Faculty & Staff

  • Image of Federico E. Rey

    Federico E. Rey

    Associate Professor of Bacteriology

    5157 Microbial Sciences Building
    Office: (608) 890-2046
    Lab: (608) 890-2366
    Google Scholar

Start and Promotion Dates

  • Assistant Professor: 2013
  • Associate Professor: 2019


Licenciado en Bioquimica (equivalent to B.S. and M.S. in Clinical Chemistry). 1998 
Facultad de Ciencias Quimicas. Universidad Nacional de Cordoba, Cordoba, Argentina.
Ph.D. Microbiology. 2006 
University of Iowa Postdoctoral Research: Center for Genome Sciences and Systems Biology, Washington University

Areas of Study

Microbiome, Microbe-diet interactions, Cardiovascular disease

Research Overview

Humans studies have revealed consistent alterations in the gut microbiomes of patients with cardiometabolic and aging-associated diseases. A major focus of my group is to understand how variations in the gut microbiome modulate the effects of diet and host’s susceptibility to cardiometabolic disease. To address these questions we use a combination of hypothesis-generating, sequencing-centered analyses of microbiomes from humans and mice, followed by proof-of-principle/proof-of-mechanism studies in gnotobiotic mouse models of disease and classic bacteriology experiments.

Dissecting the impact of microbe-diet interactions on host health:

1. Bacterial choline metabolism: Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine N-oxide (TMAO). TMAO exacerbates thrombosis and atherosclerosis in mice, and its abundance correlates with the severity of these diseases in humans. We have recently discovered that subjects with Alzheimer’s Disease (AD) have alterations in their microbiome and higher levels of TMAO in cerebrospinal fluid (CSF), and we have identified associations between this molecule and markers of AD (Vogt et al., 2017, Vogt et al., 2018). Given the importance of choline and vascular disease to AD development we are exploring the impact of choline-consuming/TMA(O)-producing bacteria on AD development using a gnotobiotic mouse model of AD (collaboration with Dr. Barbara Bendlin and Dr. Luigi Puglielli). Additionally, we are working with Dr. John Denu to explore the role of bacterial choline depletion, TMAO and bacterial metabolism on epigenetic regulation.

2. Diet-microbiota interactions that impact atherosclerosis: (a) variation in butyrate-producing bacteria: Consumption of dietary fiber decreases the risk of cardiometabolic disease. Recent studies suggest that some of the benefits associated with consumption of dietary fiber are mediated in part by gut microbes, with increased representation of butyrate-producing microbes proposed as one of the potential mediators. Moreover, gut butyrate-producing bacteria have been found at higher levels in healthy populations relative to patients suffering various inflammatory diseases such as atherosclerosis. We recently showed that the butyrate-producing bacterium Roseburia intestinalis interacts with dietary plant polysaccharides to generate large amounts of butyrate, modify epigenetic programming, impact gene expression in the intestine, and improve intestinal barrier function. These changes were associated with lower levels of pro-inflammatory molecules in systemic circulation, reduced inflammation in the aorta and smaller atherosclerotic lesions. By administering tributyrin in the diet, which delivers butyrate in the distal gut, we demonstrated that butyrate mimics the effects of R. intestinalis (Kasahara et al. 2018). We plan to identify fiber types and dietary sources that promote the growth of R. intestinalis and test whether these results can be extended to other butyrate-producing bacteria. Additionally, we are testing causal relationships of other associations that we have identified between gut microbes and atherosclerosis. (b) Interactions between gut bacteria and flavonoids: some of the health benefits associated with the consumption of fruits and vegetables are derived from flavonoids. However, our bodies do not absorb most flavonoids as they exist in food, and there is a large degree of interpersonal variation in the reported benefits. These observations in part reflect individual differences in gut microbiota, which metabolize ingested flavonoids to a variety of products that are more readily absorbed by the host, although the nature and extent of these transformations remain poorly characterized. We recently found that colonized mice fed a diet supplemented with quercetin accumulate high levels of biologically active (e.g., anti-thrombotic) metabolites and develop smaller atherosclerotic lesions relative to mice consuming a control diet, whereas age-matched germ-free Apolipoprotein E-deficient mice do not benefit from flavonoid supplementation. These preliminary results suggest that bacterial metabolism of quercetin may be necessary for some of the beneficial effects associated with flavonoid consumption. We are currently examining whether specific routes of flavonoid metabolism are required for its beneficial effects.

