Using one of the largest multicenter MDD cohorts with microbiome data and state-of-the-art causal inference tools, this study provides 'the first data-driven evidence for a potential causal role of gut microbiota in the pathophysiology of depression in humans,' identifying Eggerthella and Hungatella as potential causal contributors to MDD.
Key Findings
Results
Four gut microbial taxa showed significant differences in relative abundance between MDD patients and healthy controls.
The four taxa identified were Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020.
The study cohort consisted of N = 1,269 MDD patients and healthy controls across multiple centers.
This represents one of the largest multicenter MDD cohorts for which both microbiome data and in-depth diagnostic assessment are available.
The difference in relative abundance of these taxa was independent of antidepressant medication.
Results
Data-driven causal inference analysis found evidence that Eggerthella and Hungatella are potential causal contributors to MDD.
Causal inference was conducted using state-of-the-art, fully data-driven tools within Judea Pearl's causal framework.
The approach derives model constraints from the data rather than relying on 'potentially strong, unrealistic assumptions.'
This distinguishes the findings from typical cross-sectional association studies, which have methodological limitations regarding causal inference.
The causal analysis was applied specifically to identify directionality (gut microbiota contributing to MDD, rather than the reverse).
Results
The potential causal effects of Eggerthella and Hungatella on MDD persist beyond the influence of body mass index, revealing two distinct potential causal pathways.
BMI was examined as a potential mediator or confounder of the gut microbiome–MDD relationship.
The causal effects of both Eggerthella and Hungatella remained significant after accounting for BMI.
This finding suggests two distinct potential causal pathways linking the gut microbiome to MDD.
The persistence beyond BMI influence suggests the microbiome-MDD relationship is not simply mediated by body weight or metabolic factors.
Results
The microbiome-MDD associations were independent of antidepressant medication use.
The difference in relative abundance of the identified taxa between healthy controls and MDD patients was not attributable to antidepressant treatment.
This addresses a key confound in microbiome-depression research, as psychiatric medications are known to affect gut microbiota composition.
Independence from medication effects strengthens the interpretation that the observed microbial differences are related to MDD itself rather than its treatment.
Background
Previous literature on gut microbiome and depression has been limited by small sample sizes, inconsistent clinical assessment, and methodological limitations regarding causal inference in cross-sectional data.
The authors explicitly identify these three shortcomings in the existing literature and frame their study as addressing each one.
Animal studies have suggested a causal role of the gut microbiome in MDD pathophysiology, but 'evidence in humans is still unclear.'
The multicenter design and in-depth diagnostic assessment were used to overcome inconsistency in prior clinical assessments.
The use of Pearl's causal framework was specifically adopted to address causal inference limitations of cross-sectional designs.
Results
The study replicated previously reported microbiome-depression associations in a large multicenter cohort.
Replication was explicitly stated as the first step of the two-part analytical approach.
The cohort of N = 1,269 is described as one of the largest multicenter MDD cohorts with available microbiome data and in-depth diagnostic assessment.
The taxa identified (Eggerthella, Hungatella, Coprobacillus, Lachnospiraceae FCS020) correspond to associations previously reported in the literature.
Replication in a large, well-characterized cohort addresses the small sample size limitation of prior studies.
What This Means
This research suggests that specific bacteria living in the human gut may play a causal role in major depressive disorder (MDD), one of the world's leading causes of disability. Scientists have long known that the gut and brain communicate — often called the 'gut-brain axis' — and animal studies have hinted that gut bacteria might influence depression. However, proving this in humans has been difficult because previous studies used small groups of people, inconsistent methods for diagnosing depression, and statistical approaches that can only show association, not causation. This study addressed all three of these problems by analyzing gut microbiome data from 1,269 carefully diagnosed MDD patients and healthy controls across multiple research centers, making it one of the largest studies of its kind.
Using advanced mathematical tools designed to infer cause-and-effect relationships from data (rather than just correlations), the researchers identified four types of gut bacteria that differed between depressed and non-depressed individuals: Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020. Crucially, their causal analysis provided evidence that two of these — Eggerthella and Hungatella — may actually contribute to causing depression, rather than simply being altered as a consequence of it. These effects remained even after accounting for body weight (BMI) and were not explained by whether patients were taking antidepressant medications, suggesting the findings reflect genuine biology rather than side effects of treatment.
This research suggests that the gut microbiome is not merely a bystander in depression but may actively participate in its development through at least two distinct biological pathways. While this does not mean that changing gut bacteria alone would treat or prevent depression, it opens new directions for research into the biological mechanisms underlying MDD and may eventually inform approaches that target the gut microbiome as part of depression care. The authors describe this as 'the first data-driven evidence for a potential causal role of gut microbiota in the pathophysiology of depression in humans.'
Fehse L, Ribeiro A, Winter N, Thanarajah S, Fisch L, Welzel M, et al.. (2026). From gut to brain: data-driven evidence suggests causal contribution of gut-microbiota to major depressive disorder in humans.. Gut microbes. https://doi.org/10.1080/19490976.2026.2718589