Publications by authors named "Federico E Rey"

59 Publications

A secondary metabolite drives intraspecies antagonism in a gut symbiont that is inhibited by cell-wall acetylation.

Cell Host Microbe 2022 Apr 13. Epub 2022 Apr 13.

Department of Food Science, University of Wisconsin-Madison, Madison, WI 53706, USA; Food Research Institute, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address:

The mammalian microbiome encodes numerous secondary metabolite biosynthetic gene clusters; yet, their role in microbe-microbe interactions is unclear. Here, we characterized two polyketide synthase gene clusters (fun and pks) in the gut symbiont Limosilactobacillus reuteri. The pks, but not the fun, cluster encodes antimicrobial activity. Forty-one of 51 L. reuteri strains tested are sensitive to Pks products; this finding was independent of strains' host origin. Sensitivity to Pks was also established in intraspecies competition experiments in gnotobiotic mice. Comparative genome analyses between Pks-resistant and -sensitive strains identified an acyltransferase gene (act) unique to Pks-resistant strains. Subsequent cell-wall analysis of wild-type and act mutant strains showed that Act acetylates cell-wall components, providing resistance to Pks-mediated killing. Additionally, pks mutants lost their competitive advantage, while act mutants lost their Pks resistance in in vivo competition assays. These findings provide insight into how closely related gut symbionts can compete and co-exist in the gastrointestinal tract.
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http://dx.doi.org/10.1016/j.chom.2022.03.033DOI Listing
April 2022

The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass.

Gut Microbes 2022 Jan-Dec;14(1):2050635

Nutrition and obesities; systemic approaches (NutriOmics), Sorbonne Université, INSERM, Paris France.

Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising , and . A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals' metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.
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http://dx.doi.org/10.1080/19490976.2022.2050635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037437PMC
April 2022

Vocal fold mucus layer: Comparison of histological protocols for visualization in mice.

Laryngoscope Investig Otolaryngol 2022 Apr 25;7(2):444-453. Epub 2022 Jan 25.

Department of Surgery, School of Medicine and Public Health University of Wisconsin-Madison Madison Wisconsin USA.

Objectives: The epithelial associated mucus layer of vocal fold (VF) mucosa, plays an essential role in protecting and lubricating the tissue, as well as promoting normal voice quality. Serving as a habitat for laryngeal microbiota involved in the regulation of host immunity, VF mucus contributes to laryngeal health and disease. However, its unstable structure renders its' investigation challenging. We aim to establish a reproducible histological protocol to recover the natural appearance of the VF mucus layer for investigation.

Methods: Using a murine model, we compared the suitability of multiple fixation methods-methacarn, formalin, and cryopreservation followed by post-fixation with formalin, paraformaldehyde (PFA), acetone, and two staining methods-Alcian Blue (pH 2.5)/Periodic Acid Schiff (AB/PAS) or PAS. Fixation and staining outcomes were evaluated based on the preservation of tissue morphology and mucus layer integrity. Mucin proteins, Muc1 and Muc4, were stained to validate the presence of mucus layer overlaying the VF mucosa.

Results: Methacarn fixation followed by PAS staining was capable of preserving and displaying the smooth and continuous mucus layer, ensuring the determination of mucus thickness and mucin staining.

Conclusions: Our study if the first to establish a histological protocol for the visualization of the in situ VF mucus layer whereby facilitating the study of VF mucus biology including VF surface hydration, ion/nutrients transports, biomechanical properties that maintains normal voice quality as well as VF pathophysiology and host-microbe interactions in the larynx.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1002/lio2.743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008169PMC
April 2022

Polysaccharide utilization loci in Bacteroides determine population fitness and community-level interactions.

Cell Host Microbe 2022 02 6;30(2):200-215.e12. Epub 2022 Jan 6.

Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Chemical & Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address:

Polysaccharide utilization loci (PULs) are co-regulated bacterial genes that sense nutrients and enable glycan digestion. Human gut microbiome members, notably Bacteroides, contain numerous PULs that enable glycan utilization and shape ecological dynamics. To investigate the role of PULs on fitness and inter-species interactions, we develop a CRISPR-based genome editing tool to study 23 PULs in Bacteroides uniformis (BU). BU PULs show distinct glycan-degrading functions and transcriptional coordination that enables the population to adapt upon loss of other PULs. Exploiting a BU mutant barcoding strategy, we demonstrate that in vitro fitness and BU colonization in the murine gut are enhanced by deletion of specific PULs and modulated by glycan availability. PULs mediate glycan-dependent interactions with butyrate producers that depend on the degradation mechanism and glycan utilization ability of the butyrate producer. Thus, PULs determine community dynamics and butyrate production and provide a selective advantage or disadvantage depending on the nutritional landscape.
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http://dx.doi.org/10.1016/j.chom.2021.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9060796PMC
February 2022

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism.

Nat Microbiol 2022 01 23;7(1):73-86. Epub 2021 Dec 23.

