Background & Aims

Complex regional pain syndrome (CRPS) is a chronic primary pain disorder causing severe, disproportionate limb pain with associated autonomic & inflammatory signs. Its pathophysiology is thought to involve several mechanisms. Despite years of research,the causes of CRPS remain elusive, the diagnosis is clinical, lacking a definitive diagnostic test & treatment is challenging often leaving patients with severe symptoms. Recently, human & animal studies have demonstrated a critical role for the gut microbiome in the development of several chronic pain conditions. While the exact mechanisms allowing the gut microbiome to play this role are still being investigated, the involvement of circulating bacterial-derived metabolites, immune dysregulation & microglial activation has been demonstrated. This study aims to investigate the composition of the gut microbiota in individuals with CRPS in 2 independent cohorts & to characterize its stability over different environments & syndrome severity.

Methods

Individuals with CRPS, as well as age, gender & ethnicity-matched pain-free controls, were recruited simultaneously in 2 geographically independent pain centres: the Rambam Institute for Pain Medicine in Haifa, Israel and the Alan Edwards Pain Management Unit of the McGill University Health Centre in Montreal, Quebec, Canada. Inclusion criteria for participants were: Adult women and men, over 18 years old, diagnosed with CRPS according to the Budapest criteria (for patients) and without chronic pain (for controls), and able to give informed consent. Exclusion criteria: major comorbid illness, recent antibiotic treatment, recent acute illness, change in medication or substantial dietary alterations in the preceding month. After being evaluated by specialized pain physicians the diagnosis of CRPS was confirmed, and participants filled in the study questionnaires and gave a stool sample. Stool microbial communities were analyzed and compared using 16S rRNA gene amplification & sequencing.

Results

53 CRPS patients and 52 matched pain-free controls were recruited for this study. While the overall composition of the gut microbiome of CRPS patients was similar to that of pain-free controls, several differentially abundant bacterial species were identified, some of which are well-known short-chain fatty acid metabolizers. Among these, a marked depletion of several propionic acid metabolizers was observed as well as a marked depletion of Prevotella copri, which had also been shown to be depleted in individuals with fibromyalgia. A logistic regression model was used on a training cohort comprising 77 participants from Israel. Several sets of exact sequence variants (ESVs) were identified, which provided the best overall prediction accuracy on a test cohort. These sets were then tested on an independent validation cohort of 20 participants from Canada, yielding a prediction accuracy of 87.1-90.5% with a sensitivity of 83-90.5% and specificity of 85.7-91.1%.

Conclusions

In this study, specific compositional changes in the gut microbiome were observed in a cohort of 43 Israeli CRPS patients and 42 healthy controls, which were validated in an independent Canadian cohort of 10 patients and 10 pain-free controls. Depleted bacterial species in CRPS include propionic acid producers, potentially linked to altered metabolic pathways. Shared functional niches with fibromyalgia may suggest common mechanistic effects of the gut microbiota in both syndromes. The identified gut microbiome features serve as a CRPS-specific biosignature, as demonstrated by a validated machine learning model. Finally, CRPS-related gut microbiome composition was stable across environmental conditions. These observations suggest a robust association of the gut microbiome composition in CRPS, warranting further research regarding its causal role in the syndrome, potential mechanisms of action and possibly diagnostic and therapeutic clinical applications.

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Presenting Author

Sabrina Mitrovic

Poster Authors

Maayan Ben Sasson

MD

McGill

Lead Author

Tali Sahar

MD, MSc

Lead Author

Topics

  • Assessment and Diagnosis