From Stool to Solutions: Diagnose, Decode, Disruptors, and Deliver Interventions for the Human Gut Microbiota in Neurodegenerative Diseases.

GUT-4D tackles a pivotal frontier in biomedicine: leveraging the gut microbiome to transform the diagnosis, mechanistic understanding, and treatment of neurodegenerative diseases (NDDs) including Parkinson’s, Alzheimer’s, frontotemporal dementia, and amyotrophic lateral sclerosis. The project unites four interconnected research pillars, stool-based diagnostics, gut–disease mechanistic links, dysbiosis drivers, and microbiota-improving interventions, within a rigorously standardized clinical framework for sample and data management. First, GUT-4D will deliver clinically translatable, stool-based biomarker panels by integrating metagenomics, metaproteomics, metabolomics, and host markers with multi-class machine-learning models, overcoming the limitations of single-disease, binary classifiers and advancing omics diagnostics toward validated, assay-ready tools. Second, it will dissect causal gut–brain and gut–immune pathways by combining deeply phenotyped patient cohorts with ex vivo and in vitro mechanistic experiments, mapping microbial metabolites and host proteins, to reveal disease-specific triggers. Third, the project pioneers an exposome–microbiome pipeline that detects exogenous compounds and microbial products directly in fecal samples and applies Exposome-Wide Association analyses, followed by rapid ex vivo functional testing and targeted cellular assays, to build a Modifiable Driver Atlas of actionable dysbiosis factors. Finally, GUT-4D translates insights into therapeutic strategies with pre/pro/synbiotics, postbiotics, and other ecosystem “repair” approaches validated on adaptive ex vivo platforms. By integrating microbiology, clinical medicine, data science, and environmental health, GUT-4D provides a four-dimensional, bench-to-bedside program poised to shift NDD care from correlative observations to predictive, mechanism-guided diagnostics and interventions, strengthening Europe’s capacity for next-generation, microbiome-enabled healthcare.