Department of Chemistry, Cleveland State University, Cleveland, OH, USA.

The heightened cardiovascular disease (CVD) risk observed among omnivores is thought to be linked, in part, to gut microbiota-dependent generation of trimethylamine-N-oxide (TMAO) from L-carnitine, a nutrient abundant in red meat. Gut microbial transformation of L-carnitine into trimethylamine (TMA), the precursor of TMAO, occurs via the intermediate γ-butyrobetaine (γBB). However, the interrelationship of γBB, red meat ingestion and CVD risks, as well as the gut microbial genes responsible for the transformation of γBB to TMA, are unclear. In the present study, we show that plasma γBB levels in individuals from a clinical cohort (n = 2,918) are strongly associated with incident CVD event risks. Culture of human faecal samples and microbial transplantation studies in gnotobiotic mice with defined synthetic communities showed that the introduction of Emergencia timonensis, a human gut microbe that can metabolize γBB into TMA, is sufficient to complete the carnitine → γBB → TMA transformation, elevate TMAO levels and enhance thrombosis potential in recipients after arterial injury. RNA-sequencing analyses of E. timonensis identified a six-gene cluster, herein named the γBB utilization (gbu) gene cluster, which is upregulated in response to γBB. Combinatorial cloning and functional studies identified four genes (gbuA, gbuB, gbuC and gbuE) that are necessary and sufficient to recapitulate the conversion of γBB to TMA when coexpressed in Escherichia coli. Finally, reanalysis of samples (n = 113) from a clinical, randomized diet, intervention study showed that the abundance of faecal gbuA correlates with plasma TMAO and a red meat-rich diet. Our findings reveal a microbial gene cluster that is critical to dietary carnitine → γBB → TMA → TMAO transformation in hosts and contributes to CVD risk.
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http://dx.doi.org/10.1038/s41564-021-01010-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8732312PMC
January 2022

Identification of sample mix-ups and mixtures in microbiome data in Diversity Outbred mice.

G3 (Bethesda) 2021 10;11(11)

Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53706, USA.

In a Diversity Outbred mouse project with genotype data on 500 mice, including 297 with microbiome data, we identified three sets of sample mix-ups (two pairs and one trio) as well as at least 15 microbiome samples that appear to be mixtures of pairs of mice. The microbiome data consisted of shotgun sequencing reads from fecal DNA, used to characterize the gut microbial communities present in these mice. These sequence reads included sufficient reads derived from the host mouse to identify the individual. A number of microbiome samples appeared to contain a mixture of DNA from two mice. We describe a method for identifying sample mix-ups in such microbiome data, as well as a method for evaluating sample mixtures in this context.
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http://dx.doi.org/10.1093/g3journal/jkab308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527510PMC
October 2021

Gut microbes impact stroke severity via the trimethylamine N-oxide pathway.

Cell Host Microbe 2021 07 16;29(7):1199-1208.e5. Epub 2021 Jun 16.

Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195, USA; Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

Clinical studies have demonstrated associations between circulating levels of the gut-microbiota-derived metabolite trimethylamine-N-oxide (TMAO) and stroke incident risk. However, a causal role of gut microbes in stroke has not yet been demonstrated. Herein we show that gut microbes, through dietary choline and TMAO generation, directly impact cerebral infarct size and adverse outcomes following stroke. Fecal microbial transplantation from low- versus high-TMAO-producing human subjects into germ-free mice shows that both TMAO generation and stroke severity are transmissible traits. Furthermore, employing multiple murine stroke models and transplantation of defined microbial communities with genetically engineered human commensals into germ-free mice, we demonstrate that the microbial cutC gene (an enzymatic source of choline-to-TMA transformation) is sufficient to transmit TMA/TMAO production, heighten cerebral infarct size, and lead to functional impairment. We thus reveal that gut microbiota in general, specifically the metaorganismal TMAO pathway, directly contributes to stroke severity.
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http://dx.doi.org/10.1016/j.chom.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288076PMC
July 2021

Gut microbiome variation modulates the effects of dietary fiber on host metabolism.

Microbiome 2021 05 20;9(1):117. Epub 2021 May 20.

Department of Bacteriology, University of Wisconsin-Madison, 1550 Linden Dr., Madison, WI, 53706, USA.

Background: There is general consensus that consumption of dietary fermentable fiber improves cardiometabolic health, in part by promoting mutualistic microbes and by increasing production of beneficial metabolites in the distal gut. However, human studies have reported variations in the observed benefits among individuals consuming the same fiber. Several factors likely contribute to this variation, including host genetic and gut microbial differences. We hypothesized that gut microbial metabolism of dietary fiber represents an important and differential factor that modulates how dietary fiber impacts the host.

