Reconstruction of metagenome-scale models of the gut microbiota metabolism at species-level resolution in Inflammatory Bowel Disease

Inflammatory bowel Disease (IBD) is a chronic inflammatory condition of the intestinal tract that affects over three million Americans each year. Numerous studies have associated microbial species and microbially-derived metabolites in the gut and IBD. Nevertheless, as association studies do not necessarily point to underlying causal mechanisms, the exact microbial mechanisms of IBD pathogenesis are still unknown. To better understand the functional role of microbial species in IBD pathogenesis, we aimed to reconstruct genome-scale models (GEMs) of metabolism for bacterial species in the gut microbiota of IBD and non-IBD subjects. To this end, we are using taxonomic profiling data from fecal samples of IBD and non-IBD subjects in the Human Microbiome Project to reconstruct GEMs for all microbial species. We then integrate GEMs of species present in each sample into a community model representative of the fecal microbiota in that sample. These community GEMs are being used to computationally simulate the metabolic activity of individual microbial species and inter-species metabolic interactions in IBD and non-IBD subjects. By comparing the predicted species-level metabolite secretion and uptake fluxes, we determined how microbiota-derived metabolites and the metabolic activity of individual microbial species differs between the IBD and non-IBD models. Our analyses revealed significant fold changes in the production levels of several metabolites a number of which were previously implicated in IBD. For example, we observed higher levels of lactate linked to Enterococcus faecium and Klebsiella pneumoniae and lower levels of butyrate linked to Finegoldia magna and to Peptostreptococcus anerobius in IBD cases compared to non-IBD controls. They also enabled us to trace back microbial species that are responsible for the production of metabolites linked to IBD pathogenesis. Overall, our study is expected to provide unprecedented insight into the link between species and metabolite-level biomarkers of IBD.