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See detailComparative Genomic Analysis of the Human Gut Microbiome Reveals a Broad Distribution of Metabolic Pathways for the Degradation of Host-Synthetized Mucin Glycans and Utilization of Mucin-Derived Monosaccharides
Ravcheev, Dmitry UL; Thiele, Ines UL

in Frontiers in Genetics (2017), 8

The colonic mucus layer is a dynamic and complex structure formed by secreted and transmembrane mucins, which are high-molecular-weight and heavily glycosylated proteins. Colonic mucus consists of a loose ... [more ▼]

The colonic mucus layer is a dynamic and complex structure formed by secreted and transmembrane mucins, which are high-molecular-weight and heavily glycosylated proteins. Colonic mucus consists of a loose outer layer and a dense epithelium-attached layer. The outer layer is inhabited by various representatives of the human gut microbiota (HGM). Glycans of the colonic mucus can be used by the HGM as a source of carbon and energy when dietary fibers are not sufficiently available. Both commensals and pathogens can utilize mucin glycans. Commensals are mostly involved in the cleavage of glycans, while pathogens mostly utilize monosaccharides released by commensals. This HGM-derived degradation of the mucus layer increases pathogen susceptibility and causes many other health disorders. Here, we analyzed 397 individual HGM genomes to identify pathways for the cleavage of host-synthetized mucin glycans to monosaccharides as well as for the catabolism of the derived monosaccharides. Our key results are as follows: (i) Genes for the cleavage of mucin glycans were found in 86% of the analyzed genomes, which significantly higher than a previous estimation. (ii) Genes for the catabolism of derived monosaccharides were found in 89% of the analyzed genomes. (iii) Comparative genomic analysis identified four alternative forms of the monosaccharide-catabolizing enzymes and four alternative forms of monosaccharide transporters. (iv) Eighty-five percent of the analyzed genomes may be involved in potential feeding pathways for the monosaccharides derived from cleaved mucin glycans. (v) The analyzed genomes demonstrated different abilities to degrade known mucin glycans. Generally, the ability to degrade at least one type of mucin glycan was predicted for 81% of the analyzed genomes. (vi) Eighty-two percent of the analyzed genomes can form mutualistic pairs that are able to degrade mucin glycans and are not degradable by any of the paired organisms alone. Taken together, these findings provide further insight into the inter-microbial communications of the HGM as well as into host-HGM interactions. [less ▲]

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See detailBacArena: Individual-Based Metabolic Modeling of Heterogeneous Microbes in Complex Communities
Bauer, Eugen UL; Zimmermann, Johannes; Baldini, Federico UL et al

in PLoS Computational Biology (2017)

Recent advances focusing on the metabolic interactions within and between cellular populations, have emphasized the importance of microbial communities for human health. Constraint-based modeling, with ... [more ▼]

Recent advances focusing on the metabolic interactions within and between cellular populations, have emphasized the importance of microbial communities for human health. Constraint-based modeling, with flux balance analysis in particular, has been established as a key approach for studying microbial metabolism, whereas individual-based modeling has been commonly used to study complex dynamics between interacting organisms. In this study, we combine both techniques into the R package BacArena (https://cran.r-project.org/package=BacArena), to generate novel biological insights into Pseudomonas aeruginosa biofilm formation as well as a seven species model community of the human gut. For our P. aeruginosa model, we found that cross-feeding of fermentation products cause a spatial differentiation of emerging metabolic phenotypes in the biofilm over time. In the human gut model community, we found that spatial gradients of mucus glycans are important for niche formations, which shape the overall community structure. Additionally, we could provide novel hypothesis concerning the metabolic interactions between the microbes. These results demonstrate the importance of spatial and temporal multi-scale modeling approaches such as BacArena. [less ▲]

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See detailGut microbiota functions: metabolism of nutrients and other food components
Rowland, Ian; Gibson, Glenn; Heinken, Almut Katrin UL et al

in European Journal of Nutrition (2017)