Results: We examined genetically identical gnotobiotic mice harboring two distinct complex gut microbial communities and exposed to four isocaloric diets, each containing different fibers: (i) cellulose, (ii) inulin, (iii) pectin, (iv) a mix of 5 fermentable fibers (assorted fiber). Gut microbiome analysis showed that each transplanted community preserved a core of common taxa across diets that differentiated it from the other community, but there were variations in richness and bacterial taxa abundance within each community among the different diet treatments. Host epigenetic, transcriptional, and metabolomic analyses revealed diet-directed differences between animals colonized with the two communities, including variation in amino acids and lipid pathways that were associated with divergent health outcomes.

Conclusion: This study demonstrates that interindividual variation in the gut microbiome is causally linked to differential effects of dietary fiber on host metabolic phenotypes and suggests that a one-fits-all fiber supplementation approach to promote health is unlikely to elicit consistent effects across individuals. Overall, the presented results underscore the importance of microbe-diet interactions on host metabolism and suggest that gut microbes modulate dietary fiber efficacy. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01061-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138933PMC
May 2021

Gut-derived Flavonifractor species variants are differentially enriched during in vitro incubation with quercetin.

PLoS One 2020 2;15(12):e0227724. Epub 2020 Dec 2.

Engineering Department, Universidad de la Sabana, Chia, Colombia.

Flavonoids are a common component of the human diet with widely reported health-promoting properties. The gut microbiota transforms these compounds affecting the overall metabolic outcome of flavonoid consumption. Flavonoid-degrading bacteria are often studied in pure and mixed cultures but the multiple interactions between quercetin-degraders and the rest of the community have been overlooked. In this study, a comparative metataxonomic analysis of fecal communities supplemented with the flavonoid quercetin led us to identify a potential competitive exclusion interaction between two sequence variants related to the flavonoid-degrading species, Flavonifractor plautii, that belong to the same genus but different species. During incubation of fecal slurries with quercetin, the relative abundance of these two variants was inversely correlated; one variant, ASV_65f4, increased in relative abundance in half of the libraries and the other variant, ASV_a45d, in the other half. This pattern was also observed with 6 additional fecal samples that were transplanted into germ-free mice fed two different diets. Mouse's diet did not change the pattern of dominance of either variant, and initial relative abundances did not predict which one ended up dominating. Potential distinct metabolic capabilities of these two Flavonifractor-related species were evidenced, as only one variant, ASV_65f4, became consistently enriched in complex communities supplemented with acetate but without quercetin. Genomic comparison analysis of the close relatives of each variant revealed that ASV_65f4 may be an efficient utilizer of ethanolamine which is formed from the phospholipid phosphatidylethanolamine that is abundant in the gut and feces. Other discordant features between ASV_65f4- and ASV_a45d-related groups may be the presence of flagellar and galactose-utilization genes, respectively. Overall, we showed that the Flavonifractor genus harbors variants that present a pattern of negative co-occurrence and that may have different metabolic and morphological traits, whether these differences affect the dynamic of quercetin degradation warrants further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710108PMC
January 2021

Selective Bacterial Colonization of the Murine Larynx in a Gnotobiotic Model.

Front Microbiol 2020 4;11:594617. Epub 2020 Nov 4.

Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.

The larynx is a mucosal organ situated between the respiratory and gastrointestinal tracts. Little is known about microbial contributions to laryngeal epithelial health and pathogenesis. Developing a gnotobiotic laryngeal model will introduce new avenues for targeted explorations of microbes in laryngeal mucosal biology, allowing for enhanced understanding of host-microbe interaction in the upper airway. In this study, we first assessed the potential of using gut microbiota as a source to establish laryngeal microbiota in germ-free mice. Results demonstrated the selective nature of the upper airway and provided evidence that gut bacteria can assemble into communities that resemble the commensal resident bacteria occurring in the larynx of conventionally-raised animals phylogenetically and functionally. Then, we confirmed the reproducibility of laryngeal colonization through comparison of laryngeal microbiota in the larynx along with neighboring regions (base of tongue, esophagus, and trachea) between conventionally-raised and germ-free mice that conventionalized with cecal microbiota. Despite taxonomic differences, the established laryngeal microbiota from cecal content exhibited similarity to commensal resident microbiota in diversity within/between communities and predicted metagenomic functions. Our data also suggests little difference in bacterial distribution across the larynx and its surrounding regions and that cell motility and the ability to degrade xenobiotics is critical for bacteria colonizing upper airway. Successful colonization of laryngeal and oropharyngeal regions with gut microbiota in our study will greatly facilitate the investigation of potential localized inflammatory responses within host tissues that contribute to the disorders of essential laryngeal functions. Utilizing said gnotobiotic model to conduct future studies will allow for novel insights into direct microbial contributions to laryngeal epithelial health and pathogenesis.
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http://dx.doi.org/10.3389/fmicb.2020.594617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676279PMC
November 2020

Effects of Smoking and Smoking Cessation on the Intestinal Microbiota.

J Clin Med 2020 Sep 14;9(9). Epub 2020 Sep 14.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.

