From gut to brain: data-driven evidence suggests 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 previously reported microbiome-depression associations 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 four taxa: Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020. Second, we employ state-of-the-art, fully data-driven causal inference tools within Judea Pearl's framework, allowing us to derive model constraints from the data rather than relying on potentially strong, unrealistic assumptions. Using this approach, we found evidence for Eggerthella and Hungatella as potential causal contributors to MDD. Furthermore, we show that the potential causal effects of Eggerthella and Hungatella on MDD persist beyond the influence of body mass index, revealing two distinct potential causal pathways linking the gut microbiome to MDD. Finally, the difference in relative abundance of these taxa between healthy and MDD patients was independent of antidepressant medication. Our study provides the first data-driven evidence for a potential causal role of gut microbiota in the pathophysiology of depression in humans.

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Publication Details

Journal
Gut Microbes
Published
2026-08-21
DOI
https://doi.org/10.1080/19490976.2026.2718589
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
0.00

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article

From gut to brain: data-driven evidence suggests causal contribution of gut-microbiota to major depressive disorder in humans

L. Fisch, Corinna Bang, Danique Mulder, Marius Welzel et al.
Gut Microbes
Gut microbiota and health
article

From gut to brain: data-driven evidence suggests causal contribution of gut-microbiota to major depressive disorder in humans

L. Fisch, Corinna Bang, Danique Mulder, Marius Welzel, Benjamín Valderrama, Robert Nitsch, Alejandro Arias Vásquez, Andreas Lügering, Dominik Heider, Sarah Kittel‐Schneider, Aonghus Lavelle, André Franke, John F. Cryan, Mirjam Bloemendaal, Leon Fehse, Eugenia E. Natasha, Nina Alexander, Elisabeth J. Leehr, Adèle H. Ribeiro, Nils R. Winter, Paula Usemann, Gerard Clarke, Andreas Jansen, Susanne Meinert, Udo Dannlowski, Benjamin Straube, Andreas Reif, Sharmili Edwin Thanarajah, Frederike Stein, Igor Nenadic, Tilo Kircher, Janik Goltermann, Hamidreza Jamalabadi, Lea Teutenberg, Kira Flinkenflügel, Tim Hahn, Florian Thomas-Odenthal, Tiana Borgers
article en

Abstract

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 previously reported microbiome-depression associations 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 four taxa: Eggerthella, Hungatella, Coprobacillus, and Lachnospiraceae FCS020. Second, we employ state-of-the-art, fully data-driven causal inference tools within Judea Pearl's framework, allowing us to derive model constraints from the data rather than relying on potentially strong, unrealistic assumptions. Using this approach, we found evidence for Eggerthella and Hungatella as potential causal contributors to MDD. Furthermore, we show that the potential causal effects of Eggerthella and Hungatella on MDD persist beyond the influence of body mass index, revealing two distinct potential causal pathways linking the gut microbiome to MDD. Finally, the difference in relative abundance of these taxa between healthy and MDD patients was independent of antidepressant medication. Our study provides the first data-driven evidence for a potential causal role of gut microbiota in the pathophysiology of depression in humans.

Gut MicrobesVol. 18(1)
Radboud University Nijmegen (NL), Philipps University of Marburg (DE), University of Münster (DE), University College Cork (IE), University Medical Center (US), Radboud University Medical Center (NL), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), Max Planck Institute for Metabolism Research (DE), Klinik für Psychosomatik (DE), Universitätsklinikum Würzburg (DE), Center for HIV and Hepatogastroenterology (DE), APC Microbiome Institute (IE), Klinik und Poliklinik für Psychiatrie und Psychotherapie (DE), The Center for Mind-Body Medicine (US), RWTH Aachen University (DE)
Bundesministerium für Bildung und Forschung, Fraunhofer-Gesellschaft
Good health and well-being
Openalex Percentile: Top 17%
Gut microbiota and health
DOIOpen Access PDFOpenAlex
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