The causal connections between gut microbiota and chronic pain and pain phenotypes through the gut-brain axis: A Mendelian randomization study and mediation analysis

Recent studies have increasingly highlighted a potential link between gut microbiota (GM) and chronic pain. However, existing research has yielded mixed results, leaving many questions unanswered. We employed a two-sample Mendelian randomization design to investigate whether GM directly influences multisite chronic pain (MCP) and eight phenotypes. We then used a combination of meta-analysis, genetic colocalization analysis, and Bayesian weighted mendelian randomization to further strengthen the evidence for causal relationship. Additionally, we examined how GM might be associated with human brain structures. Finally, we used mediation analysis to explore whether the structure and function of specific brain regions play a role in the relationship between GM and MCP and the pain phenotypes. We observed a significant causal association between 13 GM and chronic pain. Eight GM protected against pain phenotypes, whereas seven increased risk. The results indicate that GM could potentially affect the area, thickness, and volume of brain region cortices involved in sensory, emotional, and cognitive aspects of pain. Importantly, our findings indicated that the causal effect between the Genus Odoribacter and neck/shoulder pain could be mediated by the mean optical density in the left Fornix cres+Stria terminalis. In conclusion, different pain phenotypes were causally associated with different GM among European ancestry. Core GM may influence chronic pain by affecting complex brain networks. Notably, we constructed a basic gut-brain axis model for neck/shoulder pain, involving the Genus Odoribacter, left Fornix cres+Stria terminalis, and neck/shoulder pain.