Gut microbiota and major depressive disorder: A bidirectional Mendelian randomization

Background: Observational studies showed an association between gut microbiota and depression, but the cau-sality relationship between them is unclear. We aimed to determine whether there is a bidirectional causal relationship between the composition of gut microbiota and major depressive disorders (MDD) and explore the role of gut microbiota in decreasing the risk of MDD. Methods: Our two-sample Mendelian randomization (MR) study acquired top SNPs associated with the compo-sition of gut microbiota (n = 18,340) and with MDDs (n = 480,359) from publicly available genome-wide as-sociation studies (GWAS). The SNPs estimates were pooled using inverse-variance weighted meta-analysis, with sensitivity analyses-weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). Results: The Actinobacteria class had protective causal effects on MDD (OR 0.88, 95%CI 0.87 to 0.9). The Bifi-dobacterium (OR 0.89, 95%CI 0.88 to 0.91) were further found to have similar effects as the Actinobacteria class. The genus Ruminococcus1 had a protective effect on MDD (OR 0.88, 95%CI 0.76 to 0.99) while the Strepto-coccaceae family and its genus had an anti-protective effect on MDD (OR 1.07, 95%CI 1.01 to 1.13), but these findings were not supported by the MR-Egger analysis. Bidirectional MR showed no effect of MDD on gut microbiota composition. Limitations: The use of summary-level data, the risk of sample overlap and low statistical power are the major limiting factors. Conclusions: Our MR analysis showed a protective effect of Actinobacteria, Bifidobacterium, and Ruminococcus and a potentially anti-protective effect of Streptococcaceae on MDD pathogenesis. Further studies are needed to transform the findings into practice.