Altered Gut Microbiome Composition and Function in Individuals with Complex Regional Pain Syndrome

Background: Complex regional pain syndrome is a chronic pain syndrome typically affecting a limb. It is characterized by severe spontaneous and evoked pain, along with vasomotor, autonomic, and motor signs and symptoms. Although dysregulation in several physiologic systems has been suggested in complex regional pain syndrome (CRPS), including aberrant inflammatory and immune responses, vasomotor dysfunction, and nervous system changes, the pathophysiologic mechanisms underlying the syndrome remain elusive. Effective treatment options are also limited. Previous research has highlighted the role of the gut microbiome in chronic pain, prompting us to investigate the composition and function of the gut microbiome in CRPS. Methods: The gut microbiomes of individuals with CRPS to age-, sex-, and ethnicity-matched pain-free control participants were compared using 16S rRNA gene amplification. To minimize environmental confounders, participants were recruited from two geographically independent regions. To explore potential changes in gut bacteria–derived metabolites, targeted metabolomic analysis of feces and plasma was performed. Finally, machine learning algorithms were trained to identify the gut microbiome composition specific to CRPS patients and were tested on a validation cohort. Results: In this study, differential abundance analysis revealed significant differences in several bacterial taxa when comparing 53 CRPS patients to 52 unrelated controls, including alterations in short-chain fatty acid–metabolizing species. Targeted stool and plasma metabolite analysis confirmed differences in fecal and plasma short-chain fatty acid levels between CRPS patients and controls. Notably, the microbiome composition alone allowed accurate classification of patients and controls in a geographically independent test cohort. Conclusions: These findings highlight unique compositional and functional changes in the gut microbiome of individuals with CRPS, thus contributing to the growing body of evidence supporting the role of the gut microbiome in chronic pain syndromes. Furthermore, they pave the way for further studies elucidating the pathophysiology of CRPS and exploring new diagnostic aids and treatment modalities.