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See detailDistributedFBA.jl: High-level, high-performance flux balance analysis in Julia.
Heirendt, Laurent UL; Thiele, Ines UL; Fleming, Ronan MT UL

in Bioinformatics (2017)

MOTIVATION: Flux balance analysis, and its variants, are widely used methods for predicting steady-state reaction rates in biochemical reaction networks. The exploration of high dimensional networks with ... [more ▼]

MOTIVATION: Flux balance analysis, and its variants, are widely used methods for predicting steady-state reaction rates in biochemical reaction networks. The exploration of high dimensional networks with such methods is currently hampered by software performance limitations. RESULTS: DistributedFBA.jl is a high-level, high-performance, open-source implementation of flux balance analysis in Julia. It is tailored to solve multiple flux balance analyses on a subset or all the reactions of large and huge-scale networks, on any number of threads or nodes. AVAILABILITY: The code is freely available on github.com/opencobra/COBRA.jl. The documentation can be found at opencobra.github.io/COBRA.jl. [less ▲]

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See detailLeigh Map: A Novel Computational Diagnostic Resource for Mitochondrial Disease
Rhaman, Joyeeta; Noronha, Alberto UL; Thiele, Ines UL et al

in Annals of Neurology (2017)

Mitochondrial disorders are amongst the most severe metabolic disorders and are beset by genetic, biochemical, and clinical heterogeneity. Variation between individuals and poor understanding of disease ... [more ▼]

Mitochondrial disorders are amongst the most severe metabolic disorders and are beset by genetic, biochemical, and clinical heterogeneity. Variation between individuals and poor understanding of disease pathophysiology pose significant diagnostic challenges. We present a novel interactive computational network, the Leigh Map, cataloguing >1700 gene-to-phenotype interactions in Leigh syndrome, the most common and genetically heterogeneous mitochondrial disorder. Blinded validation of the Leigh Map yielded an 80% success rate in correct identification of causative genes. We conclude that the Leigh Map is an efficacious resource that, in combination with whole-exome sequencing, can be utilized as a novel diagnostic resource for mitochondrial disease. [less ▲]

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See detailReliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression
Ma, Ding; Yang, Laurence; Fleming, Ronan MT UL et al

in Scientific Reports (2017)

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See detailGeneration of genome-scale metabolic reconstructions for 773 members of the human gut microbiota
Magnusdottir, Stefania UL; Heinken, Almut Katrin UL; Kutt, Laura et al

in Nature Biotechnology (2016)

Genome-scale metabolic models derived from human gut metagenomic data can be used as a framework to elucidate how microbial communities modulate human metabolism and health. We present AGORA (assembly of ... [more ▼]

Genome-scale metabolic models derived from human gut metagenomic data can be used as a framework to elucidate how microbial communities modulate human metabolism and health. We present AGORA (assembly of gut organisms through reconstruction and analysis), a resource of genome-scale metabolic reconstructions semi-automatically generated for 773 human gut bacteria. Using this resource, we identified a defined growth medium for Bacteroides caccae ATCC 34185. We also showed that interactions among modeled species depend on both the metabolic potential of each species and the nutrients available. AGORA reconstructions can integrate either metagenomic or 16S rRNA sequencing data sets to infer the metabolic diversity of microbial communities. AGORA reconstructions could provide a starting point for the generation of high-quality, manually curated metabolic reconstructions. AGORA is fully compatible with Recon 2, a comprehensive metabolic reconstruction of human metabolism, which will facilitate studies of host–microbiome interactions. [less ▲]

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See detailConditions for duality between fluxes and concentrations in biochemical networks
Fleming, Ronan MT UL; Vlassis, Nikos; Thiele, Ines UL et al

in Journal of Theoretical Biology (2016), 409(21), 1-10

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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 detailPhenotypic differentiation of gastrointestinal microbes is reflected in their encoded metabolic repertoires
Bauer, Eugen UL; Laczny, Cédric 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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