References of "Thiele, Ines 50003192"
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See detailSystems biology of bacteria-host interactions
Heinken, Almut Katrin UL; Ravcheev, Dmitry UL; Thiele, Ines UL

in Nibali, Luigi; Henderson, Brian (Eds.) The Human Microbiota and Chronic Disease: Dysbiosis as a Cause of Human Pathology (2016)

The aim of systems biology is to use computational methods to gain a complete, systems-level understanding of a cell, organism, or ecosystem. This chapter describes computational systems biology ... [more ▼]

The aim of systems biology is to use computational methods to gain a complete, systems-level understanding of a cell, organism, or ecosystem. This chapter describes computational systems biology approaches and their applications to human gut microbiome research, with particular focus on constraint-based modeling. At heart of the Constraint-Based Modeling and Analysis (COBRA) approach are accurate, well-structured metabolic reconstructions based on the target organisms’ genome sequences. Such genome-scale reconstructions (GENREs) are constructed in a bottom-up manner and describe the target organism's metabolism. The availability of high-quality reconstructions of human metabolism and of other host organisms, enables the computational modeling of host-microbe interactions. Simulating host-microbe interactions is particularly valuable since it could be used to minimize the number of animal experiments. The discussed computational modeling approaches will be valuable tools for studying microbial dysbiosis and its impact on host metabolism. Common approaches for computational modeling include ordinary differential equation (ODE) and kinetic modeling [less ▲]

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See detailModel-based dietary optimization for late-stage, levodopa-treated, Parkinson’s disease patients
Ben Guebila, Marouen UL; Thiele, Ines UL

in NPJ Systems Biology and Applications (2016), 2

Levodopa has been the gold standard for Parkinson’s disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response ... [more ▼]

Levodopa has been the gold standard for Parkinson’s disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response particularly in late-stage (stage 3 and 4 on Hoehn and Yahr scale) patients. The routine dietary intervention consists of low-protein (<0.8 g/kg) diets or the redistribution of daily protein allowance to the last meal. Computational modeling was used to examine the fluctuation of gastrointestinal levodopa absorption under consideration of the diet by (i) identifying the group of patients that could benefit from dietary interventions, (ii) comparing existing diet recommendations for their impact on levodopa bioavailability, and (iii) suggesting a mechanism-based dietary intervention. We developed a multiscale computational model consisting of an ordinary differential equations-based advanced compartmentalized absorption and transit (ACAT) gut model and metabolic genome-scale small intestine epithelial cell model. We used this model to investigate complex spatiotemporal relationship between dietary amino acids and levodopa absorption. Our model predicted an improvement in bioavailability, as reflected by blood concentrations of levodopa with protein redistribution diet by 34% compared with a low-protein diet and by 11% compared with the ante cibum (a.c.) administration. These results are consistent with the reported better outcome in late-stage patients. A systematic analysis of the effect of different amino acids in the diet suggested that a serine-rich diet could improve the bioavailability by 22% compared with the a.c. administration. In addition, the slower gastric emptying rate in PD patients exacerbates the loss of levodopa due to competition. Optimizing dietary recommendations in quantity, composition, and intake time holds the promise to improve levodopa efficiency and patient’s quality of life based on highly detailed, mechanistic models of gut physiology endowed with improved extrapolative properties, thus paving the way for precision medical treatment. [less ▲]

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See detailGenomic analysis of the human gut microbiome suggests novel enzymes involved in quinone biosynthesis
Ravcheev, Dmitry UL; Thiele, Ines UL

in Frontiers in Microbiology (2016), 7(128),

Ubiquinone and menaquinone are membrane lipid-soluble carriers of electrons that are essential for cellular respiration. Eukaryotic cells can synthesize ubiquinone but not menaquinone, whereas prokaryotes ... [more ▼]

