From Network Analysis to Functional Metabolic Modeling of the Human Gut Microbiota

ABSTRACTAn important hallmark of the human gut microbiota is its species diversity and complexity. Various diseases have been associated with a decreased diversity leading to reduced metabolic functionalities. Common approaches to investigate the human microbiota include high-throughput sequencing with subsequent correlative analyses. However, to understand the ecology of the human gut microbiota and consequently design novel treatments for diseases, it is important to represent the different interactions between microbes with their associated metabolites. Computational systems biology approaches can give further mechanistic insights by constructing data- or knowledge-driven networks that represent microbe interactions. In this minireview, we will discuss current approaches in systems biology to analyze the human gut microbiota, with a particular focus on constraint-based modeling. We will discuss various community modeling techniques with their advantages and differences, as well as their application to predict the metabolic mechanisms of intestinal microbial communities. Finally, we will discuss future perspectives and current challenges of simulating realistic and comprehensive models of the human gut microbiota.

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An extended reconstruction of human gut microbiota metabolism for personalized nutrition

10.1101/2020.10.23.350462 ◽

2020 ◽

Author(s):

Telmo Blasco ◽

Sergio Pérez-Burillo ◽

Francesco Balzerani ◽

Alberto Lerma-Aguilera ◽

Daniel Hinojosa-Nogueira ◽

...

Keyword(s):

Gut Microbiota ◽

Metabolic Networks ◽

Degradation Pathways ◽

Personalized Nutrition ◽

Human Gut ◽

Human Gut Microbiota ◽

Lack Of Information ◽

Constraint Based Modeling ◽

Genome Scale ◽

Complex Question

ABSTRACTUnderstanding how diet and gut microbiota interact in the context of human health is a key question in personalized nutrition. Genome-scale metabolic networks and constraint-based modeling approaches are promising to systematically address this complex question. However, when applied to nutritional questions, a major issue in existing reconstructions is the lack of information about degradation pathways of relevant nutrients in the diet that are metabolized by the gut microbiota. Here, we present AGREDA, an extended reconstruction of the human gut microbiota metabolism for personalized nutrition. AGREDA includes the degradation pathways of 231 nutrients present in the human diet and allows us to more comprehensively simulate the interplay between food and gut microbiota. We show that AGREDA is more accurate than existing reconstructions in predicting output metabolites of the gut microbiota. Finally, using AGREDA, we established relevant metabolic differences among clinical subgroups of Spanish children: lean, obese, allergic to foods and celiac.

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Introduction to the human gut microbiota

Biochemical Journal ◽

10.1042/bcj20160510 ◽

2017 ◽

Vol 474 (11) ◽

pp. 1823-1836 ◽

Cited By ~ 478

Author(s):

Elizabeth Thursby ◽

Nathalie Juge

Keyword(s):

Gut Microbiota ◽

Inflammatory Diseases ◽

Intestinal Bacteria ◽

Life Time ◽

Gi Tract ◽

Human Gut ◽

Human Gut Microbiota ◽

Microbe Interactions ◽

Host Microbe Interactions ◽

Dynamic Population

The human gastrointestinal (GI) tract harbours a complex and dynamic population of microorganisms, the gut microbiota, which exert a marked influence on the host during homeostasis and disease. Multiple factors contribute to the establishment of the human gut microbiota during infancy. Diet is considered as one of the main drivers in shaping the gut microbiota across the life time. Intestinal bacteria play a crucial role in maintaining immune and metabolic homeostasis and protecting against pathogens. Altered gut bacterial composition (dysbiosis) has been associated with the pathogenesis of many inflammatory diseases and infections. The interpretation of these studies relies on a better understanding of inter-individual variations, heterogeneity of bacterial communities along and across the GI tract, functional redundancy and the need to distinguish cause from effect in states of dysbiosis. This review summarises our current understanding of the development and composition of the human GI microbiota, and its impact on gut integrity and host health, underlying the need for mechanistic studies focusing on host–microbe interactions.