Deciphering the impact of host genetics on gut microbiome composition: Host genetic variation modulates the composition of the gut microbiota. We found significant variation in diabetes-related phenotypes, atherosclerosis and gut microbiota composition among different mouse strains, and identified microbes associated with these traits. Microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease (Kreznar et al., 2017) and atherosclerosis (Kasahara and Rey, unpublished). By using a genetically-diverse mouse cohort and quantitative trait loci (QTL) mapping, we are identifying gut microbes, microbial functions, microbial-derived metabolites and clinical phenotypes that are modulated by host genetics (collaboration with Dr. Alan Attie).


Microbiology 450: Diversity, Ecology, and Evolution of Microorganisms


  • 2022-2023, ASM Distinguished Lecturer

Lab Personnel

Picture of Bussan
Hailey Bussan
Grad Student
Picture of Emery
Heather Emery
Grad Student
Picture of Jillella
Mallikarjun Jillella
Picture of Kerby
Robert Kerby
Honorary Associate
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Jessamine Kuehn
Grad Student
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Michael Tallon
Research Intern
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VV (Vaibhav) Vemuganti
Grad Student
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Matthew Warren
Picture of Zhang
Qijun Zhang
Picture of Lucas
Lauren Lucas

Research Papers

  • An R, Venkatraman A, Binns J, Saric C, Rey FE, Thibeault SL (2024) Age and sex-related variations in murine laryngeal microbiota. PloS one 19((5)):e0300672 PMC6234624 · Pubmed · DOI

    The larynx undergoes significant age and sex-related changes in structure and function across the lifespan. Emerging evidence suggests that laryngeal microbiota influences immunological processes. Thus, there is a critical need to delineate microbial mechanisms that may underlie laryngeal physiological and immunological changes. As a first step, the present study explored potential age and sex-related changes in the laryngeal microbiota across the lifespan in a murine model. We compared laryngeal microbial profiles of mice across the lifespan (adolescents, young adults, older adults and elderly) to determine age and sex-related microbial variation on 16s rRNA gene sequencing. Measures of alpha diversity and beta diversity were obtained, along with differentially abundant taxa across age groups and biological sexes. There was relative stability of the laryngeal microbiota within each age group and no significant bacterial compositional shift in the laryngeal microbiome across the lifespan. There was an abundance of short-chain fatty acid producing bacteria in the adolescent group, unique to the laryngeal microbiota; taxonomic changes in the elderly resembled that of the aged gut microbiome. There were no significant changes in the laryngeal microbiota relating to biological sex. This is the first study to report age and sex-related variation in laryngeal microbiota. This data lays the groundwork for defining how age-related microbial mechanisms may govern laryngeal health and disease. Bacterial compositional changes, as a result of environmental or systemic stimuli, may not only be indicative of laryngeal-specific metabolic and immunoregulatory processes, but may precede structural and functional age-related changes in laryngeal physiology.

  • Hutchison ER, Yen MI, Peng HW, Davis CR, Vivas EI, Tallon MM, Bui TPN, de Vos WM, Yen CE, Nieuwdorp M, Rey FE (2024) The gut microbiome modulates the impact of Anaerobutyricum soehngenii supplementation on glucose homeostasis in mice. Research square : PMC8714082 · Pubmed · DOI

    There is growing interest in the development of next-generation probiotics to prevent or treat metabolic syndrome. Previous studies suggested that Anaerobutyricum soehngenii may represent a promising probiotic candidate. A recent human study showed that while A. soehngenii supplementation is well tolerated and safe, it resulted in variable responses among individuals with a subset of the subjects significantly benefiting from the treatment. We hypothesized that gut microbiome variation is linked to the heterogeneous responses to A. soehngenii treatment observed in humans.

  • Mirzaei S, DeVon HA, Cantor RM, Cupido AJ, Pan C, Ha SM, Silva LF, Hilser JR, Hartiala J, Allayee H, Rey FE, Laakso M, Lusis AJ (2024) Relationships and Mendelian Randomization of Gut Microbe-Derived Metabolites with Metabolic Syndrome Traits in the METSIM Cohort. Metabolites 14((3)): PMC8266738 · Pubmed · DOI

    The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, p = 0.033), body mass index (BMI) (β = 0.025, p = 1.3 × 10), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, p = 5.8 × 10), triglyceride (0.087, p = 1.3 × 10), systolic (β = 0.012, p = 2.5 × 10) and diastolic blood pressure (β = 0.011, p = 3.4 × 10). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, p = 4.4 × 10), and BMI (β = 0.097, p = 5.1 × 10). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = -0.19, p = 3.8 × 10) and triglycerides (β = -0.12, p = 5.9 × 10). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors.

