Metabolomics and Microbiota Metabolism

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Microbiology and Ecological Metabolomics".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 37501

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Guest Editor
Department of Medicinal Chemistry, Uppsala University, SE-75123 Uppsala, Sweden
Interests: metabolomics; microbiota; chemical biology; biomarker discovery; organic chemistry; phase II metabolism; medicinal chemistry; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolomics is the investigation of metabolites in any sample type and finds application in diverse areas including biomarker discovery, systems biology, and drug discovery. Within the past decade, it has become evident that microbiota produce a plethora of metabolites that can profoundly affect the human host by impacting physiology and disease development. These microbial communities inhabit the entire surface of the human body including the gastrointestinal tract and skin. The vastly expanded enzymatic repertoire and corresponding (bio)chemical capabilities of the microbiota compared to the human host increases the complexity of metabolomics studies. However, improved methods for the analysis of the host–microbiome co-metabolism are steadily emerging and developing.

This Special Issue highlights an analysis of microbiota metabolism using metabolomics techniques. Current challenges for targeted and untargeted microbiota metabolism studies include sample type selection, sample quality, data handling, as well as the integration of metabolomics and metagenomics data among others. We are seeking submissions describing advances in human microbiota metabolism analysis using metabolomics techniques applied to any sample type, dietary intervention studies, fecal sample investigations, computational analysis, new analytical developments, as well as targeted or untargeted approaches.

Prof. Dr. Daniel Globisch
Guest Editor

Manuscript Submission Information

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Keywords

  • Metabolomics
  • Microbiota
  • Co-Metabolism
  • Human Samples
  • Fecal samples
  • Diseases
  • Biomarker Discovery

Published Papers (9 papers)