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The Use of Defined Microbial Communities To Model Host-Microbe Interactions in the Human Gut

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00054-18 ◽

2019 ◽

Vol 83 (2) ◽

Cited By ~ 19

Author(s):

Janneke Elzinga ◽

John van der Oost ◽

Willem M. de Vos ◽

Hauke Smidt

Keyword(s):

Gut Microbiota ◽

Microbial Communities ◽

Well Being ◽

Human Gut ◽

Human Host ◽

Advantages And Disadvantages ◽

Human Gut Microbiota ◽

Microbe Interactions ◽

Host Microbe Interactions

SUMMARYThe human intestinal ecosystem is characterized by a complex interplay between different microorganisms and the host. The high variation within the human population further complicates the quest toward an adequate understanding of this complex system that is so relevant to human health and well-being. To study host-microbe interactions, defined synthetic bacterial communities have been introduced in gnotobiotic animals or in sophisticatedin vitrocell models. This review reinforces that our limited understanding has often hampered the appropriate design of defined communities that represent the human gut microbiota. On top of this, some communities have been applied toin vivomodels that differ appreciably from the human host. In this review, the advantages and disadvantages of using defined microbial communities are outlined, and suggestions for future improvement of host-microbe interaction models are provided. With respect to the host, technological advances, such as the development of a gut-on-a-chip system and intestinal organoids, may contribute to more-accuratein vitromodels of the human host. With respect to the microbiota, due to the increasing availability of representative cultured isolates and their genomic sequences, our understanding and controllability of the human gut “core microbiota” are likely to increase. Taken together, these advancements could further unravel the molecular mechanisms underlying the human gut microbiota superorganism. Such a gain of insight would provide a solid basis for the improvement of pre-, pro-, and synbiotics as well as the development of new therapeutic microbes.

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A Diverse Range of Human Gut Bacteria Have the Potential To Metabolize the Dietary Component Gallic Acid

Applied and Environmental Microbiology ◽

10.1128/aem.01558-18 ◽

2018 ◽

Vol 84 (19) ◽

Cited By ~ 4

Author(s):

María Esteban-Torres ◽

Laura Santamaría ◽

Raúl Cabrera-Rubio ◽

Laura Plaza-Vinuesa ◽

Fiona Crispie ◽

...

Keyword(s):

Gut Microbiota ◽

Gallic Acid ◽

High Throughput Sequencing ◽

Human Gut ◽

Diverse Range ◽

Fecal Samples ◽

Content Type ◽

Human Gut Microbiota ◽

Human Microbiota ◽

Phenolic Components

ABSTRACTThe human gut microbiota contains a broad variety of bacteria that possess functional genes, with resultant metabolites that affect human physiology and therefore health. Dietary gallates are phenolic components that are present in many foods and beverages and are regarded as having health-promoting attributes. However, the potential for metabolism of these phenolic compounds by the human microbiota remains largely unknown. The emergence of high-throughput sequencing (HTS) technologies allows this issue to be addressed. In this study, HTS was used to assess the incidence of gallate-decarboxylating bacteria within the gut microbiota of healthy individuals for whom bacterial diversity was previously determined to be high. This process was facilitated by the design and application of degenerate PCR primers to amplify a region encoding the catalytic C subunit of gallate decarboxylase (LpdC) from total metagenomic DNA extracted from human fecal samples. HTS resulted in the generation of a total of 3,261,967 sequence reads and revealed that the primary gallate-decarboxylating microbial phyla in the intestinal microbiota wereFirmicutes(74.6%),Proteobacteria(17.6%), andActinobacteria(7.8%). These reads corresponded to 53 genera, i.e., 47% of the bacterial genera detected previously in these samples. Among these genera,AnaerostipesandKlebsiellaaccounted for the majority of reads (40%). The usefulness of the HTS-lpdCmethod was demonstrated by the production of pyrogallol from gallic acid, as expected for functional gallate decarboxylases, among representative strains belonging to species identified in the human gut microbiota by this method.IMPORTANCEDespite the increasing wealth of sequencing data, the health contributions of many bacteria found in the human gut microbiota have yet to be elucidated. This study applies a novel experimental approach to predict the ability of gut microbes to carry out a specific metabolic activity, i.e., gallate metabolism. The study showed that, while gallate-decarboxylating bacteria represented 47% of the bacterial genera detected previously in the same human fecal samples, no gallate decarboxylase homologs were identified from representatives ofBacteroidetes. The presence of functional gallate decarboxylases was demonstrated in representativeProteobacteriaandFirmicutesstrains from the human microbiota, an observation that could be of considerable relevance to thein vivoproduction of pyrogallol, a physiologically important bioactive compound.