  • Martinelli F, Heinken A, Henning AK, Ulmer MA, Hensen T, González A, Arnold M, Asthana S, Budde K, Engelman CD, Estaki M, Grabe HJ, Heston MB, Johnson S, Kastenmüller G, Martino C, McDonald D, Rey FE, Kilimann I, Peters O, Wang X, Spruth EJ, Schneider A, Fliessbach K, Wiltfang J, Hansen N, Glanz W, Buerger K, Janowitz D, Laske C, Munk MH, Spottke A, Roy N, Nauck M, Teipel S, Knight R, Kaddurah-Daouk RF, Bendlin BB, Hertel J, Thiele I (2024) Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer's disease. Scientific reports 14((1)):6095 PMC7428328 · Pubmed · DOI

    In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

  • Zhang Q, Hutchison ER, Pan C, Warren MF, Keller MP, Attie AD, Lusis AJ, Rey FE (2024) Systems genetics approach uncovers associations between host amylase locus, gut microbiome and metabolic traits in hyperlipidemic mice. bioRxiv : the preprint server for biology : PMC5976434 · Pubmed · DOI

    The molecular basis for how host genetic variation impacts gut microbial community and bacterial metabolic niches remain largely unknown. We leveraged 90 inbred hyperlipidemic mouse strains from the Hybrid Mouse Diversity Panel (HMDP), previously studied for a variety of cardio-metabolic traits. Metagenomic analysis of cecal DNA followed by genome-wide association analysis identified genomic loci that were associated with microbial enterotypes in the gut. Among these we detected a genetic locus surrounding multiple amylase genes that was associated with abundances of Firmicutes ( Lachnospiraceae family) and Bacteroidetes ( Muribaculaceae family) taxa encoding distinct starch and sugar metabolism functions. We also found that lower amylase gene number in the mouse genome was associated with higher gut Muribaculaceae levels. Previous work suggests that modulation of host amylase activity impacts the availability of carbohydrates to the host and potentially to gut bacteria. The genetic variants described above were associated with distinct gut microbial communities (enterotypes) with different predicted metabolic capacities for carbohydrate degradation. Mendelian randomization analysis revealed host phenotypes, including liver fibrosis and plasma HDL-cholesterol levels, that were associated with gut microbiome enterotypes. This work reveals novel relationships between host genetic variation, gut microbial enterotypes and host physiology/disease phenotypes in mice.

  • Han S, Li Z, Shi Y, Cui Y, Huang J, Frost DC, Rey FE, Liu R, Li L (2024) 11-Plex DiLeu Isobaric Labeling Enables Quantitative Assessment of Brain Region Protein Association Networks Impacted by the Gut Microbiome. Analytical chemistry 96((9)):3870-3878 · Pubmed · DOI

    Gut microbiota can regulate host brain functions and influence various physiological and pathological processes through the brain-gut axis. To systematically elucidate the intervention of different gut environments on different brain regions, we implemented an integrated approach that combines 11-plex DiLeu isobaric tags with a "BRIDGE" normalization strategy to comparatively analyze the proteome of six brain regions in germ-free (GF)- and conventionally raised (ConvR)-mice. A total of 5945 proteins were identified and 5656 were quantifiable, while 1906 of them were significantly changed between GF- and ConvR-mice; 281 proteins were filtered with FC greater than 1.2 in at least one brain region, of which heatmap analysis showed clear protein profile disparities, both between brain regions and gut microbiome conditions. Gut microbiome impact is most overt in the hypothalamus and the least in the thalamus region. Collectively, this approach allows an in-depth investigation of the induced protein changes by multiple gut microbiome environments in a brain region-specific manner. This comprehensive proteomic work improves the understanding of the brain region protein association networks impacted by the gut microbiome and highlights the critical roles of the brain-gut axis.

  • Wang YC, Koay YC, Pan C, Zhou Z, Tang W, Wilcox J, Li XS, Zagouras A, Marques F, Allayee H, Rey FE, Kaye DM, O'Sullivan JF, Hazen SL, Cao Y, Lusis AJ (2024) Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction. Circulation research 134((4)):371-389 PMC9639660 · Pubmed · DOI

    Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult.