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Research

20 pages, 2561 KiB  
Article
Antibiotic-Induced Changes in Microbiome-Related Metabolites and Bile Acids in Rat Plasma
by Véronique de Bruijn, Christina Behr, Saskia Sperber, Tilmann Walk, Philipp Ternes, Markus Slopianka, Volker Haake, Karsten Beekmann and Bennard van Ravenzwaay
Metabolites 2020, 10(6), 242; https://doi.org/10.3390/metabo10060242 - 11 Jun 2020
Cited by 8 | Viewed by 2836
Abstract
Various environmental factors can alter the gut microbiome’s composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were [...] Read more.
Various environmental factors can alter the gut microbiome’s composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were compared to distinguish between microbiome-derived or -associated and systemic changes in the plasma metabolome. The resulting changes in the plasma metabolome were compared to the effects of a third reference compound, roxithromycin, which is readily bioavailable. A community analysis revealed that the oral administration of vancomycin and roxithromycin in particular leads to an altered microbial population. Antibiotic-induced changes depending on the administration routes were observed in plasma metabolite levels. Indole-3-acetic acid (IAA) and hippuric acid (HA) were identified as key metabolites of microbiome modulation, with HA being the most sensitive. Even though large variations in the plasma bile acid pool between and within rats were observed, the change in microbiome community was observed to alter the composition of the bile acid pool, especially by an accumulation of taurine-conjugated primary bile acids. In-depth investigation of the relationship between microbiome variability and their functionality, with emphasis on the bile acid pool, will be necessary to better assess the potential adverseness of environmentally induced microbiome changes. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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12 pages, 954 KiB  
Article
Developmental Signatures of Microbiota-Derived Metabolites in the Mouse Brain
by Jonathan R. Swann, Sonia O. Spitzer and Rochellys Diaz Heijtz
Metabolites 2020, 10(5), 172; https://doi.org/10.3390/metabo10050172 - 25 Apr 2020
Cited by 33 | Viewed by 5377
Abstract
The gut microbiome is recognized to exert a wide-ranging influence on host health and disease, including brain development and behavior. Commensal bacteria can produce bioactive molecules that enter the circulation and impact host physiology and homeostasis. However, little is known about the potential [...] Read more.
The gut microbiome is recognized to exert a wide-ranging influence on host health and disease, including brain development and behavior. Commensal bacteria can produce bioactive molecules that enter the circulation and impact host physiology and homeostasis. However, little is known about the potential for these metabolites to cross the blood–brain barrier and enter the developing brain under normal physiological conditions. In this study, we used a liquid chromatography–mass spectrometry-based metabolomic approach to characterize the developmental profiles of microbial-derived metabolites in the forebrains of mice across three key postnatal developmental stages, co-occurring with the maturation of the gut microbiota. We demonstrate that direct metabolites of the gut microbiome (e.g., imidazole propionate) or products of the combinatorial metabolism between the microbiome and host (e.g., 3-indoxyl-sulfate, trimethylamine-N-oxide, and phenylacetylglycine) are present in the forebrains of mice as early as the neonatal period and remain into adulthood. These findings demonstrate that microbial-associated molecules can cross the BBB either in their detected form or as precursor molecules that undergo further processing in the brain. These chemical messengers are able to bind receptors known to be expressed in the brain. Alterations in the gut microbiome may therefore influence neurodevelopmental trajectories via the regulation of these microbial-associated metabolites. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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13 pages, 2681 KiB  
Article
Metabolic Effects of Bovine Milk Oligosaccharides on Selected Commensals of the Infant Microbiome—Commensalism and Postbiotic Effects
by Louise M. A. Jakobsen, Maria X. Maldonado-Gómez, Ulrik K. Sundekilde, Henrik J. Andersen, Dennis S. Nielsen and Hanne C. Bertram
Metabolites 2020, 10(4), 167; https://doi.org/10.3390/metabo10040167 - 24 Apr 2020
Cited by 10 | Viewed by 4535
Abstract
Oligosaccharides from human or bovine milk selectively stimulate growth or metabolism of bacteria associated with the lower gastrointestinal tract of infants. Results from complex infant-type co-cultures point toward a possible synergistic effect of combining bovine milk oligosaccharides (BMO) and lactose (LAC) on enhancing [...] Read more.
