scholarly journals Gut Microbiome and Drug Metabolism

2021 ◽  
Vol 4 (1) ◽  
pp. e00146
Author(s):  
E.N. Ilina ◽  
E.M. Mayorova ◽  
A.I. Manolov ◽  
A.A. Korenkova ◽  
V.V. Bahmetjev ◽  
...  
Keyword(s):  
Microbial Community ◽  
Drug Metabolism ◽  
Gut Microbiota ◽  
Computational Models ◽  
Metabolic Reaction ◽  
Metabolic Potential ◽  
Adequate Model ◽  
Microbial Enzymes ◽  
Metabolic Reactions

The human physiology textbooks traditionally consider the intestine as a metabolically active organ, with its activity primarily associated with the production of numerous digestive enzymes. The development of molecular analysis technologies has significantly detailized this picture, primarily by decoding the metabolic potential of the intestinal microbiota. Data from numerous metagenomic studies indicate that the number of eukaryotic and bacterial cells in the human body is comparable - about 3.0×1013, while the number of genes in the intestinal metagenome is one hundred times greater than in the human genome. Obviously, the gut microbiota exhibits both direct and indirect effects on the metabolism of drugs and xenobiotics, that can affect their effectiveness and toxicity. Orally administrated xenobiotics have been found to be metabolized by intestinal microbial enzymes before being absorbed from the gastrointestinal tract into the blood flow. The metabolic reactions performed by the gut microbiota greatly differ from the metabolic reactions of the liver, providing modification of drugs by acetylation, deacetylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, etc. Despite the metabolism of xenobiotics by microbial enzymes of the intestine is rather known, information about the specific microflora mediating each metabolic reaction is still limited, mainly by the lack of an adequate model of the intestinal microbial community to allow the accumulation of experimental data for the creation of computational models. Currently, studies of drug metabolism use microfluidic chips, reproducing functions of various organs and tissues, such as the liver, kidney, lungs and intestine, as in vitro models in the form of 2D and 3D cell cultures. Supplementation of such systems with the microbial community will allow to get as close as possible to in vitro modeling of complicated biological processes in the interests of pharmacological research and the accumulation of data for constructing computational models.

I-screen: In vitro platform to study human gut microbiota induced drug metabolism and molecular transformations

2018 ◽  
Vol 33 (1) ◽  
pp. S81-S82
Author(s):  
Steven Erpelinck ◽  
Frank H.J. Schuren ◽  
Irene H.G. Nooijen ◽  
R. Scott Obach ◽  
Gregory S. Walker ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Gut Microbiota ◽  
Human Gut ◽  
Human Gut Microbiota

In silico approaches to predicting drug metabolism, toxicology and beyond

2003 ◽  
Vol 31 (3) ◽  
pp. 611-614 ◽  
Author(s):  
S. Ekins
Keyword(s):  
Drug Metabolism ◽  
Computational Models ◽  
Model Building ◽  
Quantitative Structure Activity Relationship ◽  
Metabolic Stability ◽  
Published Data ◽  
Spearman's Rho ◽  
Spearman’S Rho ◽  
Combining Data

The discovery and optimization of new drug candidates is becoming increasingly reliant upon the combination of experimental and computational approaches related to drug metabolism, toxicology and general biopharmaceutical properties. With the considerable output of high-throughput assays for cytochrome-P450-mediated drug–drug interactions, metabolic stability and assays for toxicology, we have orders of magnitude more data that will facilitate model building. A recursive partitioning model for human liver microsomal metabolic stability based on over 800 structurally diverse molecules was used to predict molecules with known log in vitro clearance data (Spearman's rho −0.64, P<0.0001). In addition, with solely published data, a quantitative structure–activity relationship for 66 inhibitors of the potassium channel human ether-a-gogo (hERG) that has been implicated in the failure of a number of recent drugs has been generated. This model has been validated with further published data for 25 molecules (Spearman's rho 0.83, P<0.0001). If continued value is to be realized from these types of computational models, there needs to be some applied research on their validation and optimization with new data. Some relatively simple approaches may have value when it comes to combining data from multiple models in order to improve and focus drug discovery on the molecules most likely to succeed.

scholarly journals Effects of Antibiotic Pretreatment of an Ulcerative Colitis-Derived Fecal Microbial Community on the Integration of Therapeutic Bacteria In Vitro

