A gap-filling algorithm for prediction of metabolic interactions in microbial communities

The study of microbial communities and their interactions has attracted the interest of the scientific community, because of their potential for applications in biotechnology, ecology and medicine. The complexity of interspecies interactions, which are key for the macroscopic behavior of microbial communities, cannot be studied easily experimentally. For this reason, the modeling of microbial communities has begun to leverage the knowledge of established constraint-based methods, which have long been used for studying and analyzing the microbial metabolism of individual species based on genome-scale metabolic reconstructions of microorganisms. A main problem of genome-scale metabolic reconstructions is that they usually contain metabolic gaps due to genome misannotations and unknown enzyme functions. This problem is traditionally solved by using gap-filling algorithms that add biochemical reactions from external databases to the metabolic reconstruction, in order to restore model growth. However, gap-filling algorithms could evolve by taking into account metabolic interactions among species that coexist in microbial communities. In this work, a gap-filling method that resolves metabolic gaps at the community level was developed. The efficacy of the algorithm was tested by analyzing its ability to resolve metabolic gaps on a synthetic community of auxotrophic Escherichia coli strains. Subsequently, the algorithm was applied to resolve metabolic gaps and predict metabolic interactions in a community of Bifidobacterium adolescentis and Faecalibacterium prausnitzii, two species present in the human gut microbiota, and in an experimentally studied community of Dehalobacter and Bacteroidales species of the ACT-3 community. The community gap-filling method can facilitate the improvement of metabolic models and the identification of metabolic interactions that are difficult to identify experimentally in microbial communities.Author summary: Microbes are the most abundant form of life on earth and they are almost never found in isolation as they live in close association with one another and with other organisms. The metabolic capacity of individual microbial species dictates their ways of interacting with other species as well as with their environment. The metabolic interactions among microorganisms has been recognised as the driving force for the properties of microbial communities. For this reason, understanding the effect of microbial metabolism on interspecies metabolic interactions is essential for the study of microbial communities. This study can benefit from metabolic modeling and the insights offered by constraint-based methods which have been developed for interrogating metabolic models. In this paper, we present an algorithm that predicts cooperative and competitive metabolic interactions between species while it resolves metabolic gaps in their metabolic models in a computationally efficient way. We use our community gap-filling algorithm to study microbial communities with interesting environmental and health-related applications.