Dissecting the association between gut microbiota, body mass index and specific depressive symptoms: a mediation Mendelian randomisation study

Background Observational studies highlight the association between gut microbiota (GM) composition and depression; however, evidence for the causal relationship between GM and specific depressive symptoms remains lacking. Aims We aimed to evaluate the causal relationship between GM and specific depressive symptoms as well as the mediating role of body mass index (BMI). Methods We performed a two-sample Mendelian randomisation (MR) analysis using genetic variants associated with GM and specific depressive symptoms from genome-wide association studies. The mediating role of BMI was subsequently explored using mediation analysis via two-step MR. Results MR evidence suggested the Bifidobacterium genus (β=–0.03; 95% CI –0.05 to –0.02; p<0.001 and β=–0.03; 95% CI –0.05 to –0.02; p<0.001) and Actinobacteria phylum (β=–0.04; 95% CI –0.06 to –0.02; p<0.001 and β=–0.03; 95% CI –0.05 to –0.03; p=0.001) had protective effects on both anhedonia and depressed mood. The Actinobacteria phylum also had protective effects on appetite changes (β=–0.04; 95% CI –0.06 to –0.01; p=0.005), while the Family XI had an antiprotective effect (β=0.03; 95% CI 0.01 to 0.04; p<0.001). The Bifidobacteriaceae family (β=–0.01; 95% CI –0.02 to –0.01; p=0.001) and Actinobacteria phylum (β=–0.02; 95% CI –0.03 to –0.01; p=0.001) showed protective effects against suicidality. The two-step MR analysis revealed that BMI also acted as a mediating moderator between the Actinobacteria phylum and appetite changes (mediated proportion, 34.42%) and that BMI partially mediated the effect of the Bifidobacterium genus (14.14% and 8.05%) and Actinobacteria phylum (13.10% and 8.31%) on both anhedonia and depressed mood. Conclusions These findings suggest a potential therapeutic effect of Actinobacteria and Bifidobacterium on both depression and obesity. Further studies are required to translate these findings into clinical practice. Data are available in a public, open access repository. All GWAS summary statistics are publicly available for download. The GWASs data for gut microbiota were provided by MiBioGen consortium (). The GWASs data for specific depressive symptoms were sourced from UK Biobank (). The GWASs for BMI were provided by GIANT consortium ([https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT\_consortium\_data_files][1]). [1]: https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files