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Kaitlyn Oliphant ◽  
Kyla Cochrane ◽  
Kathleen Schroeter ◽  
Michelle C. Daigneault ◽  
Sandi Yen ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Microbial Community ◽  
Side Effects ◽  
Antimicrobial Resistance ◽  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Clinical Success ◽  
Distinct Species ◽  
Fecal Microbiota

ABSTRACT Fecal microbiota transplantation (FMT) is a proposedly useful strategy for the treatment of gastrointestinal (GI) disorders through remediation of the patient gut microbiota. However, its therapeutic success has been variable, necessitating research to uncover mechanisms that improve patient response. Antibiotic pretreatment has been proposed as one method to enhance the success rate by increasing niche availability for introduced species. Several limitations hinder exploring this hypothesis in clinical studies, such as deleterious side effects and the development of antimicrobial resistance in patients. Thus, the purpose of this study was to evaluate the use of an in vitro, bioreactor-based, colonic ecosystem model as a form of preclinical testing by determining how pretreatment with the antibiotic rifaximin influenced engraftment of bacterial strains sourced from a healthy donor into an ulcerative colitis-derived defined microbial community. Distinct species integrated under the pretreated and untreated conditions, with the relative rifaximin resistance of the microbial strains being an important influencer. However, both conditions resulted in the integration of taxa from Clostridium clusters IV and XIVa, a concomitant reduction of Proteobacteria, and similar decreases in metabolites associated with poor health status. Our results agree with the findings of similar research in the clinic by others, which observed no difference in primary patient outcomes whether or not patients were given rifaximin prior to FMT. We therefore conclude that our model is useful for screening for antibiotics that could improve efficacy of FMT when used as a pretreatment. IMPORTANCE Patients with gastrointestinal disorders often exhibit derangements in their gut microbiota, which can exacerbate their symptoms. Replenishing these ecosystems with beneficial bacteria through fecal microbiota transplantation is thus a proposedly useful therapeutic; however, clinical success has varied, necessitating research into strategies to improve outcomes. Antibiotic pretreatment has been suggested as one such approach, but concerns over harmful side effects have hindered testing this hypothesis clinically. Here, we evaluate the use of bioreactors supporting defined microbial communities derived from human fecal samples as models of the colonic microbiota in determining the effectiveness of antibiotic pretreatment. We found that relative antimicrobial resistance was a key determinant of successful microbial engraftment with rifaximin (broad-spectrum antibiotic) pretreatment, despite careful timing of the application of the therapeutic agents, resulting in distinct species profiles from those of the control but with similar overall outcomes. Our model had results comparable to the clinical findings and thus can be used to screen for useful antibiotics.

scholarly journals Effect of Freezing on Gut Microbiota Composition and Functionality for In Vitro Fermentation Experiments

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2207
Author(s):  
Sergio Pérez-Burillo ◽  
Daniel Hinojosa-Nogueira ◽  
Beatriz Navajas-Porras ◽  
Telmo Blasco ◽  
Francesco Balzerani ◽  
...  
Keyword(s):  
Microbial Community ◽  
Gut Microbiota ◽  
Metabolic Reconstruction ◽  
Rrna Gene ◽  
Metagenomic Sequencing ◽  
Fecal Material ◽  
In Vitro Fermentation ◽  
A Genome ◽  
Sequencing Studies

The gut microbiota has a profound effect on human health and is modulated by food and bioactive compounds. To study such interaction, in vitro batch fermentations are performed with fecal material, and some experimental designs may require that such fermentations be performed with previously frozen stools. Although it is known that freezing fecal material does not alter the composition of the microbial community in 16S rRNA gene amplicon and metagenomic sequencing studies, it is not known whether the microbial community in frozen samples could still be used for in vitro fermentations. To explore this, we undertook a pilot study in which in vitro fermentations were performed with fecal material from celiac, cow’s milk allergic, obese, or lean children that was frozen (or not) with 20% glycerol. Before fermentation, the fecal material was incubated in a nutritious medium for 6 days, with the aim of giving the microbial community time to recover from the effects of freezing. An aliquot was taken daily from the stabilization vessel and used for the in vitro batch fermentation of lentils. The microbial community structure was significantly different between fresh and frozen samples, but the variation introduced by freezing a sample was always smaller than the variation among individuals, both before and after fermentation. Moreover, the potential functionality (as determined in silico by a genome-scaled metabolic reconstruction) did not differ significantly, possibly due to functional redundancy. The most affected genus was Bacteroides, a fiber degrader. In conclusion, if frozen fecal material is to be used for in vitro fermentation purposes, our preliminary analyses indicate that the functionality of microbial communities can be preserved after stabilization.