Ubiquinone and menaquinone are membrane lipid-soluble carriers of electrons that are essential for cellular respiration. Eukaryotic cells can synthesize ubiquinone but not menaquinone, whereas prokaryotes can synthesize both quinones. So far, most of the human gut microbiome (HGM) studies have been based on metagenomic analysis. Here, we applied an analysis of individual HGM genomes to the identification of ubiquinone and menaquinone biosynthetic pathways. In our opinion, the shift from metagenomics to analysis of individual genomes is a pivotal milestone in investigation of bacterial communities, including the HGM. The key results of this study are as follows. (i) The distribution of the canonical pathways in the HGM genomes was consistent with previous reports and with the distribution of the quinone-dependent reductases for electron acceptors. (ii) The comparative genomics analysis identified four alternative forms of the previously known enzymes for quinone biosynthesis. (iii) Genes for the previously unknown part of the futalosine pathway were identified, and the corresponding biochemical reactions were proposed. We discuss the remaining gaps in the menaquinone and ubiquinone pathways in some of the microbes, which indicate the existence of further alternate genes or routes. Together, these findings provide further insight into the biosynthesis of quinones in bacteria and the physiology of the HGM. [less ▲]

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See detailThe Human Gutome: Journey of Microbes and Health
Dimitrov, Dimiter; Thiele, Ines UL; Ferguson, Lynnette Robin

in Frontiers in Genetics (2016)

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See detailMetabolomics enables precision medicine: A White Paper, Community Perspective
Beger, DR; Dunn, W; Schmidt, MA et al

in Metabolomics : Official journal of the Metabolomic Society (2016)

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See detailReconMap: An interactive visualisation of human metabolism
Noronha, Alberto UL; Danielsdóttir, Anna Dröfn; Jóhannsson, Freyr et al

in Bioinformatics (2016)

A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualise its content integrated with omics data and simulation results. We manually drew ... [more ▼]

A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualise its content integrated with omics data and simulation results. We manually drew a comprehensive map, ReconMap 2.0, that is consistent with the content of Recon 2. We present it within a web interface that allows content query, visualization of custom datasets and submission of feedback to manual curators. ReconMap can be accessed via http://vmh.uni.lu, with network export in a Systems Biology Graphical Notation compliant format. A Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension to interact with ReconMap is available via https://github.com/opencobra/cobratoolbox. [less ▲]

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See detailComputational modeling of human metabolism and its application to systems biomedicine
Aurich, Maike Kathrin UL; Thiele, Ines UL

in Wolkenhauer, Olaf; Schmitz, Ulf (Eds.) Systems Medicine (2015)

Modern high-throughput techniques offer immense opportunities to investigate whole-systems behavior, such as those underlying human diseases. However, the complexity of the data presents challenges in ... [more ▼]

Modern high-throughput techniques offer immense opportunities to investigate whole-systems behavior, such as those underlying human diseases. However, the complexity of the data presents challenges in interpretation, and new avenues are needed to address the complexity of both diseases and data. Constraint-based modeling is one formalism applied in systems biology. It relies on a genome-scale reconstruction that captures extensive biochemical knowledge regarding an organism. The human genome-scale metabolic reconstruction is increasingly used to understand normal cellular and disease states because metabolism is an important factor in many human diseases. The application of human genome-scale reconstruction ranges from mere querying of the model as a knowledge-base to studies that take advantage of the model’s topology, and most notably, to functional predictions based on cell- and condition-specific metabolic models built based on omics data. An increasing number and diversity of biomedical questions are being addressed using constraint-based modeling and metabolic models. One of the most successful biomedical applications to date is cancer metabolism, but constraint-based modeling also holds great potential for inborn errors of metabolism or obesity. In addition, it offers great prospects for individualized approaches to diagnostics and the design of disease prevention and intervention strategies. Metabolic models support this endeavor by providing easy access to complex high-throughput datasets. Personalized metabolic models have been introduced. Finally, constraint-based modeling can be used to model whole-body metabolism, which will enable the elucidation of metabolic interactions between organs and disturbances of these interactions as either causes or consequence of metabolic diseases. This chapter introduces constraint-based modeling and describes some of its contributions to systems biomedicine. [less ▲]

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See detailSystematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes
Magnusdottir, Stefania UL; Ravcheev, Dmitry UL; de Crecy-Lagard, Valerie et al

in Frontiers in Genetics (2015), 6

The human gut microbiota supplies its host with essential nutrients, including B-vitamins. Using the PubSEED platform, we systematically assessed the genomes of 256 common human gut bacteria for the ... [more ▼]

