More than just a gut feeling: constraint-based genome-scale metabolic models for predicting functions of human intestinal microbes

Abstract

The human gut is colonized with a myriad of microbes, with substantial interpersonal variation. This complex ecosystem is an integral part of the gastrointestinal tract and plays a major role in the maintenance of homeostasis. Its dysfunction has been correlated to a wide array of diseases, but the understanding of causal mechanisms is hampered by the limited amount of cultured microbes, poor understanding of phenotypes, and the limited knowledge about interspecies interactions. Genome-scale metabolic models (GEMs) have been used in many different fields, ranging from metabolic engineering to the prediction of interspecies interactions. We provide showcase examples for the application of GEMs for gut microbes and focus on (i) the prediction of minimal, synthetic, or defined media; (ii) the prediction of possible functions and phenotypes; and (iii) the prediction of interspecies interactions. All three applications are key in understanding the role of individual species in the gut ecosystem as well as the role of the microbiota as a whole. Using GEMs in the described fashions has led to designs of minimal growth media, an increased understanding of microbial phenotypes and their influence on the host immune system, and dietary interventions to improve human health. Ultimately, an increased understanding of the gut ecosystem will enable targeted interventions in gut microbial composition to restore homeostasis and appropriate host-microbe crosstalk.

The Use of Defined Microbial Communities To Model Host-Microbe Interactions in the Human Gut

“…Key is further expanding our knowledge about the intestinal microbiome in health and disease, in which the NIH Human Microbiome Project and the European MetaHit project have played a crucial role (106,163) (bottom-up). The characterization of the gut microbiota and genome sequences facilitates the in silico prediction of host-microbe interactions through constraint-based genome-scale metabolic modeling (164) or other types of mathematical modeling (165) and, subsequently, the in silico design of representative defined communities (bottom-up). Further exploring our whole microbiome, including phages, fungi, and archaea, will revolutionize the design of microbial communities as well (bottom-up).…”

Consistency, Inconsistency and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome Scale Metabolic Modelling

“…Therefore, there is a need for models that can help combine both types of measurements. As a result, there are on-going efforts to define modelling frameworks, based on combining GEMs of individual organisms, to characterize the behaviour of the community [21,22,37,38]. Enabling unambiguous mapping will be required to take full advantage of these on-going developments.…”

Computational Modeling of the Human Microbiome

“…Additional application of single species GEMs associated with the gut microbiome consists of three main areas: (1) construction of in silico growth media; (2) phenotype prediction of the gut microbes; and (3) defining interspecies metabolic interactions [22]. In designing media, GEMs play a crucial role by identifying the metabolites required and how growth is computed.…”

“…1 Computational analyses such as network analysis, agent-based modeling, and genome scale metabolic modeling (GEM) have used to study various aspects of the human microbiome including structure, dynamics, and coordinated function [22][23][24]. While a variety of specific analyses are encompassed in network analysis, generally this approach considers connectivity of components to consider structure-function relationships.…”