An Explainable Knowledge Graph-Driven Approach to Decipher the Link Between Brain Disorders and the Gut Microbiome

Motivation The communication between the gut microbiome and the brain, known as the microbiome-gut-brain axis (MGBA), is emerging as a critical factor in neurological and psychiatric disorders. This communication involves complex pathways including neural, hormonal, and immune interactions that enable gut microbes to modulate brain function and behavior. However, the specific mechanisms through which gut microbes influence brain function remain poorly understood, and existing computational efforts to understand these mechanisms are simplistic or have limited scope. Results This work presents a comprehensive approach for elucidating the interactions that allows gut microbes to influence brain disorders. We construct a large curated biomedical knowledge graph comprising 586,318 nodes across 16 entity types and 3,573,936 edges spanning 103 relation types, integrating ontological and experimental data relevant to the MGBA. On this graph, we train GNN-GBA, a GraphSAGE-based graph neural network with a DistMult relation-aware decoder, achieving an AUC-ROC of 0.997 and an F1-score of 0.981 on link prediction, outperforming nine baseline methods across four categories. Using GNNExplainer, we extract and rank mechanistic pathways connecting gut microbes to brain disorders, and demonstrate their stability across multiple random initializations. GNN-GBA successfully identified pathways for 125 brain disorders, revealing shared metabolite hubs (including flavonoids, bile acids, and short-chain fatty acids) that mediate gut–brain communication across diverse neurological conditions. Furthermore, we show that the top pathways are consistent with existing literature for three common disorders. Lastly, we develop an interactive dashboard (GutBrainExplorer) to explore thousands of potential mechanistic pathways across 125 brain disorders, which is publicly available at https://sds-genetic-interaction-analysis.opendfki.de/gut_brain/ . Availability Code and data are available at https://github.com/naafey-aamer/GNN-GBA . Contact [email protected]