Substrate utilization and cross-feeding synergistically determine microbiome resistance to pathogen invasion

Understanding how plant-associated microbiomes resist phytopathogen invasion remains a key challenge in natural ecosystems. Here we combined genome-scale metabolic models with synthetic community experiments, both in vitro and in planta, to unravel the mechanisms driving pathogen suppression. We developed curated genome-scale models for each strain, incorporating 48 common resource utilization profiles to fully capture their metabolic capacities. Trophic interactions inferred from models effectively predicted pathogen invasion outcomes across diverse microbial communities and nutrient environments. Importantly, considering both substrate and metabolite features provided a more holistic understanding of pathogen suppression. In particular, cross-feeding metabolites within the native community emerged as crucial yet often overlooked predictors of community resistance, disproportionally favouring native species over invaders. This study lays the foundation for designing disease-resistant microbiomes, with broad implications for mitigating pathogen exposure in diverse environments.