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•The human gut microbiome is a complex ecosystem with hundreds of species.•Metabolic modeling can help identifying metabolic cross-talk among gut microbes.•Diverse dietary components ...and microbiome compositions can be studied.•Personalized gut microbiome models can be created by integrating diverse data types.
The human gut microbiome plays an important part in human health. The complexity of the microbiome makes it difficult to determine the detailed metabolic functions and cross-talk occurs between the individual species. In silico systems biology studies of the microbiome can help to identify metabolite exchanges among gut microbes. Constraint-based reconstruction and analysis methods use biochemically accurate genome-scale metabolic networks of microorganisms to simulate metabolism between species in a given microbiome and help generate novel hypotheses on microbial interactions. Here, we review metabolic modeling studies that have investigated metabolic functions of the gut microbiome.
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.
In recent years, metagenome-assembled genomes (MAGs) have provided glimpses into the intra- and interspecies genetic diversity and interactions that form the bases of complex microbial communities. ...High-throughput reconstruction of genome-scale metabolic networks (GEMs) from MAGs is a promising avenue to disentangle the myriad trophic interactions stabilizing these communities. However, high-throughput reconstruction of GEMs relies on accurate gap filling of metabolic pathways using automated algorithms. Here, we systematically explore how the composition of the media (specification of the available nutrients and metabolites) during gap filling influences the resulting GEMs concerning predicted auxotrophies for fully sequenced model organisms and environmental isolates. We expand this analysis by using 106 MAGs from the same species with differing quality. We find that although the completeness of MAGs influences the fraction of gap-filled reactions, the composition of the media plays the dominant role in the accurate prediction of auxotrophies that form the basis of myriad community interactions. We propose that constraining the media composition for gap filling through both experimental approaches and computational approaches will increase the reliability of high-throughput reconstruction of genome-scale metabolic models from MAGs and paves the way for culture independent prediction of trophic interactions in complex microbial communities.
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.
Microorganisms rely on binding‐protein assisted, active transport systems to scavenge for scarce nutrients. Several advantages of using binding proteins in such uptake systems have been proposed. ...However, a systematic, rigorous and quantitative analysis of the function of binding proteins is lacking. By combining knowledge of selection pressure and physiochemical constraints, we derive kinetic, thermodynamic, and stoichiometric properties of binding‐protein dependent transport systems that enable a maximal import activity per amount of transporter. Under the hypothesis that this maximal specific activity of the transport complex is the selection objective, binding protein concentrations should exceed the concentration of both the scarce nutrient and the transporter. This increases the encounter rate of transporter with loaded binding protein at low substrate concentrations, thereby enhancing the affinity and specific uptake rate. These predictions are experimentally testable, and a number of observations confirm them.
Abstract
Motivation
Manual curation of genome-scale reconstructions is laborious, yet existing automated curation tools do not typically take species-specific experimental and curated genomic data ...into account.
Results
We developed Data-drivEn METabolic nEtwork Refinement (DEMETER), a Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension, which enables the efficient, simultaneous refinement of thousands of draft genome-scale reconstructions, while ensuring adherence to the quality standards in the field, agreement with available experimental data and refinement of pathways based on manually refined genome annotations.
Availability and implementation
DEMETER and tutorials are freely available at https://github.com/opencobra.
Supplementary information
Supplementary data are available at Bioinformatics online.
Every year, millions of deaths are associated with the increased spread of antimicrobial resistance genes (ARGs) in bacteria. With the increasing urbanization of the global population, the spread of ...ARGs in urban bacteria has become a more severe threat to human health.
In this study, we used metagenome-assembled genomes (MAGs) recovered from 1,153 urban metagenomes in multiple urban locations to investigate the fate and occurrence of ARGs in urban bacteria. Additionally, we analyzed the occurrence of these ARGs on plasmids and estimated the virulence of the bacterial species.
Our results showed that multidrug and glycopeptide ARGs are ubiquitous among urban bacteria. Additionally, we analyzed the deterministic effects of phylogeny on the spread of these ARGs and found ARG classes that have a non-random distribution within the phylogeny of our recovered MAGs. However, few ARGs were found on plasmids and most of the recovered MAGs contained few virulence factors.
Our results suggest that the observed non-random spreads of ARGs are not due to the transfer of plasmids and that most of the bacteria observed in the study are unlikely to be virulent. Additional research is needed to evaluate whether the ubiquitous and widespread ARG classes will become entirely prevalent among urban bacteria and how they spread among phylogenetically distinct species.
Introduction
To decrease antibiotic resistance, their use as growth promoters in the agricultural sector has been largely abandoned. This may lead to decreased health due to infectious disease or ...microbiome changes leading to gut inflammation.
Objectives
We aimed to generate a m/z signature classifying chicken health in blood, and obtain biological insights from the resulting m/z signature.
Methods
We used direct infusion mass-spectrometry to determine a machine-learned metabolomics signature that classifies chicken health from a blood sample. We then challenged the resulting models by investigating the classification capability of the signature on novel data obtained at poultry houses in previously unseen countries using a Leave-One-Country-Out (LOCO) cross-validation strategy. Additionally, we optimised the number of mass/charge (m/z) values required to maximise the classification capability of Random Forest models, by developing a novel ranking system based on combined univariate t-test and fold-change analyses and building models based on this ranking through forward and reverse feature selection.
Results
The multi-country and LOCO models could classify chicken health. Both resulting 25-m/z and 3784-m/z signatures reliably classified chicken health in multiple countries. Through
mummichog
enrichment analysis on the large m/z signature, we found changes in amino acid metabolism, including branched chain amino acids and polyamines.
Conclusion
We reliably classified chicken health from blood, independent of genetic-, farm-, feed- and country-specific confounding factors. The 25-m/z signature can be used to aid development of a per-metabolite panel. The extended 3784-m/z version can be used to gain a deeper understanding of the metabolic causes and consequences of low chicken health. Together, they may facilitate future treatment, prevention and intervention.
The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, ...interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor (Fxr) is involved in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr remain elusive. Herein, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning.
Fxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in the intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S sequencing), and mucus barrier function by ex vivo imaging were analysed.
Despite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in the colons of Fxr-livKO mice than in those of Fxr-intKO and Fxr-totKO mice (3272, 731, and 1824, respectively). The colons of Fxr-livKO showed increased expression of antimicrobial genes, Toll-like receptors, inflammasome-related genes and genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Fxr-livKO mice have a microbiome profile favourable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO mice.
Targeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases such as inflammatory bowel disease, and we show that this might be done by antagonising FXR in the liver.
This study shows that the communication of the liver to the intestine is crucial for intestinal health. Bile acids are key players in this liver-to-gut communication, and when Fxr, the master regulator of bile acid homoeostasis, is ablated in the liver, colonic gene expression is largely affected, and the protective capacity of the mucus barrier is increased.
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•Fxr ablation in the mouse liver has a major impact on colonic gene expression.•Fxr signalling is induced in the colons of liver Fxr knockout (Fxr-livKO) mice.•In Fxr-livKO colons, expression of antimicrobial and mucus genes is increased.•Microbiome of Fxr-livKO mice is indicative of enhanced mucus barrier function.•Fxr-livKO mice have an increased mucus barrier.
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