We evaluated associations of smoking heaviness markers and the effects of smoking cessation on the intestinal microbiota and cardiovascular disease risk factors in current smokers undertaking a quit attempt. Participants were current smokers enrolled in a prospective randomized clinical trial of smoking cessation therapies with visits at baseline, 2, and 12 weeks. Genomic DNA was extracted from fecal samples followed by 16S rRNA gene sequencing and analysis using the QIIME2 software workflow. Relative abundances of bacterial taxa and alpha- and beta-diversity measures were used for comparisons. The 36 smokers were (mean (standard deviation)) 51.5 (11.1) years old (42% male) and smoked 15.1 (6.4) cigarettes per day for 22.7 (11.9) pack-years. Relative abundances of the phylum Actinobacteria correlated with pack-years (rho = -0.44, = 0.008) and Cyanobacteria correlated with CO levels (rho = 0.39, = 0.021). After 12 weeks, relative abundances of the phylum Bacteroidetes increased ( = 0.048) and Firmicutes decreased ( = 0.036) among abstainers compared to continuing smokers. Increases in alpha-diversity were associated with heart rates (rho = -0.59, = 0.037), systolic blood pressures (rho = -0.58, = 0.043), and C-reactive protein (rho = -0.60, = 0.034). Smoking cessation led to minor changes in the intestinal microbiota. It is unclear if the proven health benefits of smoking cessation lead to salutary changes in the intestinal microbiota.
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http://dx.doi.org/10.3390/jcm9092963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564179PMC
September 2020

Integrated Label-Free and 10-Plex DiLeu Isobaric Tag Quantitative Methods for Profiling Changes in the Mouse Hypothalamic Neuropeptidome and Proteome: Assessment of the Impact of the Gut Microbiome.

Anal Chem 2020 10 28;92(20):14021-14030. Epub 2020 Sep 28.

School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

Gut microbiota can regulate host physiological and pathological status through gut-brain communications or pathways. However, the impact of the gut microbiome on neuropeptides and proteins involved in regulating brain functions and behaviors is still not clearly understood. To address the problem, integrated label-free and 10-plex DiLeu isobaric tag-based quantitative methods were implemented to compare the profiling of neuropeptides and proteins in the hypothalamus of germ-free (GF)- vs conventionally raised (ConvR)-mice. A total of 2943 endogenous peptides from 63 neuropeptide precursors and 3971 proteins in the mouse hypothalamus were identified. Among these 368 significantly changed peptides (fold changes over 1.5 and a -value of <0.05), 73.6% of the peptides showed higher levels in GF-mice than in ConvR-mice, and 26.4% of the peptides had higher levels in ConvR-mice than in GF-mice. These peptides were mainly from secretogranin-2, phosphatidylethanolamine-binding protein-1, ProSAAS, and proenkephalin-A. A quantitative proteomic analysis employing DiLeu isobaric tags revealed that 282 proteins were significantly up- or down-regulated (fold changes over 1.2 and a -value of <0.05) among the 3277 quantified proteins. These neuropeptides and proteins were mainly involved in regulating behaviors, transmitter release, signaling pathways, and synapses. Interestingly, pathways including long-term potentiation, long-term depression, and circadian entrainment were involved. In the present study, a combined label-free and 10-plex DiLeu-based quantitative method enabled a comprehensive profiling of gut microbiome-induced dynamic changes of neuropeptides and proteins in the hypothalamus, suggesting that the gut microbiome might mediate a range of behavioral changes, brain development, and learning and memory through these neuropeptides and proteins.
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http://dx.doi.org/10.1021/acs.analchem.0c02939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577927PMC
October 2020

Extraction optimization for combined metabolomics, peptidomics, and proteomics analysis of gut microbiota samples.

J Mass Spectrom 2021 Apr 3;56(4):e4625. Epub 2020 Sep 3.

Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, 53705, USA.

Multiomic studies are increasingly performed to gain a deeper understanding of molecular processes occurring in a biological system, such as the complex microbial communities (i.e., microbiota) that reside the distal gut. While a combination of metabolomics and proteomics is more commonly used, multiomics studies including peptidomcis characterization are less frequently undertaken. Here, we investigated three different extraction methods, chosen for their previous use in extracting metabolites, peptides, and proteins, and compared their ability to perform metabolomic, peptidomic, and proteomic analysis of mouse cecum content. The methanol/chloroform/water extraction performed the best for metabolomic and peptidomic analysis as it detected the largest number of small molecules and identified the largest number of peptides, but the acidified methanol extraction performed best for proteomics analysis as it had the highest number of protein identifications. The methanol/chloroform/water extraction was further analyzed by identifying metabolites with tandem mass spectrometry (MS/MS) analysis and by gene ontology analysis for the peptide and protein results to provide a multiomics analysis of the gut microbiota.
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http://dx.doi.org/10.1002/jms.4625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855350PMC
April 2021

A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors.