The human gut microbiota supplies its host with essential nutrients, including B-vitamins. Using the PubSEED platform, we systematically assessed the genomes of 256 common human gut bacteria for the presence of biosynthesis pathways for eight B-vitamins: biotin, cobalamin, folate, niacin, pantothenate, pyridoxine, riboflavin, and thiamin. On the basis of the presence and absence of genome annotations, we predicted that each of the eight vitamins was produced by 40–65% of the 256 human gut microbes. The distribution of synthesis pathways was diverse; some genomes had all eight biosynthesis pathways, whereas others contained no de novo synthesis pathways. We compared our predictions to experimental data from 16 organisms and found 88% of our predictions to be in agreement with published data. In addition, we identified several pairs of organisms whose vitamin synthesis pathway pattern complemented those of other organisms. This analysis suggests that human gut bacteria actively exchange B-vitamins among each other, thereby enabling the survival of organisms that do not synthesize any of these essential cofactors. This result indicates the co-evolution of the gut microbes in the human gut environment. Our work presents the first comprehensive assessment of the B-vitamin synthesis capabilities of the human gut microbiota. We propose that in addition to diet, the gut microbiota is an important source of B-vitamins, and that changes in the gut microbiota composition can severely affect our dietary B-vitamin requirements. [less ▲]

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See detailAnoxic conditions promote species-specific mutualism between gut microbes in silico
Heinken, Almut Katrin UL; Thiele, Ines UL

in Applied and Environmental Microbiology (2015), 81(12), 4049-4061

The human gut is inhabited by thousands of microbial species, most of which are still uncharacterized. Gut microbes have adapted to each other’s presence as well as to the host and engage in complex cross ... [more ▼]

The human gut is inhabited by thousands of microbial species, most of which are still uncharacterized. Gut microbes have adapted to each other’s presence as well as to the host and engage in complex cross-feeding. Constraint-based modeling has been successfully applied to predicting microbe-microbe interactions, such as commensalism, mutualism, and competition. Here, we apply a constraint-based approach to model pairwise interactions between 11 representative gut microbes. Microbe-microbe interactions were computationally modeled in conjunction with human small intestinal enterocytes and subjected to three diets with varying levels of carbohydrate, fat, and protein in normoxic or anoxic environments. Each microbe engaged in species-specific commensal, parasitic, mutualistic, or competitive interactions. For instance, Streptococcus thermophilus efficiently outcompeted paired microbes in agreement with the domination of streptococci in the small intestinal microbiota. Under anoxic conditions, the probiotic Lactobacillus plantarum displayed mutualistic behavior towards six other species, which, surprisingly, were almost entirely abolished under normoxic conditions. This finding suggests that the anoxic conditions in the large intestine drive mutualistic cross-feeding, leading to the evolvement of a more complex ecosystem than the small intestinal microbiota. Moreover, we predict that the presence of the small intestinal enterocyte induces competition over host-derived nutrients. The presented framework can readily be expanded to a larger gut microbial community. This modeling approach will be of great value for subsequent studies aiming to predict conditions favoring desirable microbes or suppressing pathogens. [less ▲]

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See detailPhenotypic differentiation of gastrointestinal microbes is reflected in their encoded metabolic repertoires
Bauer, Eugen UL; Laczny, Cedric Christian UL; Magnusdottir, Stefania UL et al

in Microbiome (2015), 3(55), 1-13

Background: The human gastrointestinal tract harbors a diverse microbial community, in which metabolic phenotypes play important roles for the human host. Recent developments in meta-omics attempt to ... [more ▼]

