BACKGROUND: Extensive research indicates a link between gut microbiota dysbiosis and psychiatric disorders. However, the causal relationships between gut microbiota and different types of psychiatric disorders, as well as whether inflammatory factors mediate these relationships, remain unclear. METHODS: We utilized summary statistics from the largest genome-wide association studies to date for gut microbiota (n = 18,340 in MiBioGen consortium), circulating inflammatory factors (n = 8293 for 41 factors and n = 14,824 for 91 factors in GWAS catalog), and six major psychiatric disorders from the Psychiatric Genomics Consortium (PGC): attention deficit hyperactivity disorder (ADHD, n = 38,691), anxiety disorder (ANX, n = 2248), bipolar disorder (BIP, n = 41,917), anorexia nervosa (AN, n = 16,992), schizophrenia (SCZ, n = 36,989), and autism spectrum disorder (ASD, n = 18,381). We conducted bidirectional Mendelian randomization (MR) analysis to explore the causal relationships between gut microbiota and psychiatric disorders. Additionally, we performed two-step MR and multivariable MR (MVMR) analyses to identify potential mediating inflammatory factors. RESULTS: We found significant causal relationships between 11 gut microbiota and ADHD, 2 gut microbiota and ANX, 11 gut microbiota and BIP, 8 gut microbiota and AN, 15 gut microbiota and SCZ, and 5 gut microbiota and ASD. There were 16 positive and 15 negative causal effects between inflammatory factors and psychiatric disorders. Furthermore, MVMR analysis results indicated that the correlation between genus Roseburia and ADHD was mediated by MCSF, with a mediation proportion of 3.3 %
the correlation between genus Erysipelotrichaceae UCG003 and BIP was mediated by GDNF, with a mediation proportion of 3.7 %
and the correlation between family Prevotellaceae and SCZ was mediated by CD40, with a mediation proportion of 8.2 %. CONCLUSIONS: The MR analysis results supported causal relationships between gut microbiota and six psychiatric disorders, as well as the potential mediating role of inflammatory factors. This study highlights the potential role of the gut microbiota-inflammation-brain axis in psychiatric disorders.