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.