Systematic prediction of health-relevant human-microbial co-metabolism through a computational framework

Abstract

Keywords: human gut microbiome, in silico, metabolome, metabolic modelingThe gut microbiota is well known to affect host metabolic phenotypes. The systemic effects of the gut microbiota on host metabolism are generally evaluated via the comparison of germfree and conventional mice, which is impossible to perform for humans. Hence, it remains difficult to determine the impact of the gut microbiota on human metabolic phenotypes. We demonstrate that a constraint-based modeling framework that simulates "germfree" and "exgermfree" human individuals can partially fill this gap and allow for in silico predictions of systemic human-microbial cometabolism. To this end, we constructed the first constraint-based host-microbial community model, comprising the most comprehensive model of human metabolism and 11 manually curated, validated metabolic models of commensals, probiotics, pathogens, and opportunistic pathogens. We used this host-microbiota model to predict potential metabolic host-microbe interactions under 4 in silico dietary regimes. Our model predicts that gut microbes secrete numerous health-relevant metabolites into the lumen, thereby modulating the molecular composition of the body fluid metabolome. Our key results include the following: 1. Replacing a commensal community with pathogens caused a loss of important host metabolic functions. 2. The gut microbiota can produce important precursors of host hormone synthesis and thus serves as an endocrine organ. 3. The synthesis of important neurotransmitters is elevated in the presence of the gut microbiota. 4. Gut microbes contribute essential precursors for glutathione, taurine, and leukotrienes. This computational modeling framework provides novel insight into complex metabolic host-microbiota interactions and can serve as a powerful tool with which to generate novel, non-obvious hypotheses regarding host-microbe co-metabolism.

Anoxic Conditions Promote Species-Specific Mutualism between Gut Microbes In Silico

“…The model gut microbiota community consisted of 11 strains belonging to nine species. The 11 microbes account for three of the four main phyla in the human gut microbiome (see Table S1 in the supplemental material), and their metabolic functions are representative of those detected in the gut microbiomes of 124 human volunteers (1,24). Moreover, they contained metabolically similar species, such as Escherichia coli MG1655 and Klebsiella pneumoniae, but they also had metabolically distant representatives (24), the presence of which has been proposed to be important for collaboration in a community (38).…”

“…We used 11 manually curated, published gut microbe reconstructions (23,(26)(27)(28)(29)(30)(31)(32)(33) that we had refined previously (24). The reconstructed strains are listed in Table S1 in the supplemental material, and the reconstructions are shown in spreadsheet format in Table S2 in the supplemental material.…”

“…The applications of constraint-based multispecies modeling to the complex ecosystem residing in the human gut are particularly promising (16). For instance, constraint-based models of an ex-germfree mouse colonized with a single gut symbiont (23) and of a human gut containing up to 11 microbes, including commensals, probiotics, and pathogens, in different combinations have been constructed and analyzed (24). In the latter study, the model community of 11 microbes was shown to significantly affect the human metabolism and to increase the secretion flux of host body fluid metabolites by up to 100 times (24).…”

“…For instance, constraint-based models of an ex-germfree mouse colonized with a single gut symbiont (23) and of a human gut containing up to 11 microbes, including commensals, probiotics, and pathogens, in different combinations have been constructed and analyzed (24). In the latter study, the model community of 11 microbes was shown to significantly affect the human metabolism and to increase the secretion flux of host body fluid metabolites by up to 100 times (24). In the present study, the pairwise interactions between 11 microbes were systematically investigated while imposing various environmental constraints on the pairs.…”

Systems and synthetic biology perspective of the versatile plant-pathogenic and polysaccharide-producing bacterium Xanthomonas campestris

“…The results indicate that M. tuberculosis acquires a mixture of amino acids, C1 and C2 substrates, and it consumes substrates which generate 13 C labelled 3-carbon glycolytic intermediates from its host cell. Other approaches targeted the metabolic interactions of gut symbionts with their hosts [232][233][234][235]. Two recent reviews focus comprehensively on the systems biology of host (gut)-microbe interactions [34,236].…”