Oligosaccharides from human or bovine milk selectively stimulate growth or metabolism of bacteria associated with the lower gastrointestinal tract of infants. Results from complex infant-type co-cultures point toward a possible synergistic effect of combining bovine milk oligosaccharides (BMO) and lactose (LAC) on enhancing the metabolism of Bifidobacterium longum subsp. longum and inhibition of Clostridium perfringens. We examine the interaction between B. longum subsp. longum and the commensal Parabacteroides distasonis, by culturing them in mono- and co-culture with different carbohydrates available. To understand the interaction between BMO and lactose on B. longum subsp. longum and test the potential postbiotic effect on C. perfringens growth and/or metabolic activity, we inoculated C. perfringens into fresh media and compared the metabolic changes to C. perfringens in cell-free supernatant from B. longum subsp. longum fermented media. In co-culture, B. longum subsp. longum benefits from P. distasonis (commensalism), especially in a lactose-rich environment. Furthermore, B. longum subsp. longum fermentation of BMO + LAC impaired C. perfringens’ ability to utilize BMO as a carbon source (potential postbiotic effect). Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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11 pages, 1180 KiB  
Article
Towards Predicting Gut Microbial Metabolism: Integration of Flux Balance Analysis and Untargeted Metabolomics
by Ellen Kuang, Matthew Marney, Daniel Cuevas, Robert A. Edwards and Erica M. Forsberg
Metabolites 2020, 10(4), 156; https://doi.org/10.3390/metabo10040156 - 17 Apr 2020
Cited by 10 | Viewed by 4039
Abstract
Genomics-based metabolic models of microorganisms currently have no easy way of corroborating predicted biomass with the actual metabolites being produced. This study uses untargeted mass spectrometry-based metabolomics data to generate a list of accurate metabolite masses produced from the human commensal bacteria Citrobacter [...] Read more.
Genomics-based metabolic models of microorganisms currently have no easy way of corroborating predicted biomass with the actual metabolites being produced. This study uses untargeted mass spectrometry-based metabolomics data to generate a list of accurate metabolite masses produced from the human commensal bacteria Citrobacter sedlakii grown in the presence of a simple glucose carbon source. A genomics-based flux balance metabolic model of this bacterium was previously generated using the bioinformatics tool PyFBA and phenotypic growth curve data. The high-resolution mass spectrometry data obtained through timed metabolic extractions were integrated with the predicted metabolic model through a program called MS_FBA. This program correlated untargeted metabolomics features from C. sedlakii with 218 of the 699 metabolites in the model using an exact mass match, with 51 metabolites further confirmed using predicted isotope ratios. Over 1400 metabolites were matched with additional metabolites in the ModelSEED database, indicating the need to incorporate more specific gene annotations into the predictive model through metabolomics-guided gap filling. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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17 pages, 2168 KiB  
Article
Microbiome-Metabolome Signature of Acute Kidney Injury
by Nadezda V. Andrianova, Vasily A. Popkov, Natalia S. Klimenko, Alexander V. Tyakht, Galina V. Baydakova, Olga Y. Frolova, Ljubava D. Zorova, Irina B. Pevzner, Dmitry B. Zorov and Egor Y. Plotnikov
Metabolites 2020, 10(4), 142; https://doi.org/10.3390/metabo10040142 - 4 Apr 2020
Cited by 33 | Viewed by 4918
Abstract
Intestinal microbiota play a considerable role in the host’s organism, broadly affecting its organs and tissues. The kidney can also be the target of the microbiome and its metabolites (especially short-chain fatty acids), which can influence renal tissue, both by direct action and [...] Read more.
Intestinal microbiota play a considerable role in the host’s organism, broadly affecting its organs and tissues. The kidney can also be the target of the microbiome and its metabolites (especially short-chain fatty acids), which can influence renal tissue, both by direct action and through modulation of the immune response. This impact is crucial, especially during kidney injury, because the modulation of inflammation or reparative processes could affect the severity of the resulting damage or recovery of kidney function. In this study, we compared the composition of rat gut microbiota with its outcome, in experimental acute ischemic kidney injury and named the bacterial taxa that play putatively negative or positive roles in the progression of ischemic kidney injury. We investigated the link between serum creatinine, urea, and a number of metabolites (acylcarnitines and amino acids), and the relative abundance of various bacterial taxa in rat feces. Our analysis revealed an increase in levels of 32 acylcarnitines in serum, after renal ischemia/reperfusion and correlation with creatinine and urea, while levels of three amino acids (tyrosine, tryptophan, and proline) had decreased. We detected associations between bacterial abundance and metabolite levels, using a compositionality-aware approach—Rothia and Staphylococcus levels were positively associated with creatinine and urea levels, respectively. Our findings indicate that the gut microbial community contains specific members whose presence might ameliorate or, on the contrary, aggravate ischemic kidney injury. These bacterial taxa could present perspective targets for therapeutical interventions in kidney pathologies, including acute kidney injury. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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12 pages, 2208 KiB  
