From bag-of-genes to bag-of-genomes: metabolic modelling of communities in the era of metagenome-assembled genomes

Metagenomic sequencing of complete microbial communities has greatly enhanced our understanding of the taxonomic composition of microbiotas. This has led to breakthrough developments in bioinformatic disciplines such as assembly, gene clustering, metagenomic binning of species genomes and the discovery of an incredible, so far undiscovered, taxonomic diversity. However, functional annotations and estimating metabolic processes from single species - or communities - is still challenging. Earlier approaches relied mostly on inferring the presence of key enzymes for metabolic pathways in the whole metagenome, ignoring the genomic context of such enzymes, resulting in the 'bag-of-genes' approach to estimate functional capacities of microbiotas. Here, we review recent developments in metagenomic bioinformatics, with a special focus on emerging technologies to simulate and estimate metabolic information, that can be derived from metagenomic assembled genomes. Genome-scale metabolic models can be used to model the emergent properties of microbial consortia and whole communities, and the progress in this area is reviewed. While this subfield of metagenomics is still in its infancy, it is becoming evident that there is a dire need for further bioinformatic tools to address the complex combinatorial problems in modelling the metabolism of large communities as a 'bag-of-genomes'.