Abstract
BACKGROUND: Although previous studies have indicated a potential association between gut–brain axis dysfunction and chronic pain, the causal relationship and underlying pathogenic mechanisms remain unclear. Therefore, this study employed Mendelian Randomization (MR) analysis to investigate the causal effect of the gut–brain axis on chronic pain from a genetic perspective. METHODS: This study utilized the largest available genome-wide association study (GWAS) summary statistics to date, incorporating data on gut microbiota (n = 18,340 from MiBioGen consortium), brain structural connectivity (n = 26,333 from the GWAS Catalog), and 15 chronic pain conditions from FinnGen consortium, including trigeminal neuralgia, postherpetic neuralgia, small fiber neuropathy, diabetic neuropathy, sciatica, atypical facial pain, idiopathic peripheral autonomic neuropathy, intercostal neuropathy, thoracic spine pain, drug-induced polyneuropathy, alcohol-induced polyneuropathy, migraine, migraine with aura, migraine without aura, and cluster headache. We conducted two-sample Mendelian Randomization (TSMR) analyses to examine the causal relationships among gut microbial abundance, brain structural connectivity, and chronic pain. In addition, mediation analysis was performed to construct a gut microbiota–brain structural connectivity-chronic pain axis, aiming to evaluate the mediating role of brain connectivity in these causal pathways. A series of sensitivity analyses were also carried out to assess the robustness of our findings. RESULTS: The results revealed 101 gut microbial abundances with potential causal associations to chronic pain, of which 48 were predicted as potential risk factors and 53 as potential protective factors. Similarly, 127 brain structural connectivity phenotypes showed potential causal relationships with chronic pain, including 73 predicted as risk factors and 54 as protective factors. Mediation analysis identified 10 significant gut microbiota-brain structural connectivity-chronic pain pathways. Notably, the causal effect of genus Eubacterium brachy on sciatica was mediated by right-hemisphere salience/ventral attention network (SAN/VAN) connectivity to the putamen, with the highest mediation proportion of 27.07%. CONCLUSION: This study investigated the causal relationship between the gut–brain axis and chronic pain, providing novel insights into the pathogenesis and therapeutic strategies of chronic pain. Moreover, it identified potential biomarkers for personalized pain management and early diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00876-w.