Article
Bile Acid Profile and its Changes in Response to Cefoperazone Treatment in MR1 Deficient Mice
by Jinchun Sun, Zhijun Cao, Ashley D. Smith, Paul E. Carlson Jr, Michael Coryell, Huizhong Chen and Richard D. Beger
Metabolites 2020, 10(4), 127; https://doi.org/10.3390/metabo10040127 - 26 Mar 2020
Cited by 7 | Viewed by 3291
Abstract
Mucosal associated invariant T-cells (MAIT cells) are activated following recognition of bacterial antigens (riboflavin intermediates) presented on major histocompatibility complex class I-related molecule (MR1). Our previous study showed that MR1−/− knock-out (KO) mice (lacking MAIT cells) harbor a unique microbiota that is [...] Read more.
Mucosal associated invariant T-cells (MAIT cells) are activated following recognition of bacterial antigens (riboflavin intermediates) presented on major histocompatibility complex class I-related molecule (MR1). Our previous study showed that MR1−/− knock-out (KO) mice (lacking MAIT cells) harbor a unique microbiota that is resistant to antibiotic disruption and Clostridioides difficile colonization. While we have characterized the microbiota of this mouse strain, changes in global metabolic activity in these KO mice have not been assessed. Here, LC/MS-based untargeted metabolomics was applied to investigate the differences in the metabolome, specifically in the bile acid (BA) profile of wild-type (WT) and MR1−/− KO mice, as well as how antibiotics change these profiles. BA changes were evaluated in the intestinal content, cecum content, and stool samples from MR1−/− mice and WT mice treated with cefoperazone (Cef). Fecal pellets were collected daily and both intestinal and cecal contents were harvested at predetermined endpoints on day 0 (D0), day 1 (D1), day 3 (D3), and day 5 (D5). KO mice exhibited no changes in 6-hydroxymethyl-8-D-ribityllumazine (rRL-6-CH2OH; an MR1-restricted riboflavin derivative) in the stool samples at either time point vs. D0, while WT mice showed significant decreases in rRL-6-CH2OH in the stool samples on all treatment days vs. D0. Metabolomics analysis from cecal and stool samples showed that KO mice had more total BA intensity (KO/WT = ~1.7 and ~3.3 fold higher) than that from WT mice prior to Cef treatment, while the fold change difference (KO/WT = ~4.5 and ~4.4 fold) increased after five days of Cef treatment. Both KO and WT mice showed decreases in total BA intensity in response to Cef treatment, however, less dramatic decreases were present in KO vs. WT mice. Increases in taurocholic acid (TCA) intensity and decreases in deoxycholic acid (DCA) intensity in the stool samples from WT mice were associated with the depletion of certain gut bacteria, which was consistent with the previously reported microbiome data. Furthermore, the non-detected TCA and relatively higher DCA intensity in the KO mice might be related to Clostridioides difficile infection resistance, although this needs further investigation. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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24 pages, 2544 KiB  
Article
Nematode-Trapping Fungi Produce Diverse Metabolites during Predator–Prey Interaction
by Ting-Hao Kuo, Ching-Ting Yang, Hsin-Yuan Chang, Yen-Ping Hsueh and Cheng-Chih Hsu
Metabolites 2020, 10(3), 117; https://doi.org/10.3390/metabo10030117 - 20 Mar 2020
Cited by 27 | Viewed by 4906
Abstract
Nematode-trapping fungi are natural antagonists of nematodes. These predatory fungi are capable of switching their lifestyle from a saprophytic to predatory stage in the presence of nematodes by developing specialized trapping devices to capture and consume nematodes. The biochemical mechanisms of such predator–prey [...] Read more.
Nematode-trapping fungi are natural antagonists of nematodes. These predatory fungi are capable of switching their lifestyle from a saprophytic to predatory stage in the presence of nematodes by developing specialized trapping devices to capture and consume nematodes. The biochemical mechanisms of such predator–prey interaction have become increasingly studied given the potential application of nematode-trapping fungi as biocontrol agents, but the involved fungal metabolites remain underexplored. Here, we report a comprehensive liquid–chromatography mass spectrometry (LC–MS) metabolomics study on one hundred wild isolates of nematode-trapping fungi in three different species, Arthrobotrys oligospora, Arthrobotrys thaumasia, and Arthrobotrys musiformis. Molecular networking analysis revealed that the fungi were capable of producing thousands of metabolites, and such chemical diversity of metabolites was notably increased as the fungi switched lifestyle to the predatory stage. Structural annotations by tandem mass spectrometry revealed that those fungal metabolites belonged to various structural families, such as peptide, siderophore, fatty alcohol, and fatty acid amide, and their production exhibited species specificity. Several small peptides (<1.5 kDa) produced by A. musiformis in the predatory stage were found, with their partial amino acid sequences resolved by the tandem mass spectra. Four fungal metabolites (desferriferrichrome, linoleyl alcohol, nonadecanamide, and citicoline) that were significantly enriched in the predatory stage were identified and validated by chemical standards, and their bioactivities against nematode prey were assessed. The availability of the metabolomics datasets will facilitate comparative studies on the metabolites of nematode-trapping fungi in the future. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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14 pages, 508 KiB  