scholarly journals A network-based data-mining approach to investigate indole-related microbiota-host co-metabolism

2019 ◽  
Author(s):  
Ana Luisa Neves ◽  
Andrea Rodriguez-Martinez ◽  
Rafael Ayala ◽  
Joram M Posma ◽  
MR Abellona U ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Bacterial Species ◽  
Human Gut ◽  
New Members ◽  
Human Gut Microbiota ◽  
Genome Data ◽  
Data Mining Approach ◽  
Cardiometabolic Disorders ◽  
Metabolic Reactions

AbstractMotivationIndoles have been shown to play a significant role in cardiometabolic disorders. While some individual bacterial species are known to produce indole-adducts, to our best knowledge no studies have made use of publicly available genome data to identify prokaryotes, specifically those associated with the human gut microbiota, contributing to the indole metabolic network.ResultsHere, we propose a computational strategy, comprising the integration of KEGG and BLAST, to identify prokaryote-specific metabolic reactions relevant for the production of indoles, as well as to predict new members of the human gut microbiota potentially involved in these reactions. By identifying relevant prokaryotic species for further validation studiesin vitro, this strategy represents a useful approach for those interrogating the metabolism of other gut-derived microbial metabolites relevant to human health.AvailabilityAll R scripts and files (gut microbial dataset, FASTA protein sequences, BLASTP output files) are available fromhttps://github.com/AndreaRMICL/Microbial_networks.ContactARM:[email protected]; LH:[email protected].

scholarly journals The metabolic footprint of Clostridia and Erysipelotrichia reveals their role in depleting sugar alcohols in the cecum

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Connor R. Tiffany ◽  
Jee-Yon Lee ◽  
Andrew W. L. Rogers ◽  
Erin E. Olsan ◽  
Pavel Morales ◽  
...  
Keyword(s):  
Microbial Community ◽  
Gut Microbiota ◽  
Marked Decrease ◽  
Intestinal Lumen ◽  
Artificial Sweetener ◽  
Targeted Metabolomics ◽  
Sugar Alcohols ◽  
Germ Free ◽  
Gnotobiotic Mice

Abstract Background The catabolic activity of the microbiota contributes to health by aiding in nutrition, immune education, and niche protection against pathogens. However, the nutrients consumed by common taxa within the gut microbiota remain incompletely understood. Methods Here we combined microbiota profiling with an un-targeted metabolomics approach to determine whether depletion of small metabolites in the cecum of mice correlated with the presence of specific bacterial taxa. Causality was investigated by engrafting germ-free or antibiotic-treated mice with complex or defined microbial communities. Results We noted that a depletion of Clostridia and Erysipelotrichia from the gut microbiota triggered by antibiotic treatment was associated with an increase in the cecal concentration of sugar acids and sugar alcohols (polyols). Notably, when we inoculated germ-free mice with a defined microbial community of 14 Clostridia and 3 Erysipelotrichia isolates, we observed the inverse, with a marked decrease in the concentrations of sugar acids and polyols in cecal contents. The carbohydrate footprint produced by the defined microbial community was similar to that observed in gnotobiotic mice receiving a cecal microbiota transplant from conventional mice. Supplementation with sorbitol, a polyol used as artificial sweetener, increased cecal sorbitol concentrations in antibiotic-treated mice, which was abrogated after inoculation with a Clostridia isolate able to grow on sorbitol in vitro. Conclusions We conclude that consumption of sugar alcohols by Clostridia and Erysipelotrichia species depletes these metabolites from the intestinal lumen during homeostasis.

scholarly journals Assessment of Biolog EcoplateTM method for functional metabolic diversity of aerotolerant pig fecal microbiota

2021 ◽  
Author(s):  
A. Checcucci ◽  
D. Luise ◽  
M. Modesto ◽  
F. Correa ◽  
P. Bosi ◽  
...  
Keyword(s):  
Microbial Community ◽  
Gut Microbiota ◽  
Metabolic Activity ◽  
Fecal Sample ◽  
Storage Conditions ◽  
Fecal Microbiota ◽  
Host Animal ◽  
Metabolic Potential ◽  
Fecal Samples ◽  
Feces Sample

