Metagenome-informed metaproteomic decoding of diet-host-microbiome drivers of human Crohn’s disease

Background and aims We aim to unravel the functional mechanisms underlying Crohn’s disease by using our newly developed Integrated Proteo-genomics of HOst-MicrobiomE-Diet (IPHOMED). Specifically, we will (1) identify disease-driving host-microbiome hubs, (2) discover functional biomarkers of disease severity and treatment response, and (3) characterize dietary and malabsorption patterns in Crohn’s disease. Aim 1: Define functional host–microbiome–dietary interactions in paediatric Crohn’s disease using longitudinal multi-omic profiling. Aim 2: Identify disease-relevant mechanisms and biomarkers by distinguishing functional vs. compositional dysbiosis, assess nutrient absorption and treatment compliance, and discover novel trans-kingdom biomarkers of disease activity and response. Aim 3: Validate causal mechanisms disease–associated pathobionts, dietary patterns, and biomarkers in germ-free, IBD-prone mouse models to accelerate translation into therapeutic strategies. Methods We will perform longitudinal IPHOMED profiling in 35 new-onset CD patients, followed for one year from diagnosis. Each patient contributed ∼30 fecal samples (>1100 total), paired with extensive metadata including IBD severity scores, detailed activity and dietary logs (via a custom smartphone app), weekly home calprotectin tests, and clinical laboratory and imaging data. IPHOMED will be applied to distinguish compositional versus functional dysbiosis, define host-microbiome-dietary interactions, and generate AI-based treatment response predictors. Complex dynamical modelling will be leveraged to study the interaction between diet, microbiome and disease activity. Key human-derived microbial and dietary findings will be validated in notobiotic IBD mouse models. Anticipated impact This project will transform our understanding of IBD pathogenesis by identifying upstream host-microbe drivers and novel trans-kingdom biomarkers of disease activity and treatment response. In the medium to long term, these insights will support the development of precision nutrition strategies and reveal druggable host-microbiome protein interactions, enabling patient-tailored interventions to prevent exacerbations and mitigate sub-clinical malabsorption in Crohn’s disease.