Cell 2020 03;180(5):862-877.e22

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA; Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44106, USA. Electronic address:

Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
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http://dx.doi.org/10.1016/j.cell.2020.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402401PMC
March 2020

The emerging role of gut microbial metabolism on cardiovascular disease.

Curr Opin Microbiol 2019 08 3;50:64-70. Epub 2019 Nov 3.

Department of Bacteriology, University of Wisconsin-Madison, 1550 Linden Dr., Madison, WI 53706, USA. Electronic address:

The gut microbiome has been implicated in the progression of cardiovascular diseases (CVD) including hypertension, dyslipidemia, atherosclerosis, thrombosis, heart failure, and ischemic stroke. Metabolomics studies in humans and diverse mouse populations have revealed associations between diet-derived gut bacterial metabolites, including trimethylamine-N-oxide, short-chain fatty acids, and intermediates of aromatic amino acid breakdown, with progression of CVD. Functional studies in animals fed diets of defined composition have been instrumental for establishing causal links between these metabolites, the microbes that produce them, dietary substrates and disease. The purpose of this review is to discuss recent progress in our understanding of how gut microbial metabolism of food influences the development of CVD and to outline experimental approaches that can be useful for addressing crucial knowledge gaps in the field. Together, this body of work supports the notion that the gut microbiomes mediate many of the effects of diet.
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http://dx.doi.org/10.1016/j.mib.2019.09.007DOI Listing
August 2019

Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction.

Cell Metab 2019 12 19;30(6):1141-1151.e5. Epub 2019 Sep 19.

Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

The gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) is increased by insulin resistance and associated with several sequelae of metabolic syndrome in humans, including cardiovascular, renal, and neurodegenerative disease. The mechanism by which TMAO promotes disease is unclear. We now reveal the endoplasmic reticulum stress kinase PERK (EIF2AK3) as a receptor for TMAO: TMAO binds to PERK at physiologically relevant concentrations; selectively activates the PERK branch of the unfolded protein response; and induces the transcription factor FoxO1, a key driver of metabolic disease, in a PERK-dependent manner. Furthermore, interventions to reduce TMAO, either by manipulation of the gut microbiota or by inhibition of the TMAO synthesizing enzyme, flavin-containing monooxygenase 3, can reduce PERK activation and FoxO1 levels in the liver. Taken together, these data suggest TMAO and PERK may be central to the pathogenesis of the metabolic syndrome.
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http://dx.doi.org/10.1016/j.cmet.2019.08.021DOI Listing
December 2019

Genetic determinants of gut microbiota composition and bile acid profiles in mice.

PLoS Genet 2019 08 29;15(8):e1008073. Epub 2019 Aug 29.

Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.
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http://dx.doi.org/10.1371/journal.pgen.1008073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715156PMC
August 2019

Starch Utilization Promotes Quercetin Degradation and Butyrate Production by .

Front Microbiol 2019 29;10:1145. Epub 2019 May 29.

Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, United States.

Consumption of flavonoids has been associated with protection against cardiovascular and neurodegenerative diseases. Most dietary flavonoids are subjected to bacterial transformations in the gut where they are converted into biologically active metabolites that are more bioavailable and have distinct effects relative to the parent compounds. While some of the pathways involved in the breakdown of flavonoids are emerging, little it is known about the impact of carbon source availability and community dynamics on flavonoid metabolism. This is relevant in the gut where there is a fierce competition for nutrients. In this study, we show that metabolism of one of the most commonly consumed flavonoids, quercetin, by the gut-associated bacterium is dependent on interspecies cross-feeding interactions when starch is the only energy source available. can degrade quercetin in the presence of glucose but is unable to use starch for growth or quercetin degradation. However, the starch-metabolizing bacterium , which does not metabolize quercetin, stimulates degradation of quercetin and butyrate production by via cross-feeding of glucose and maltose molecules released from starch. These results suggest that dietary substrates and interactions between species modulate the degradation of flavonoids and production of butyrate, thus shaping their bioavailability and bioactivity, and likely impacting their health-promoting effects in humans.
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http://dx.doi.org/10.3389/fmicb.2019.01145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548854PMC
May 2019

Differential Catabolism of an Anthocyanin-Rich Elderberry Extract by Three Gut Microbiota Bacterial Species.

J Agric Food Chem 2020 Feb 18;68(7):1837-1843. Epub 2019 Apr 18.

Department of Bacteriology , University of Wisconsin-Madison , Madison , Wisconsin 53706 , United States.