Abstract In the last decades, gut microbiota and its role in mammal host development and health have been increasingly investigated. Metabolites produced by gut microbiota can affect intestinal homeostasis and immune system maturity and activation, and in turn, they can influence the health and growth performance of livestock. Therefore, a better understanding of the functional metabolic capability of the gut microbiota would be appreciated by the scientific community. In this study, the BiologTM Ecoplates technology was applied for studying the metabolic potential of the aerotolerant microbial community of pig fecal samples, evaluating the interference of different storage conditions and cell concentrations. The length of time for which a fecal sample maintained detectable and unchanged microbial metabolic activity was also investigated. Two assays aimed to evaluate differences in the metabolic activities between fresh and snap-frozen fecal samples at different dilutions and at different lengths of times of preservation at −80°C were carried out. The biodiversity and the predicted functionality of the entire bacterial community through a targeted metagenomic approach were also explored. The results highlighted that snap freezing of fecal samples preserved the metabolic activity of the microbial community when compared to fresh feces. Sample storage at −80 °C did not significantly affect the metabolic activity of the microbial community, which was stable for 150 days. Furthermore, the highest metabolic activity was detected with 1:2 to 1:5 dilutions of the stock suspension. BiologTM Ecoplates technology is a rapid and useful method to explore microbial communities’ metabolism in animal fecal samples contributing to investigate host animal physiology. Key points • Freezing of samples can preserve the functional activity of the aerotolerant microbial community for 150 days. • The concentration of microbial cells strongly influences metabolic activity detection. • Sequencing coupled with the BiologTMEcoplates could be a strategy to evaluate the metabolic potential of the microbiota of the fecal sample. Graphical abstract

scholarly journals Sharing a β-Glucan Meal: Transcriptomic Eavesdropping on a Bacteroides ovatus-Subdoligranulum variabile-Hungatella hathewayi Consortium

2020 ◽  
Vol 86 (20) ◽  
Author(s):  
Manuela Centanni ◽  
Ian M. Sims ◽  
Tracey J. Bell ◽  
Ambarish Biswas ◽  
Gerald W. Tannock
Keyword(s):  
Microbial Community ◽  
Gut Microbiota ◽  
Dietary Fiber ◽  
Bacterial Species ◽  
Human Gut ◽  
Additional Energy ◽  
Content Type ◽  
Human Gut Microbiota ◽  
Bacteroides Ovatus

ABSTRACT Whole-transcriptome analysis was used to investigate the molecular interplay between three bacterial species that are members of the human gut microbiota. Bacteroides ovatus, Subdoligranulum variabile, and Hungatella hathewayi formed associations in cocultures fed barley β-glucan, a constituent of dietary fiber. B. ovatus depolymerized β-glucan and released, but did not utilize, 3-O-β-cellobiosyl-d-glucose (DP3) and 3-O-β-cellotriosyl-d-glucose (DP4). These oligosaccharides provided growth substrates for S. variabile and H. hathewayi with a preference for DP4 in the case of the latter species. There was increased transcription of a B. ovatus mixed-linkage-β-glucan utilization locus, as well as carbohydrate transporters in S. variabile and H. hathewayi when in batch coculture. Increased transcription of the β-glucan utilization locus did not occur in continuous culture. Evidence for interactions relating to provision of cobalamin, alterations to signaling, and modulation of the “stringent response” (an adaptation to nutrient deprivation) were detected. Overall, we established a bacterial consortium based on barley β-glucan in vitro, which can be used to investigate aspects of the functional blueprint of the human gut microbiota. IMPORTANCE The microbial community, mostly composed of bacterial species, residing in the human gut degrades and ferments polysaccharides derived from plants (dietary fiber) that would not otherwise be digested. In this way, the collective metabolic actions of community members extract additional energy from the human diet. While the variety of bacteria present in the microbial community is well known, the formation of bacterial consortia, and the consequent interactions that result in the digestion of dietary polysaccharides, has not been studied extensively. The importance of our work was the establishment, under laboratory conditions, of a consortium of gut bacteria that formed around a dietary constituent commonly present in cereals. This enabled the metabolic interplay between the bacterial species to be studied. This kind of knowledge is required to construct an interactive, metabolic blueprint of the microbial community that inhabits the human gut.

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