From Gut to Brain: Evidence for a Causal Contribution of Gut-Microbiota to Major Depressive Disorder in Humans

Major Depressive Disorder (MDD) is a highly prevalent, severe mental health condition that constitutes one of the leading causes of disability worldwide. While recent animal studies suggest a causal role of the gut microbiome in the pathophysiology of MDD models, evidence in humans is still unclear due to small sample sizes, inconsistent clinical assessment of MDD diagnosis, and methodological limitations regarding causal inference in cross-sectional data. Here, we explicitly address these shortcomings to investigate the potential causal link between the gut microbiome and MDD: First, we replicate previous findings using one of the largest multicenter MDD cohorts for which microbiome data and in-depth diagnostic assessment are available (N=1,269 MDD patients and controls). We find a significant difference between healthy controls and MDD patients for the relative abundance of the four taxa Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020. Second, we employ state-of-the-art, fully data-driven causal inference tools within Judea Pearls framework, allowing us to derive model constraints from the data rather than relying on potentially strong, unrealistic assumptions. Using this approach, we found data-driven evidence for Eggerthella and Hungatella as causal contributors to MDD. Furthermore, we show that Eggerthella and Hungatella abundances are associated with MDD beyond the influence of body mass index, identifying two distinct pathways linking MDD to the gut microbiome. Finally, the difference in relative abundance of these taxa between healthy and MDD patients was independent of antidepressant medication. Our study provides the first evidence for a potential causal role of gut-microbiota in the pathophysiology of depression in humans.