Elderberries are good sources of anthocyanins, which are poorly absorbed in the upper gastrointestinal tract but extensively transformed into phenolic metabolites at the colonic level. Because different gut microbiota strains have different metabolism, the catabolism of anthocyanins may lead to interindividual differences in metabolite production. In this work, an anthocyanin-rich elderberry extract was incubated with three single gut microbial strains (, , and ) up to 4 days, to assess differences in their phenolic metabolism. All of the strains degraded the elderberry anthocyanins, but the metabolic pathways followed were different. Although some metabolites were common for all of the strains, a wide disparity was observed in the kind and amount of several phenolic metabolites produced by each species. These preliminary results may be of help in the interpretation of the bioavailability of anthocyanins and give a clue to understand interindividual variability in metabolite production.
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http://dx.doi.org/10.1021/acs.jafc.9b00247DOI Listing
February 2020

Autometa: automated extraction of microbial genomes from individual shotgun metagenomes.

Nucleic Acids Res 2019 06;47(10):e57

Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.

Shotgun metagenomics is a powerful, high-resolution technique enabling the study of microbial communities in situ. However, species-level resolution is only achieved after a process of 'binning' where contigs predicted to originate from the same genome are clustered. Such culture-independent sequencing frequently unearths novel microbes, and so various methods have been devised for reference-free binning. As novel microbiomes of increasing complexity are explored, sometimes associated with non-model hosts, robust automated binning methods are required. Existing methods struggle with eukaryotic contamination and cannot handle highly complex single metagenomes. We therefore developed an automated binning pipeline, termed 'Autometa', to address these issues. This command-line application integrates sequence homology, nucleotide composition, coverage and the presence of single-copy marker genes to separate microbial genomes from non-model host genomes and other eukaryotic contaminants, before deconvoluting individual genomes from single metagenomes. The method is able to effectively separate over 1000 genomes from a metagenome, allowing the study of previously intractably complex environments at the level of single species. Autometa is freely available at https://bitbucket.org/jason_c_kwan/autometa and as a docker image at https://hub.docker.com/r/jasonkwan/autometa under the GNU Affero General Public License 3 (AGPL 3).
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http://dx.doi.org/10.1093/nar/gkz148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547426PMC
June 2019

Critical symbiont signals drive both local and systemic changes in diel and developmental host gene expression.

Proc Natl Acad Sci U S A 2019 04 4;116(16):7990-7999. Epub 2019 Mar 4.

Pacific Biosciences Research Center, University of Hawai'i at Mānoa, Honolulu, HI 96822;

The colonization of an animal's tissues by its microbial partners creates networks of communication across the host's body. We used the natural binary light-organ symbiosis between the squid and its luminous bacterial partner, , to define the impact of colonization on transcriptomic networks in the host. A night-active predator, coordinates the bioluminescence of its symbiont with visual cues from the environment to camouflage against moon and starlight. Like mammals, this symbiosis has a complex developmental program and a strong day/night rhythm. We determined how symbiont colonization impacted gene expression in the light organ itself, as well as in two anatomically remote organs: the eye and gill. While the overall transcriptional signature of light organ and gill were more alike, the impact of symbiosis was most pronounced and similar in light organ and eye, both in juvenile and adult animals. Furthermore, the presence of a symbiosis drove daily rhythms of transcription within all three organs. Finally, a single mutation in -specifically, deletion of the operon, which abrogates symbiont luminescence-reduced the symbiosis-dependent transcriptome of the light organ by two-thirds. In addition, while the gills responded similarly to light-organ colonization by either the wild-type or mutant, luminescence was required for all of the colonization-associated transcriptional responses in the juvenile eye. This study defines not only the impact of symbiont colonization on the coordination of animal transcriptomes, but also provides insight into how such changes might impact the behavior and ecology of the host.
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http://dx.doi.org/10.1073/pnas.1819897116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475425PMC
April 2019

Close social relationships correlate with human gut microbiota composition.

Sci Rep 2019 01 24;9(1):703. Epub 2019 Jan 24.

Center for the Demography of Health and Aging, 1180 Observatory Drive, Madison, WI, 53706, USA.

Social relationships shape human health and mortality via behavioral, psychosocial, and physiological mechanisms, including inflammatory and immune responses. Though not tested in human studies, recent primate studies indicate that the gut microbiome may also be a biological mechanism linking relationships to health. Integrating microbiota data into the 60-year-old Wisconsin Longitudinal Study, we found that socialness with family and friends is associated with differences in the human fecal microbiota. Analysis of spouse (N = 94) and sibling pairs (N = 83) further revealed that spouses have more similar microbiota and more bacterial taxa in common than siblings, with no observed differences between sibling and unrelated pairs. These differences held even after accounting for dietary factors. The differences between unrelated individuals and married couples was driven entirely by couples who reported close relationships; there were no differences in similarity between couples reporting somewhat close relationships and unrelated individuals. Moreover, married individuals harbor microbial communities of greater diversity and richness relative to those living alone, with the greatest diversity among couples reporting close relationships, which is notable given decades of research documenting the health benefits of marriage. These results suggest that human interactions, especially sustained, close marital relationships, influence the gut microbiota.
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http://dx.doi.org/10.1038/s41598-018-37298-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345772PMC
January 2019

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

Circulation 2019 01;139(5):647-659

Program in Molecular Medicine, National Yang Ming University and Academia Sinica, Taipei, Taiwan (T.W.H.T., P.C.C.H.).