  • Cross TL, Simpson AMR, Lin CY, Hottmann NM, Bhatt AP, Pellock SJ, Nelson ER, Loman BR, Wallig MA, Vivas EI, Suchodolski J, Redinbo MR, Rey FE, Swanson KS (2023) Gut microbiome responds to alteration in female sex hormone status and exacerbates metabolic dysfunction. Gut microbes 16((1)):2295429 PMC7360769 · Pubmed · DOI

    Women are at significantly greater risk of metabolic dysfunction after menopause, which subsequently leads to numerous chronic illnesses. The gut microbiome is associated with obesity and metabolic dysfunction, but its interaction with female sex hormone status and the resulting impact on host metabolism remains unclear. Herein, we characterized inflammatory and metabolic phenotypes as well as the gut microbiome associated with ovariectomy and high-fat diet feeding, compared to gonadal intact and low-fat diet controls. We then performed fecal microbiota transplantation (FMT) using gnotobiotic mice to identify the impact of ovariectomy-associated gut microbiome on inflammatory and metabolic outcomes. We demonstrated that ovariectomy led to greater gastrointestinal permeability and inflammation of the gut and metabolic organs, and that a high-fat diet exacerbated these phenotypes. Ovariectomy also led to alteration of the gut microbiome, including greater fecal β-glucuronidase activity. However, differential changes in the gut microbiome only occurred when fed a low-fat diet, not the high-fat diet. Gnotobiotic mice that received the gut microbiome from ovariectomized mice fed the low-fat diet had greater weight gain and hepatic gene expression related to metabolic dysfunction and inflammation than those that received intact sham control-associated microbiome. These results indicate that the gut microbiome responds to alterations in female sex hormone status and contributes to metabolic dysfunction. Identifying and developing gut microbiome-targeted modulators to regulate sex hormones may be useful therapeutically in remediating menopause-related diseases.

  • Liu Y, Cheng YY, Thompson J, Zhou Z, Vivas EI, Warren MF, Rey FE, Anantharaman K, Venturelli OS (2023) Shaping human gut community assembly and butyrate production by controlling the arginine dihydrolase pathway. bioRxiv : the preprint server for biology : PMC4489315 · Pubmed · DOI

    The arginine dihydrolase pathway ( arc operon) present in a subset of diverse human gut species enables arginine catabolism. This specialized metabolic pathway can alter environmental pH and nitrogen availability, which in turn could shape gut microbiota inter-species interactions. By exploiting synthetic control of gene expression, we investigated the role of the arc operon in probiotic Escherichia coli Nissle 1917 on human gut community assembly and health-relevant metabolite profiles in vitro and in the murine gut. By stabilizing environmental pH, the arc operon reduced variability in community composition across different initial pH perturbations. The abundance of butyrate producing bacteria were altered in response to arc operon activity and butyrate production was enhanced in a physiologically relevant pH range. While the presence of the arc operon altered community dynamics, it did not impact production of short chain fatty acids. Dynamic computational modeling of pH-mediated interactions reveals the quantitative contribution of this mechanism to community assembly. In sum, our framework to quantify the contribution of molecular pathways and mechanism modalities on microbial community dynamics and functions could be applied more broadly.

  • Heston MB, Hanslik KL, Zarbock KR, Harding SJ, Davenport-Sis NJ, Kerby RL, Chin N, Sun Y, Hoeft A, Deming Y, Vogt NM, Betthauser TJ, Johnson SC, Asthana S, Kollmorgen G, Suridjan I, Wild N, Zetterberg H, Blennow K, Rey FE, Bendlin BB, Ulland TK (2023) Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study. Scientific reports 13((1)):18924 PMC7366247 · Pubmed · DOI

    Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.

