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Ecology-guided prediction of cross-feeding interactions in the human gut microbiome. Nature communications Understanding a complex microbial ecosystem such as the human gut microbiome requires information about both microbial species and the metabolites they produce and secrete. These metabolites are exchanged via a large network of cross-feeding interactions, and are crucial for predicting the functional state of the microbiome. However, till date, we only have information for a part of this network, limited by experimental throughput. Here, we propose an ecology-based computational method, GutCP, using which we predict hundreds of new experimentally untested cross-feeding interactions in the human gut microbiome. GutCP utilizes a mechanistic model of the gut microbiome with the explicit exchange of metabolites and their effects on the growth of microbial species. To build GutCP, we combine metagenomic and metabolomic measurements from the gut microbiome with optimization techniques from machine learning. Close to 65% of the cross-feeding interactions predicted by GutCP are supported by evidence from genome annotations, which we provide for experimental testing. Our method has the potential to greatly improve existing models of the human gut microbiome, as well as our ability to predict the metabolic profile of the gut. 10.1038/s41467-021-21586-6