Background: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.

Methods: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.

Results: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.

Conclusions: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035235DOI Listing
January 2019

The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer's disease.

Alzheimers Res Ther 2018 12 22;10(1):124. Epub 2018 Dec 22.

Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.

Background: Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease.

Methods: In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein).

Results: CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ) and neuronal degeneration (total tau and neurofilament light chain protein).

Conclusions: These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.
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http://dx.doi.org/10.1186/s13195-018-0451-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303862PMC
December 2018

Dietary Prevention of Colitis by Aronia Berry is Mediated Through Increased Th17 and Treg.

Mol Nutr Food Res 2019 03 13;63(5):e1800985. Epub 2018 Dec 13.

Department of Food Science, University of Wisconsin-Madison, Madison, WI, 53706, USA.

Scope: Increased fruit consumption is associated with reduced risk of colitis. It has been investigated whether the anti-colitic effects of the polyphenol-rich aronia berry (Aronia mitschurinii 'Viking') are mediated through Th17 and Treg.

Methods And Results: Colitis is induced in recombinase activating gene-1 deficient mice injected with syngeneic CD4 CD62L naïve T cells. Mice consume either 4.5% w/w aronia-berry-supplemented or a control diet concurrent with T cell transfer. The extent of colitis and immunocyte populations are evaluated at weeks 3 to 7 after transfer. Aronia consumption prevents colitic wasting and reduces colon weight/length ratios relative to the control diet at weeks 5 and 7. Compared to the control diet, aronia feeding increases Treg in mesenteric lymph node at all colitis stages. Treg and regulatory Th17 subpopulations (IL-17A IL-10 and IL-17A IL-22 ) are increased in lamina propria and spleen at week 5 in aronia-fed mice. Aronia feeding also decreases total CD4 cells but increases colonic Tregs. The ability of aronia to modulate colonic cytokines is associated with functional T cell IL-10 and increased diversity of microbiota.

Conclusions: Aronia berry consumption inhibits adoptive transfer colitis by increasing Treg and regulatory Th17 cells. Dietary modulation of T cells is dynamic and precedes colitic wasting.
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http://dx.doi.org/10.1002/mnfr.201800985DOI Listing
March 2019

Gut Microbial and Metabolic Responses to Salmonella enterica Serovar Typhimurium and Candida albicans.

mBio 2018 11 6;9(6). Epub 2018 Nov 6.

Department of Bacteriology, University of Wisconsin, Madison, Wisconsin, USA

The gut microbiota confers resistance to pathogens of the intestinal ecosystem, yet the dynamics of pathogen-microbiome interactions and the metabolites involved in this process remain largely unknown. Here, we use gnotobiotic mice infected with the virulent pathogen serovar Typhimurium or the opportunistic pathogen in combination with metagenomics and discovery metabolomics to identify changes in the community and metabolome during infection. To isolate the role of the microbiota in response to pathogens, we compared mice monocolonized with the pathogen, uninfected mice "humanized" with a synthetic human microbiome, or infected humanized mice. In -infected mice, by 3 days into infection, microbiome community structure and function changed substantially, with a rise in strains and a reduction in biosynthetic gene cluster potential. In contrast, -infected mice had few microbiome changes. The LC-MS metabolomic fingerprint of the cecum differed between mice monocolonized with either pathogen and humanized infected mice. Specifically, we identified an increase in glutathione disulfide, glutathione cysteine disulfide, inosine 5'-monophosphate, and hydroxybutyrylcarnitine in mice infected with in contrast to uninfected mice and mice monocolonized with These metabolites potentially play a role in pathogen-induced oxidative stress. These results provide insight into how the microbiota community members interact with each other and with pathogens on a metabolic level. The gut microbiota is increasingly recognized for playing a critical role in human health and disease, especially in conferring resistance to both virulent pathogens such as , which infects 1.2 million people in the United States every year (E. Scallan, R. M. Hoekstra, F. J. Angulo, R. V. Tauxe, et al., Emerg Infect Dis 17:7-15, 2011, https://doi.org/10.3201/eid1701.P11101), and opportunistic pathogens like , which causes an estimated 46,000 cases of invasive candidiasis each year in the United States (Centers for Disease Control and Prevention, s, , 2013). Using a gnotobiotic mouse model, we investigate potential changes in gut microbial community structure and function during infection using metagenomics and metabolomics. We observe that changes in the community and in biosynthetic gene cluster potential occur within 3 days for the virulent serovar Typhimurium, but there are minimal changes with a poorly colonizing In addition, the metabolome shifts depending on infection status, including changes in glutathione metabolites in response to a infection, potentially in response to host oxidative stress.
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http://dx.doi.org/10.1128/mBio.02032-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222126PMC
November 2018

Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model.