Article
The Antimethanogenic Nitrocompounds Can be Cleaved into Nitrite by Rumen Microorganisms: A Comparison of Nitroethane, 2-Nitroethanol, and 2-Nitro-1-propanol
by Zhen-Wei Zhang, Yan-Lu Wang, Wei-Kang Wang, Yong-Yang Chen, Xue-Meng Si, Ya-Jing Wang, Wei Wang, Zhi-Jun Cao, Sheng-Li Li and Hong-Jian Yang
Metabolites 2020, 10(1), 15; https://doi.org/10.3390/metabo10010015 - 25 Dec 2019
Cited by 5 | Viewed by 2644
Abstract
A class of aliphatic short chain nitrocompounds have been reported as being capable of CH4 reduction both in vitro and in vivo. However, the laboratory evidence associated with the metabolic fate of nitrocompounds in the rumen has not been well documented. The [...] Read more.
A class of aliphatic short chain nitrocompounds have been reported as being capable of CH4 reduction both in vitro and in vivo. However, the laboratory evidence associated with the metabolic fate of nitrocompounds in the rumen has not been well documented. The present study was conducted to compare in vitro degradation and metabolism of nitroethane (NE), 2-nitroethanol (NEOH), and 2-nitro-1-propanol (NPOH) incubated with mixed rumen microorganisms of dairy cows. After 10 mM supplementation of nitrocompounds, a serious of batch cultures were carried out for 120 h under the presence of two substrates differing in the ratio of maize meal to alfalfa hay (HF, 1:4; LF, 4:1). Compared to the control, methane production was reduced by 59% in NPOH and by >97% in both NE and NEOH, and such antimethanogenic effects were more pronounced in the LF than the HF group. Although NE, NEOH, and NPOH addition did not alter total VFA production, the rumen fermentation pattern shifted toward increasing propionate and butyrate and decreasing acetate production. The kinetic disappearance of each nitrocompound was well fitted to the one-compartment model, and the disappearance rate (k, %/h) of NE was 2.6 to 5.2 times greater than those of NEOH and NPOH. Higher intermediates of nitrite occurred in NEOH in comparison with NPOH and NE while ammonia N production was lowest in NEOH. Consequently, a stepwise accumulation of bacterial crude protein (BCP) in response to the nitrocompound addition was observed in both the HF and LF group. In brief, both NE and NEOH in comparison with NPOH presented greater antimethanogenic activity via the shift of rumen fermentation. In addition, the present study provided the first direct evidence that rumen microbes were able to cleave these nitrocompounds into nitrite, and the subsequent metabolism of nitrite into ammonia N may enhance the growth of rumen microbes or promote microbial activities. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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16 pages, 3018 KiB  
Article
Korean Traditional Medicine (Jakyakgamcho-tang) Ameliorates Colitis by Regulating Gut Microbiota
by Seung-Ho Seo, Tatsuya Unno, Seong-Eun Park, Eun-Ju Kim, Yu-Mi Lee, Chang-Su Na and Hong-Seok Son
Metabolites 2019, 9(10), 226; https://doi.org/10.3390/metabo9100226 - 14 Oct 2019
Cited by 12 | Viewed by 3990
Abstract
The objective of this study was to examine the anti-colitis activity of Jakyakgamcho-tang (JGT) in dextran sulfate sodium (DSS)-induced colitis and explore changes of the gut microbial community using 16S rRNA amplicon sequencing and metabolomics approaches. It was found that treatment with JGT [...] Read more.
The objective of this study was to examine the anti-colitis activity of Jakyakgamcho-tang (JGT) in dextran sulfate sodium (DSS)-induced colitis and explore changes of the gut microbial community using 16S rRNA amplicon sequencing and metabolomics approaches. It was found that treatment with JGT or 5-aminosalicylic acid (5-ASA) alleviated the severity of colitis symptoms by suppressing inflammatory cytokine levels of IL-6, IL-12, and IFN-γ. The non-metric multidimensional scaling analysis of gut microbiome revealed that JGT groups were clearly separated from the DSS group, suggesting that JGT administration altered gut microbiota. The operational taxonomic units (OTUs) that were decreased by DSS but increased by JGT include Akkermansia and Allobaculum. On the other hand, OTUs that were increased by DSS but decreased by 5-ASA or JGT treatments include Bacteroidales S24-7, Ruminococcaceae, and Rikenellaceae, and the genera Bacteroides, Parabacteroides, Oscillospira, and Coprobacillus. After JGT administration, the metabolites, including most amino acids and lactic acid that were altered by colitis induction, became similar to those of the control group. This study demonstrates that JGT might have potential to effectively treat colitis by restoring dysbiosis of gut microbiota and host metabolites. Full article
(This article belongs to the Special Issue Metabolomics and Microbiota Metabolism)
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