Background: The human gastrointestinal tract harbors a diverse microbial community, in which metabolic phenotypes play important roles for the human host. Recent developments in meta-omics attempt to unravel metabolic roles of microbes by linking genotypic and phenotypic characteristics. This connection, however, still remains poorly understood with respect to its evolutionary and ecological context. Results: We generated automatically refined draft genome-scale metabolic models of 301 representative intestinal microbes in silico. We applied a combination of unsupervised machine-learning and systems biology techniques to study individual and global differences in genomic content and inferred metabolic capabilities. Based on the global metabolic differences, we found that energy metabolism and membrane synthesis play important roles in delineating different taxonomic groups. Furthermore, we found an exponential relationship between phylogeny and the reaction composition, meaning that closely related microbes of the same genus can exhibit pronounced differences with respect to their metabolic capabilities while at the family level only marginal metabolic differences can be observed. This finding was further substantiated by the metabolic divergence within different genera. In particular, we could distinguish three sub-type clusters based on membrane and energy metabolism within the Lactobacilli as well as two clusters within the Bifidobacteria and Bacteroides. Conclusions: We demonstrate that phenotypic differentiation within closely related species could be explained by their metabolic repertoire rather than their phylogenetic relationships. These results have important implications in our understanding of the ecological and evolutionary complexity of the human gastrointestinal microbiome. [less ▲]

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See detailDo Genome-scale Models Need Exact Solvers or Clearer Standards?
Ebrahim, Ali; Almaas, Eivind; Bauer, Eugen UL et al

in Molecular Systems Biology (2015), 11(10), 1

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See detailPrediction of intracellular metabolic states from extracellular metabolomic data
Aurich, Maike Kathrin UL; Paglia, Guiseppe; Rolfsson, Ottar et al

in Metabolomics : Official journal of the Metabolomic Society (2015), 11(3), 603-619

Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of ... [more ▼]

Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of the altered metabolic pathway utilization is the selection of metabolites consumed and released by cells. However, methods for the inference of intracellular metabolic states from extracellular measurements in the context of metabolic models remain underdeveloped compared to methods for other omics data. Herein, we describe a workflow for such an integrative analysis emphasizing on extracellular metabolomics data. We demonstrate, using the lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM, how our methods can reveal differences in cell metabolism. Our models explain metabolite uptake and secretion by predicting a more glycolytic phenotype for the CCRFCEM model and a more oxidative phenotype for the Molt-4 model, which was supported by our experimental data. Gene expression analysis revealed altered expression of gene products at key regulatory steps in those central metabolic pathways, and literature query emphasized the role of these genes in cancer metabolism. Moreover, in silico gene knock-outs identified unique control points for each cell line model, e.g., phosphoglycerate dehydrogenase for the Molt-4 model. Thus, our workflow is well-suited to the characterization of cellular metabolic traits based on extracellular metabolomic data, and it allows the integration of multiple omics data sets into a cohesive picture based on a defined model context. [less ▲]

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See detailSystematic prediction of health-relevant human-microbial co-metabolism through a computational framework
Heinken, Almut Katrin UL; Thiele, Ines UL

in Gut Microbes (2015), 6(2), 120-130

The 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 ... [more ▼]

The 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. [less ▲]

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See detailSystems biology of host-microbe metabolomics
Heinken, Almut Katrin UL; Thiele, Ines UL

in Wiley Interdisciplinary Reviews. Systems Biology and Medicine (2015)

The human gut microbiota performs essential functions for host and wellbeing, but has also been linked to a variety of disease states, e.g., obesity and type 2 diabetes. The mammalian body fluid and ... [more ▼]

The human gut microbiota performs essential functions for host and wellbeing, but has also been linked to a variety of disease states, e.g., obesity and type 2 diabetes. The mammalian body fluid and tissue metabolomes are greatly influenced by the microbiota, with many health-relevant metabolites being considered “mammalian-microbial co-metabolites”. To systematically investigate this complex host-microbial co-metabolism, a systems biology approach integrating high-throughput data and computational network models is required. Here, we review established top-down and bottom-up systems biology approaches that have successfully elucidated relationships between gut microbiota-derived metabolites and host health and disease. We particularly focus on the constraint-based modeling and analysis approach, which enables the prediction of mechanisms behind metabolic host-microbe interactions on the molecular level. We illustrate that constraint-based models are a useful tool for the contextualization of metabolomic measurements and can further our insight into host-microbe interactions, yielding, e.g., in potential novel drugs and biomarkers. [less ▲]