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In vitro study of the interaction between human gut microbiota and herbal extracts using willow bark extract as an example

Planta Medica ◽

10.1055/s-0036-1596386 ◽

2016 ◽

Vol 81 (S 01) ◽

pp. S1-S381

Author(s):

EM Pferschy-Wenzig ◽

K Koskinen ◽

C Moissl-Eichinger ◽

R Bauer

Keyword(s):

Gut Microbiota ◽

In Vitro Study ◽

Vitro Study ◽

Bark Extract ◽

Herbal Extracts ◽

Human Gut ◽

Human Gut Microbiota ◽

Willow Bark

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Metabolization of the herbal combination STW-5 by human gut microbiota in vitro

10.1055/s-0037-1608399 ◽

2017 ◽

Author(s):

EM Pferschy-Wenzig ◽

A Roßmann ◽

K Koskinen ◽

H Abdel-Aziz ◽

C Moissl-Eichinger ◽

...

Keyword(s):

Gut Microbiota ◽

Human Gut ◽

Human Gut Microbiota

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Substrate use prioritization by a coculture of five species of gut bacteria fed mixtures of arabinoxylan, xyloglucan, β-glucan, and pectin

10.26686/wgtn.12585620.v1 ◽

2020 ◽

Author(s):

Y Liu ◽

AL Heath ◽

B Galland ◽

N Rehrer ◽

L Drummond ◽

...

Keyword(s):

Gut Microbiota ◽

Dietary Fiber ◽

Plant Cell Wall ◽

Bacterial Species ◽

Short Chain ◽

Emergent Properties ◽

Human Gut ◽

Fermentation Products ◽

Plant Polysaccharides ◽

Human Gut Microbiota

© 2020 American Society for Microbiology. Dietary fiber provides growth substrates for bacterial species that belong to the colonic microbiota of humans. The microbiota degrades and ferments substrates, producing characteristic short-chain fatty acid profiles. Dietary fiber contains plant cell wall-associated polysaccharides (hemicelluloses and pectins) that are chemically diverse in composition and structure. Thus, depending on plant sources, dietary fiber daily presents the microbiota with mixtures of plant polysaccharides of various types and complexity. We studied the extent and preferential order in which mixtures of plant polysaccharides (arabinoxylan, xyloglucan, β-glucan, and pectin) were utilized by a coculture of five bacterial species (Bacteroides ovatus, Bifidobacterium longum subspecies longum, Megasphaera elsdenii, Ruminococcus gnavus, and Veillonella parvula). These species are members of the human gut microbiota and have the biochemical capacity, collectively, to degrade and ferment the polysaccharides and produce short-chain fatty acids (SCFAs). B. ovatus utilized glycans in the order β-glucan, pectin, xyloglucan, and arabinoxylan, whereas B. longum subsp. longum utilization was in the order arabinoxylan, arabinan, pectin, and β-glucan. Propionate, as a proportion of total SCFAs, was augmented when polysaccharide mixtures contained galactan, resulting in greater succinate production by B. ovatus and conversion of succinate to propionate by V. parvula. Overall, we derived a synthetic ecological community that carries out SCFA production by the common pathways used by bacterial species for this purpose. Systems like this might be used to predict changes to the emergent properties of the gut ecosystem when diet is altered, with the aim of beneficially affecting human physiology. This study addresses the question as to how bacterial species, characteristic of the human gut microbiota, collectively utilize mixtures of plant polysaccharides such as are found in dietary fiber. Five bacterial species with the capacity to degrade polymers and/or produce acidic fermentation products detectable in human feces were used in the experiments. The bacteria showed preferential use of certain polysaccharides over others for growth, and this influenced their fermentation output qualitatively. These kinds of studies are essential in developing concepts of how the gut microbial community shares habitat resources, directly and indirectly, when presented with mixtures of polysaccharides that are found in human diets. The concepts are required in planning dietary interventions that might correct imbalances in the functioning of the human microbiota so as to support measures to reduce metabolic conditions such as obesity.

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