Exploring the mechanisms of action of probiotics in depression: Results from a randomized controlled pilot trial

Background: We previously reported greater reductions in depression and anxiety following probiotic supplementation in people with major depressive disorder (MDD) in a randomised double-blind placebo-controlled pilot trial (Nikolova et al., 2023). Here, we investigate the mechanisms underlying these effects. Methods: 49 people with MDD received a multi-strain probiotic (n = 24) or placebo (n = 25) for 8 weeks in addition to their antidepressant. Stool and blood samples were collected to analyse gut microbiota composition and inflammatory cytokines. Stool samples from 25 matched healthy volunteers (HVs) were also obtained. Results: Within the probiotic group, there was a significant increase in richness according to Chao1(bias-corrected) (w4 p = 0.04) and a trend for increased Total count (w4 p = 0.06, w8 p = 0.09) compared to baseline, but not to placebo. When compared to HVs post-treatment, only the placebo group had a significant decrease in Shannon' entropy (p = 0.03) and a trend for decreased Total count (p = 0.08) and Simpson's index (p = 0.09). Between-group differences in beta diversity were observed at week 4 (p = 0.04), but not week 8. Consistent between-group differences were seen in family Bacilleceae post-treatment (FDR p < 0.05), which correlated with decreases in anxiety (FDR p < 0.05). There were no differences in inflammatory markers. Limitations: This study was limited by data loss during the COVID-19 Pandemic. Conclusion: Probiotics may positively impact the microbiota by normalising diversity and increasing levels of health-related taxa, which may partially account for their benefits in MDD. Understanding how these changes relate to symptom improvement can inform their targeted use in clinical practice. Larger trials incorporating functional multi-omics are needed.