Genome-Scale Metabolic Modelling of the Human Gut Microbiome Reveals Changes of the Glyoxylate and Dicarboxylate Metabolism in Metabolic Disorders

Abstract

The human gut microbiome has been associated with metabolic disorders such as obesity, type 2 diabetes and atherosclerosis. Understanding the contribution of metabolic changes in the microbiome is an important facet in elucidating the role of gut bacteria in regulating host metabolism. Here, we used the available metagenomics data from three key metabolic disorders, together with genome-scale metabolic modelling of the key bacteria in individual and community-level to investigate the link between the mechanistic role of the gut microbiome in metabolic diseases. Modelling predicted an increased level of glutamate consumption along with production of ammonia, arginine and L-proline in gut bacteria common in all three disorders. Using abundance profiles and network-dependent analysis, we identified enrichment of tartrate dehydrogenase as common in all the disorders. Moreover, independent plasma metabolite levels including L-proline and L-tyrosine showed an increased tartrate metabolism in healthy obese individuals relative to normal weight subjects from a sperate cohort. We therefore propose that tartrate metabolism could be a significant mediator of the microbiome metabolic changes in metabolic disorders as a result of diet-microbiome-host interactions.

Keywords: Gut microbiome, metabolic disorders, genome-scale metabolic model, Community modelling