A systems biology approach to studying the role of microbes in human health

Thiele, Ines; Heinken, Almut; Fleming, Ronan M. T.

doi:10.1016/j.copbio.2012.10.001

Cited by 98 publications

(97 citation statements)

References 56 publications

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“…If this was the case with a unicellular organism or with relatively uniform cell lines [54], then further levels of complexity are to be expected in the gut microbiome ecosystem, where communities of unicellular organisms coexist in balance with the human multicellular tissues. Systems biology approaches for such complex communities are inevitable but are still in early development [55,56]. From a holistic perspective, tailoring a pharmacotherapy that accommodates intraindividual and interindividual variations would take into account the variations in the host's genetic makeup, its associated-microbiome, and metabolomic interactions between the host and its associated microbiota (i.e., co-metabolome).…”

Section: Carcinogenic Agentsmentioning

confidence: 99%

Diet-Microbiota Interactions and their Implications for Healthy Living

2014

Health and the Gut

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The influence of resident gut microbes on xenobiotic metabolism has been investigated at different levels throughout the past five decades. However, with the advance in sequencing and pyrotagging technologies, addressing the influence of microbes on xenobiotics had to evolve from assessing direct metabolic effects on toxins and botanicals by conventional culture-based techniques to elucidating the role of community composition on drugs metabolic profiles through DNA sequence-based phylogeny and metagenomics. Following the completion of the Human Genome Project, the rapid, substantial growth of the Human Microbiome Project (HMP) opens new horizons for studying how microbiome compositional and functional variations affect drug action, fate, and toxicity (pharmacomicrobiomics), notably in the human gut. The HMP continues to characterize the microbial communities associated with the human gut, determine whether there is a common gut microbiome profile shared among healthy humans, and investigate the effect of its alterations on health. Here, we offer a glimpse into the known effects of the gut microbiota on xenobiotic metabolism, with emphasis on cases where microbiome variations lead to different therapeutic outcomes. We discuss a few examples representing how the microbiome interacts with human metabolic enzymes in the liver and intestine. In addition, we attempt to envisage a roadmap for the future implications of the HMP on therapeutics and personalized medicine.

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Section: Carcinogenic Agentsmentioning

confidence: 99%

Diet-Microbiota Interactions and their Implications for Healthy Living

2014

Health and the Gut

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“…12 Over 25 metabolic reconstructions for microbes inhabiting the human body are available. 11 Using the COBRA approach, we previously demonstrated, for the first time, that the metabolite exchange between a mouse and its gut symbiont Bacteroides thetaiotaomicron could be predicted in silico. 13 However, no studies have modeled the interaction between a host and more than one microbe hitherto.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the constraint-based reconstruction and analysis (COBRA) approach allows for the modeling of interspecies interactions by utilizing well-curated, organism-resolved metabolic networks constructed in a bottom-up manner. 11 Such metabolic reconstructions can be converted into mathematical models, which can be constrained according to environmental conditions, e.g., the availability of dietary nutrients. Subsequently, functional states can be predicted under various nutrient conditions or enzyme defects.…”

Section: Introductionmentioning

confidence: 99%

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

2015

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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.

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“…The number of well-curated GENREs is increasing steadily (15). Particularly well represented are microbes colonizing the human body (16). GENREs have been applied successfully to the elucidation of biochemical and metabolic properties of a variety of microorganisms, including the Fe(III) reducer Geobacter sulfurreducens (17), the photosynthetic alga Chlamydomonas reinhardtii (18), and the human pathogen Mycoplasma pneumoniae (19).…”

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confidence: 99%

Functional Metabolic Map of Faecalibacterium prausnitzii, a Beneficial Human Gut Microbe

et al. 2014

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eThe human gut microbiota plays a central role in human well-being and disease. In this study, we present an integrated, iterative approach of computational modeling, in vitro experiments, metabolomics, and genomic analysis to accelerate the identification of metabolic capabilities for poorly characterized (anaerobic) microorganisms. We demonstrate this approach for the beneficial human gut microbe Faecalibacterium prausnitzii strain A2-165. We generated an automated draft reconstruction, which we curated against the limited biochemical data. This reconstruction modeling was used to develop in silico and in vitro a chemically defined medium (CDM), which was validated experimentally. Subsequent metabolomic analysis of the spent medium for growth on CDM was performed. We refined our metabolic reconstruction according to in vitro observed metabolite consumption and secretion and propose improvements to the current genome annotation of F. prausnitzii A2-165. We then used the reconstruction to systematically characterize its metabolic properties. Novel carbon source utilization capabilities and inabilities were predicted based on metabolic modeling and validated experimentally. This study resulted in a functional metabolic map of F. prausnitzii, which is available for further applications. The presented workflow can be readily extended to other poorly characterized and uncharacterized organisms to yield novel biochemical insights about the target organism.

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A systems biology approach to studying the role of microbes in human health

Cited by 98 publications

References 56 publications

Diet-Microbiota Interactions and their Implications for Healthy Living

Diet-Microbiota Interactions and their Implications for Healthy Living

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

Functional Metabolic Map of Faecalibacterium prausnitzii, a Beneficial Human Gut Microbe

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