Nat Microbiol 2018 12 5;3(12):1461-1471. Epub 2018 Nov 5.

Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.

Humans with metabolic and inflammatory diseases frequently harbour lower levels of butyrate-producing bacteria in their gut. However, it is not known whether variation in the levels of these organisms is causally linked with disease development and whether diet modifies the impact of these bacteria on health. Here we show that a prominent gut-associated butyrate-producing bacterial genus (Roseburia) is inversely correlated with atherosclerotic lesion development in a genetically diverse mouse population. We use germ-free apolipoprotein E-deficient mice colonized with synthetic microbial communities that differ in their capacity to generate butyrate to demonstrate that Roseburia intestinalis interacts with dietary plant polysaccharides to: impact gene expression in the intestine, directing metabolism away from glycolysis and toward fatty acid utilization; lower systemic inflammation; and ameliorate atherosclerosis. Furthermore, intestinal administration of butyrate reduces endotoxaemia and atherosclerosis development. Together, our results illustrate how modifiable diet-by-microbiota interactions impact cardiovascular disease, and suggest that interventions aimed at increasing the representation of butyrate-producing bacteria may provide protection against atherosclerosis.
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http://dx.doi.org/10.1038/s41564-018-0272-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280189PMC
December 2018

Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential.

Circ Res 2018 10;123(10):1164-1176

Center for Microbiome and Human Health, Lerner Research Institute (S.M.S., W.Z., K.A.R., Z.W., J.K., J.A.D., W.H.W.T., S.L.H.), Cleveland Clinic, OH.

Rationale: Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)-the precursor to TMAO-is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the cutC/D (choline utilization C/D) genes in multiple human commensals.

Objective: Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported.

Methods And Results: Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes Δ cutC).

Conclusions: Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223262PMC
October 2018

Is maternal microbial metabolism an early-life determinant of health?

Lab Anim (NY) 2018 09 24;47(9):239-243. Epub 2018 Aug 24.

Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.

Mounting evidence suggests that environmental stress experienced in utero (for example, maternal nutritional deficits) establishes a predisposition in the newborn to the development of chronic diseases later in life. This concept is often referred to as the "fetal origins hypothesis" or "developmental origins of health and disease". Since its first proposal, epigenetics has emerged as an underlying mechanism explaining how environmental cues become gestationally "encoded". Many of the enzymes that impart and maintain epigenetic modifications are highly sensitive to nutrient availability, which can be influenced by the metabolic activities of the intestinal microbiota. Therefore, the maternal microbiome has the potential to influence epigenetics in utero and modulate offspring's long-term health trajectories. Here we summarize the current understanding of the interactions that occur between the maternal gut microbiome and the essential nutrient choline, that is not only required for fetal development and epigenetic regulation but is also a growth substrate for some microbes. Bacteria able to metabolize choline benefit from the presence of this nutrient and compete with the host for its access, which under extreme conditions may elicit signatures of choline deficiency. Another consequence of bacterial choline metabolism is the accumulation of the pro-inflammatory, pro-thrombotic metabolite trimethylamine-N-oxide (TMAO). Finally, we discuss how these different facets of microbial choline metabolism may influence infant development and health trajectories via epigenetic mechanisms and more broadly place a call to action to better understand how maternal microbial metabolism can shape their offspring's propensity to chronic disease development later in life.
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http://dx.doi.org/10.1038/s41684-018-0129-1DOI Listing
September 2018

Sexual dimorphism of cardiometabolic dysfunction: Gut microbiome in the play?

Mol Metab 2018 09 30;15:70-81. Epub 2018 May 30.

Cardiovascular Research Center, University of Wisconsin-Madison, Madison, WI, 53705, United States; Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, 53706, United States. Electronic address:

Background: Sex is one of the most powerful modifiers of disease development. Clear sexual dimorphism exists in cardiometabolic health susceptibility, likely due to differences in sex steroid hormones. Changes in the gut microbiome have been linked with the development of obesity, type 2 diabetes, and atherosclerosis; however, the impact of microbes in sex-biased cardiometabolic disorders remains unclear. The gut microbiome is critical for maintaining a normal estrous cycle, testosterone levels, and reproductive function. Gut microbes modulate the enterohepatic recirculation of estrogens and androgens, affecting local and systemic levels of sex steroid hormones. Gut bacteria can also generate androgens from glucocorticoids.

Scope Of Review: This review summarizes current knowledge of the complex interplay between sexual dimorphism in cardiometabolic disease and the gut microbiome.

Major Conclusions: Emerging evidence suggests the role of gut microbiome as a modifier of disease susceptibility due to sex; however, the impact on cardiometabolic disease in this complex interplay is lacking. Elucidating the role of gut microbiome on sex-biased susceptibility in cardiometabolic disease is of high relevance to public health given its high prevalence and significant financial burden.
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http://dx.doi.org/10.1016/j.molmet.2018.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066746PMC
September 2018
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