  • Nemet I, Funabashi M, Li XS, Dwidar M, Sangwan N, Skye SM, Romano KA, Cajka T, Needham BD, Mazmanian SK, Hajjar AM, Rey FE, Fiehn O, Tang WHW, Fischbach MA, Hazen SL (2023) Microbe-derived uremic solutes enhance thrombosis potential in the host. mBio 14((6)):e0133123 PMC5075697 · Pubmed · DOI

    p -Cresol sulfate ( p CS) and indoxyl sulfate (IS), gut microbiome-derived metabolites, are traditionally associated with cardiovascular disease (CVD) risks in the setting of impaired kidney function. While pharmacologic provision of p CS or IS can promote pro-thrombotic phenotypes, neither the microbial enzymes involved nor direct gut microbial production have been linked to CVD. Untargeted metabolomics was performed on a discovery cohort ( n = 1,149) with relatively preserved kidney function, followed by stable isotope-dilution mass spectrometry quantification of p CS and IS in an independent validation cohort ( n = 3,954). Genetic engineering of human commensals to produce p -cresol and indole gain-of-function and loss-of-function mutants, followed by colonization of germ-free mice, and studies on host thrombosis were performed. Systemic p CS and IS levels were independently associated with all-cause mortality. Both in vitro and within colonized germ-free mice p -cresol productions were recapitulated by collaboration of two organisms: a Bacteroides strain that converts tyrosine to 4-hydroxyphenylacetate, and a Clostridium strain that decarboxylates 4-hydroxyphenylacetate to p- cresol. We then engineered a single organism, Bacteroides thetaiotaomicron , to produce p- cresol, indole, or both metabolites. Colonizing germ-free mice with engineered strains , we show the gut microbial genes for p- cresol ( hpdBCA ) and indole ( tryptophanase ) are sufficient to confer a pro-thrombotic phenotype in vivo . Moreover, human fecal metagenomics analyses show that abundances of hpdBCA and tryptophanase are associated with CVD. These studies show that p CS and IS, two abundant microbiome-derived metabolites, play a broader potential role in CVD than was previously known. They also suggest that therapeutic targeting of gut microbial p- cresol- and indole-producing pathways represent rational targets for CVD.IMPORTANCEAlterations in gut microbial composition and function have been linked to numerous diseases. Identifying microbial pathways responsible for producing molecules that adversely impact the host is an important first step in the development of therapeutic interventions. Here, we first use large-scale clinical observations to link blood levels of defined microbial products to cardiovascular disease risks. Notably, the previously identified uremic toxins p -cresol sulfate and indoxyl sulfate were shown to predict 5-year mortality risks. After identifying the microbes and microbial enzymes involved in the generation of these uremic toxins, we used bioengineering technologies coupled with colonization of germ-free mice to show that the gut microbial genes that generate p -cresol and indole are sufficient to confer p -cresol sulfate and indoxyl sulfate formation, and a pro-thrombotic phenotype in vivo . The findings and tools developed serve as a critical step in both the study and targeting of these gut microbial pathways in vivo .

  • Chen HC, Liu YW, Chang KC, Wu YW, Chen YM, Chao YK, You MY, Lundy DJ, Lin CJ, Hsieh ML, Cheng YC, Prajnamitra RP, Lin PJ, Ruan SC, Chen DH, Shih ESC, Chen KW, Chang SS, Chang CMC, Puntney R, Moy AW, Cheng YY, Chien HY, Lee JJ, Wu DC, Hwang MJ, Coonen J, Hacker TA, Yen CE, Rey FE, Kamp TJ, Hsieh PCH (2023) Gut butyrate-producers confer post-infarction cardiac protection. Nature communications 14((1)):7249 PMC10683868 · Pubmed · DOI

    The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.

  • McPherson RL, Isabella CR, Walker RL, Sergio D, Bae S, Gaca T, Raman S, Nguyen LTT, Wesener DA, Halim M, Wuo MG, Dugan A, Kerby R, Ghosh S, Rey FE, Dhennezel C, Pishchany G, Lensch V, Vlamakis H, Alm EJ, Xavier RJ, Kiessling LL (2023) Lectin-Seq: A method to profile lectin-microbe interactions in native communities. Science advances 9((30)):eadd8766 PMC167889 · Pubmed · DOI

    Soluble human lectins are critical components of innate immunity. Genetic models suggest that lectins influence host-resident microbiota, but their specificity for commensal and mutualist species is understudied. Elucidating lectins' roles in regulating microbiota requires an understanding of which microbial species they bind within native communities. To profile human lectin recognition, we developed Lectin-Seq. We apply Lectin-Seq to human fecal microbiota using the soluble mannose-binding lectin (MBL) and intelectin-1 (hItln1). Although each lectin binds a substantial percentage of the samples (10 to 20%), the microbial interactomes of MBL and hItln1 differ markedly in composition and diversity. MBL binding is highly selective for a small subset of species commonly associated with humans. In contrast, hItln1's interaction profile encompasses a broad range of lower-abundance species. Our data uncover stark differences in the commensal recognition properties of human lectins.

