiodepressive-related behaviors (Sucrose Splash Test). Statistical analyses were performed using Mann-Whitney tests.

Results: RA-FMT (n = 136 neurons, N = 10 mice) did not alter the proportion of nodose neurons responding to serotonin and nicotine compared to HC-FMT (n = 98 neurons, N = 5 mice), with response rates of 52% and 71% for RA-FMT versus 48% and 75% for HC-FMT, respectively. However, RA-FMT neurons exhibited a significant reduction in nicotine response amplitude (p = 0.038, n = 48 RA-FMT neurons vs. 70 HC-FMT neurons). No difference in serotonin response amplitude was observed (n = 30 RA-FMT neurons; 46 HC-FMT neurons). In vivo , RA-FMT did not affect mechanical sensitivity but induced depressive-like behaviors, evidenced by reduced grooming time in the Sucrose Splash Test (p = 0.067, n = 6 RA-FMT mice; 4 HC-FMT mice).

Conclusion: Our findings, supported by HRV analysis and calcium imaging, suggest that gut microbiota from RA patients modulates VN afferent neuronal responses and may contribute to depressive-related behaviors in vivo . Ongoing studies aim to elucidate the underlying mechanisms of this modulation. Targeting the gut microbiota-VN axis represents a promising therapeutic avenue for managing chronic pain in RA.

REFERENCES: NIL.

Acknowledgements: NIL.

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.