Systematic Analysis of the Metabolic Interactions in a Model Gut Microbiota Community and Its Impact on Host Metabolism

Systematic analysis of the metabolic interactions in a model gut microbiota community and its impact on host metabolism

The human intestine possesses a diverse microbial ecosystem, the gut microbiota, whose metabolic interactions with its host play a central role in human well-being and disease. A variety of studies have demonstrated that multi-scale constraint-based modeling successfully captures interspecies interactions but rarely in the context of the gut microbiota. Recently, we constructed the first genome-scale model of a human gut microbe community, consisting of 11 manually curated and validated gut microbe reconstructions spanning three phyla. The model was applied to systematically predict host-microbe and microbe-microbe interactions in silico.

To predict the model gut community’s impact on human metabolism, it was joined with the global human reconstruction, Recon2 (1). The effects of the different microbes on host metabolic tasks were systematically explored while simulating four different dietary regimes (2). A variety of human body fluid metabolites were influenced by microbial presence, including many that have been measured in vivo and found to be affected by the microbiota. The secretion of amino acid derivatives including hormones by the host was increased by up to 100-fold in the presence of the microbes, in agreement with the role of the microbiota as an additional organ. When comparing two five-member model communities, the more diverse group had a significantly more pronounced effect on host metabolism. The microbes further provided a variety of metabolic products relevant for host health, e.g., energy sources, vitamins, and potentially toxic metabolites. Specific microbes combined with dietary fatty acid supply were able to increase host production of pro-inflammatory leukotrienes as well as increased production of taurine-containing bile acids (2).

Moreover, the 11 microbes were joined pairwise in all possible combinations with and without a reconstruction of the small intestine enterocyte (3) as background (4). A variety of interactions including commensalism, mutualism, and competition was predicted depending on the nutrient environment. Notably, anoxic conditions promoted mutualistic behavior in the lactic acid bacterium Lactobacillus plantarum towards other species such as Escherichia coli. The availability of oxygen abolished these syntrophic interactions, resulting in competition. Recurring cross-feeding patterns between microbes were identified, providing insight into the mechanisms behind the observed microbe-microbe interactions on a molecular level (4). In a more extensive follow-up work, a representative community of 321 human gut microbes was constructed using a semi-automated pipeline (5). The pairwise interactions were explored systematically on six nutrient environments resulting in over 50,000 microbe-microbe pairs. This work represents the most extensive constraint-based model of a mammalian intestinal ecosystem to date. It will prove useful in future efforts to elucidate the metabolism of the complex ecosystem in the human gut and its effects on human health.

1.         I. Thiele et al., Nat Biotechnol 31, 419-425 (2013).

2.         A. Heinken et al., Gut Microbes, 6, 120-30 (2015).

3.         S. Sahoo et al., Human molecular genetics 22, 2705-2722 (2013).

4.         A. Heinken et al., Appl Environ Microbiol 81, 4049-4061 (2015).

5.         S. Magnusdottir et al., in preparation  (2015).