Gut microbiotas, inflammatory factors, and mental-behavioral disorders: A mendelian randomization study

The Mendelian randomization approach has emerged as a powerful tool, leveraging genetic variations as natural random experiments to minimize confounding and infer causality with unique advantages. Previous research has highlighted the crucial roles of gut microbiotas and inflammatory factors in mental-behavioral disorders, albeit to varying degrees. However, the precise causal relationship between gut microbiotas and mental-behavioral disorders remains elusive, and the potential role of inflammatory factors as mediators in this process is unclear.

To investigate the associations between gut microbiotas, inflammatory factors, and mental-behavioral disorders, we pooled data from large-scale genome-wide association studies (GWAS). Our study screened 27 diseases, encompassing nine subtypes of mental-behavioral disorders: neurodevelopmental disorders, eating disorders, sleep disorders, schizophrenia spectrum disorders, stress- and trauma-related disorders, mood and affective disorders, cognitive and executive function disorders, personality and somatization disorders, and addiction disorders. Mendelian randomization(MR) was employed to assess causal relationships between gut microbiotas, inflammatory factors, and these mental-behavioral disorders, with inverse variance weighting (IVW) as the primary statistical method. Furthermore, we explored whether inflammatory factors mediate the relationship between gut microbiotas and mental-behavioral disorders.

Having investigated the intricate interplay among gut microbiota, inflammatory factors, and mental-behavioral disorders, we have identified nine pivotal inflammatory factors that intricately regulate the progression of eight distinct disease subtypes. Noteworthy among these findings, levels of CC motif chemokine ligand 28 (CCL28) and CC motif chemokine ligand 25 (CCL25) are associated with the progression of attention-deficit/hyperactivity disorder (ADHD), interleukin-18 (IL-18) levels are linked to anorexia, IL-12β levels are related to schizophrenia (SZ) progression, IL-8 levels are associated with manic episodes, and IL-10 and monocyte chemoattractant protein-2 (MCP-2) levels are closely related to enduring personality changes(EPC). Additionally, fibroblast growth factor 19 (FGF19) levels are associated with cognitive disorders, while C-X-C motif chemokine ligand 1 (CXCL1) levels are related to executive functioning.

Gut microbiotas and mental-behavioral disorders have causal relationships, with inflammatory factors mediating the pathway from gut microbiotas to these disorders.