Metatranscriptomics-guided genome-scale metabolic modeling of microbial communities

Multi-omics data integration via mechanistic models of metabolism is a scalable and flexible framework for exploring biological hypotheses in microbial systems. However, although most microorganisms are unculturable, such multi-omics modeling is limited to isolate microbes or simple synthetic communities. Here, we developed an approach for modeling microbial activity and interactions that leverages the reconstruction of metagenome-assembled genomes and associated genome-centric metatranscriptomes. At its core, we designed a method for condition-specific metabolic modeling of microbial communities through the integration of metatranscriptomic data. Using this approach, we explored the behavior of anaerobic digestion consortia driven by hydrogen availability and human gut microbiota dysbiosis associated with Crohn's disease, identifying condition-dependent amino acid requirements in archaeal species and a reduced short-chain fatty acid exchange network associated with disease, respectively. Our approach can be applied to complex microbial communities, allowing a mechanistic contextualization of multi-omics data on a metagenome scale.