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See detailSystematic genomic analysis reveals the complementary aerobic and anaerobic respiration capacities of the human gut microbiota
Ravcheev, Dmitry UL; Thiele, Ines UL

in Frontiers in Microbiology (2014)

Because of the specific anatomical and physiological properties of the human intestine, a specific oxygen gradient builds up within this organ that influences the intestinal microbiota. The intestinal ... [more ▼]

Because of the specific anatomical and physiological properties of the human intestine, a specific oxygen gradient builds up within this organ that influences the intestinal microbiota. The intestinal microbiome has been intensively studied in recent years, and certain respiratory substrates used by gut inhabiting microbes have been shown to play a crucial role in human health. Unfortunately, a systematic analysis has not been previously performed to determine the respiratory capabilities of human gut microbes (HGM). Here, we analyzed the distribution of aerobic and anaerobic respiratory reductases in 254 HGM genomes. In addition to the annotation of known enzymes, we also predicted a novel microaerobic reductase and novel thiosulfate reductase. Based on this comprehensive assessment of respiratory reductases in the HGM, we proposed a number of exchange pathways among different bacteria involved in the reduction of various nitrogen oxides. The results significantly expanded our knowledge of HGM metabolism and interactions in bacterial communities. [less ▲]

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See detailA functional metabolic map of Faecalibacterium prausnitzii, a beneficial human gut microbe
Heinken, Almut Katrin UL; Khan, M Tanweer; Paglia, Giuseppe et al

in Journal of Bacteriology (2014), 196(18), 3289-3302

The 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 ... [more ▼]

The 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. [less ▲]

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See detailMembrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease
Sahoo, Swagatika UL; Aurich, Maike Kathrin UL; Jonsson, Jon et al

in Frontiers in Physiology (2014), 5

Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network ... [more ▼]

Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network reconstructions capture genomic, physiological, and biochemical knowledge of a target organism, along with a detailed representation of the cellular metabolite transport mechanisms. Since the first reconstruction of human metabolism, Recon 1, published in 2007, progress has been made in the field of metabolite transport. Recently, we published an updated reconstruction, Recon 2, which significantly improved the metabolic coverage and functionality. Human metabolic reconstructions have been used to investigate the role of metabolism in disease and to predict biomarkers and drug targets. Given the importance of cellular transport systems in understanding human metabolism in health and disease, we analyzed the coverage of transport systems for various metabolite classes in Recon 2. We will review the current knowledge on transporters (i.e., their preferred substrates, transport mechanisms, metabolic relevance, and disease association for each metabolite class). We will assess missing coverage and propose modifications and additions through a transport module that is functional when combined with Recon 2. This information will be valuable for further refinements. These data will also provide starting points for further experiments by highlighting areas of incomplete knowledge. This review represents the first comprehensive overview of the transporters involved in central metabolism and their transport mechanisms, thus serving as a compendium of metabolite transporters specific for human metabolic reconstructions. [less ▲]

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See detailModeling the effects of commonly used drugs on human metabolism
Sahoo, Swagatika UL; Haraldsdottir, Hulda UL; Fleming, Ronan MT UL et al

in FEBS Journal (2014)

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein ... [more ▼]

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein, we assembled a comprehensive, literature-based drug metabolic reconstruction of the 18 most highly prescribed drug groups including statins, antihypertensives, immunosuppressants, and analgesics. This reconstruction captures in detail our current understanding of their absorption, intra-cellular distribution, metabolism, and elimination. We combined this drug module with the most comprehensive reconstruction of human metabolism, Recon 2, yielding Recon2_DM1796, which accounts for 2803 metabolites and 8161 reactions. By defining 50 specific drug objectives that captured the overall drug metabolism of these compounds, we investigated effects of dietary composition and inherited metabolic disorders on drug metabolism and drug-drug interactions. Our main findings include (i) shift in dietary patterns significantly affect statins and acetaminophen metabolism, (ii) disturbed statin metabolism contributes to the clinical phenotype of mitochondrial energy disorders, and (iii) the interaction between statins and cyclosporine can be explained by several common metabolic and transport pathways other than the previously established CYP3A4 connection. This work holds the potential for studying adverse drug reactions and designing patient-specific therapies. [less ▲]

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