  • Kasahara K, Kerby RL, Zhang Q, Pradhan M, Mehrabian M, Lusis AJ, Bergström G, Bäckhed F, Rey FE (2023) Gut bacterial metabolism contributes to host global purine homeostasis. Cell host & microbe 31((6)):1038-1053.e10 PMC6883579 · Pubmed · DOI

    The microbes and microbial pathways that influence host inflammatory disease progression remain largely undefined. Here, we show that variation in atherosclerosis burden is partially driven by gut microbiota and is associated with circulating levels of uric acid (UA) in mice and humans. We identify gut bacterial taxa spanning multiple phyla, including Bacillota, Fusobacteriota, and Pseudomonadota, that use multiple purines, including UA as carbon and energy sources anaerobically. We identify a gene cluster that encodes key steps of anaerobic purine degradation and that is widely distributed among gut-dwelling bacteria. Furthermore, we show that colonization of gnotobiotic mice with purine-degrading bacteria modulates levels of UA and other purines in the gut and systemically. Thus, gut microbes are important drivers of host global purine homeostasis and serum UA levels, and gut bacterial catabolism of purines may represent a mechanism by which gut bacteria influence health.

  • Hutchison ER, Kasahara K, Zhang Q, Vivas EI, Cross TL, Rey FE (2023) Dissecting the impact of dietary fiber type on atherosclerosis in mice colonized with different gut microbial communities. NPJ biofilms and microbiomes 9((1)):31 PMC4375400 · Pubmed · DOI

    Dietary fiber consumption has been linked with improved cardiometabolic health, however, human studies have reported large interindividual variations in the observed benefits. We tested whether the effects of dietary fiber on atherosclerosis are influenced by the gut microbiome. We colonized germ-free ApoE mice with fecal samples from three human donors (DonA, DonB, and DonC) and fed them diets supplemented with either a mix of 5 fermentable fibers (FF) or non-fermentable cellulose control (CC) diet. We found that DonA-colonized mice had reduced atherosclerosis burden with FF feeding compared to their CC-fed counterparts, whereas the type of fiber did not affect atherosclerosis in mice colonized with microbiota from the other donors. Microbial shifts associated with FF feeding in DonA mice were characterized by higher relative abundances of butyrate-producing taxa, higher butyrate levels, and enrichment of genes involved in synthesis of B vitamins. Our results suggest that atheroprotection in response to FF is not universal and is influenced by the gut microbiome.

  • Actis Dato V, Paz MC, Rey FE, Sánchez MC, Llorente-Cortés V, Chiabrando GA, Ceschin DG (2023) Transcriptional analysis reveals that the intracellular lipid accumulation impairs gene expression profiles involved in insulin response-associated cardiac functionality. Scientific reports 13((1)):8761 PMC6889727 · Pubmed · DOI

    Cardiovascular disease (CVD) is a multisystemic and multicellular pathology that is generally associated with high levels of atherogenic lipoproteins in circulation. These lipoproteins tend to be retained and modified, for example, aggregated low-density lipoprotein (aggLDL), in the extracellular matrix of different tissues, such as the vascular wall and heart. The uptake of aggLDL generates a significant increase in cholesteryl ester (CE) in these tissues. We previously found that the accumulation of CE generates alterations in the insulin response in the heart. Although the insulin response is mainly associated with the uptake and metabolism of glucose, other studies have shown that insulin would fulfill functions in this tissue, such as regulating the calcium cycle and cardiac contractility. Here, we found that aggLDL induced-lipid accumulation altered the gene expression profile involved in processes essential for cardiac functionality, including insulin response and glucose uptake (Insr, Ins1, Pik3ip1, Slc2a4 gene expression), calcium cycle (Cacna1s and Gjc2 gene expression) and calcium-dependent cardiac contractility (Myh3), and cholesterol efflux (Abca1), in HL-1 cardiomyocytes. These observations were recapitulated using an in vivo model of hypercholesterolemic ApoE-KO mice. Altogether, these results may explain the deleterious effect of lipid accumulation in the myocardium, with important implications for lipid-overloaded associated CVD, including impaired insulin response, disrupted lipid metabolism, altered cardiac structure, and increased susceptibility to cardiovascular events.

