Dissecting Causal Relationships Between Gut Microbiota Imbalance, Inflammatory Cytokines, and Structural Connectivity in the Brain: A Mendelian Randomization Study.

PURPOSE: Growing evidence indicates that the imbalances in gut microbiota influence brain structural connectivity, a key component of the microbiota-gut-brain axis. However, a deeper understanding of this complex bidirectional relationship remains elusive. This study aims to deepen our understanding of this bidirectional relationship by examining the underlying causal relationship and the mediating role of inflammatory cytokines. METHODS: This study analyzed GWAS data from 18,340 participants to investigate gut microbiota composition and MRI data from 82,382 participants to examine brain structural connectivity. We conducted a bidirectional two-sample Mendelian randomization (MR) to explore potential causal relationships between 211 gut microbiota taxa and 206 brain connectivity features. A two-step mediation analysis involving 41 inflammatory cytokines was performed, using the inverse variance weighted (IVW) method as the main analytical approach, supplemented by sensitivity analyses and reverse MR to check for robustness, reverse causation, heterogeneity, and horizontal pleiotropy. FINDING: After Bonferroni correction, MR analysis identified significant correlations between 11 pairs of gut microbiota taxa and brain connectivity traits, with six positive and five negative associations. Reverse MR confirmed positive associations in nine pairs. Sensitivity analyses found no evidence of horizontal pleiotropy, heterogeneity, or reverse causality. Inflammatory cytokines, such as RANTES, HGF, and IL-13, mediated 10%-30% of these relationships, mainly through JAK-STAT, IL-17, and MAPK pathways. CONCLUSION: This research establishes potential causal links between gut microbiota and brain structural connectivity, bridging a crucial gap in the microbiota-gut-brain axis research. These findings enhance our understanding of the axis and suggest new therapeutic targets for neurological disorders.