Systems-level characterization of a host-microbe metabolic symbiosis in the mammalian gut

Abstract

The human gut microbiota consists of ten times more microorganisms than there are cells in our body, processes otherwise indigestible nutrients, and produces important energy precursors, essential amino acids, and vitamins. In this study, we assembled and validated a genome-scale metabolic reconstruction of Bacteroides thetaiotaomicron (iAH991), a prominent representative of the human gut microbiota, consisting of 1488 reactions, 1152 metabolites, and 991 genes. To create a comprehensive metabolic model of host-microbe interactions, we integrated iAH991 with a previously published mouse metabolic reconstruction, which was extended for intestinal transport and absorption reactions. The two metabolic models were linked through a joint compartment, the lumen, allowing metabolite exchange and providing a route for simulating different dietary regimes. The resulting model consists of 7239 reactions, 5164 metabolites, and 2769 genes. We simultaneously modeled growth of mouse and B. thetaiotaomicron on five different diets varying in fat, carbohydrate, and protein content. The integrated model captured mutually beneficial cross-feeding as well as competitive interactions. Furthermore, we identified metabolites that were exchanged between the two organisms, which were compared with published metabolomics data. This analysis resulted for the first time in a comprehensive description of the co-metabolism between a host and its commensal microbe. We also demonstrate in silico that the presence of B. thetaiotaomicron could rescue the growth phenotype of the host with an otherwise lethal enzymopathy and vice versa. This systems approach represents a powerful tool for modeling metabolic interactions between a gut microbe and its host in health and disease.

Keywords: Bacteroidesthetaiotaomicron; Mus musculus; computational modeling; constraint-based modeling; host-microbe interactions; metabolism; systems biology.

Figure 1. Simultaneous optimization of mouse and B. thetaiotaomicron growth rate using an integrated model of host and gut symbiont metabolism. (A) Schematic representation of iexGFMM_BΘ and the possible metabolite exchange between iAH991 and iSS1393. Compartments: [u], lumen; [b], body fluids; [c], cytoplasm; [e], extracellular. The numbers of exchanged and secreted metabolites on a Western diet are shown. Green arrows indicate metabolites B. thetaiotaomicron provides to the mouse model. Purple arrows indicate mouse metabolites provided to B. thetaiotaomicron. (B) Compositions of diets simulated in this study. CHO = carbohydrate. (C) Predicted growth rates for mouse and B. thetaiotaomicron in iexGFMM_BΘ, and in the individual models are listed for the five dietary regimes employed in this study. Note that the computed mouse growth rates were not realistic, since the biomass reaction summed the required fractions of biomass precursors for a new cell but not for an entire new mouse. (D) Trade-off between the two organisms’ maximal achievable growth rates in iexGFMM_BΘ (Pareto optimality curve). Due to the constraints imposed by the ATP maintenance reactions in iexGFMM_BΘ, fixing either biomass reaction at very low growth rates produces an infeasible solution.

Figure 2. Metabolite dependency of mouse and B. thetaiotaomicron in iexGFMM_BΘ. On a Western diet, changes in flux rates in iexGFMM_BΘ, when maximizing for mouse growth rate, were compared with those in the maximally growing germfree mouse model and depicted by arrows (up: increased flux, down: decreased flux compared with germfree mouse). For simplicity not all observed changes and related pathways are shown. Metabolites with increased exchange flux compared with the germfree model are shown in green, while metabolites with reduced exchange flux are shown in red. Metabolites that only secreted in iexGFMM_BΘ are shown in blue. Orange arrows indicate metabolites that B. thetaiotaomicron provides to the mouse. Purple arrows indicate mouse metabolites provided to B. thetaiotaomicron. CHO, carbohydrate; Bas, bile acids; TCA cycle, tricarboxylic acid cycle; = B. thetaiotaomicron’s polysaccharide- degrading enzyme repertoire.