  • Dato VA, Paz MC, Rey FE, Sánchez MC, Llorente-Cortés V, Chiabrando GA, Ceschin DG (2023) Transcriptional analysis reveals that the intracellular lipid accumulation impairs gene expression profiles involved in insulin response-associated cardiac functionality. Research square : PMC7779061 · Pubmed · DOI

    Cardiovascular disease (CVD) is a multisystemic and multicellular pathology that is generally associated with high levels of atherogenic lipoproteins in circulation. These lipoproteins tend to be retained and modified, for example, aggregated low-density lipoprotein (aggLDL), in the extracellular matrix of different tissues, such as the vascular wall and heart. The uptake of aggLDL generates a significant increase in cholesteryl ester (CE) in these tissues. We previously found that the accumulation of CE generates alterations in the insulin response in the heart. Although the insulin response is mainly associated with the uptake and metabolism of glucose, other studies have shown that insulin would fulfill functions in this tissue, such as regulating the calcium cycle and cardiac contractility. Here, we found that aggLDL induced-lipid accumulation altered the gene expression profile involved in processes essential for cardiac functionality, including insulin response and glucose uptake ( Insr , Ins1 , Pik3ip1 , Slc2a4 gene expression), calcium cycle ( Cacna1s and Gjc2 gene expression) and calcium-dependent cardiac contractility ( Myh3 ), and cholesterol efflux ( Abca1 ), in HL-1 cardiomyocytes. These observations were recapitulated using an in vivo model of hypercholesterolemic ApoE-KO mice. Altogether, these results may explain the deleterious effect of lipid accumulation in the myocardium, with important implications for lipid-overloaded associated CVD.

  • Zhang Q, Linke V, Overmyer KA, Traeger LL, Kasahara K, Miller IJ, Manson DE, Polaske TJ, Kerby RL, Kemis JH, Trujillo EA, Reddy TR, Russell JD, Schueler KL, Stapleton DS, Rabaglia ME, Seldin M, Gatti DM, Keele GR, Pham DT, Gerdt JP, Vivas EI, Lusis AJ, Keller MP, Churchill GA, Blackwell HE, Broman KW, Attie AD, Coon JJ, Rey FE (2023) Author Correction: Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut. Nature microbiology 8((4)):745 PMC10066032 · Pubmed · DOI

    No abstract available.

  • Zhang Q, Linke V, Overmyer KA, Traeger LL, Kasahara K, Miller IJ, Manson DE, Polaske TJ, Kerby RL, Kemis JH, Trujillo EA, Reddy TR, Russell JD, Schueler KL, Stapleton DS, Rabaglia ME, Seldin M, Gatti DM, Keele GR, Pham DT, Gerdt JP, Vivas EI, Lusis AJ, Keller MP, Churchill GA, Blackwell HE, Broman KW, Attie AD, Coon JJ, Rey FE (2023) Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut. Nature microbiology 8((3)):424-440 PMC2168041 · Pubmed · DOI

    The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.

  • Zarbock KR, Han JH, Singh AP, Thomas SP, Bendlin BB, Denu JM, Yu JJ, Rey FE, Ulland TK (2022) Trimethylamine N-Oxide Reduces Neurite Density and Plaque Intensity in a Murine Model of Alzheimer's Disease. Journal of Alzheimer's disease : JAD 90((2)):585-597 · Pubmed · DOI

    Alzheimer's disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N-oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology.

  • Cao Y, Aquino-Martinez R, Hutchison E, Allayee H, Lusis AJ, Rey FE (2022) Role of gut microbe-derived metabolites in cardiometabolic diseases: Systems based approach. Molecular metabolism 64:101557 PMC7641989 · Pubmed · DOI

    The gut microbiome influences host physiology and cardiometabolic diseases by interacting directly with intestinal cells or by producing molecules that enter the host circulation. Given the large number of microbial species present in the gut and the numerous factors that influence gut bacterial composition, it has been challenging to understand the underlying biological mechanisms that modulate risk of cardiometabolic disease.

  • Özçam M, Oh JH, Tocmo R, Acharya D, Zhang S, Astmann TJ, Heggen M, Ruiz-Ramírez S, Li F, Cheng CC, Vivas E, Rey FE, Claesen J, Bugni TS, Walter J, van Pijkeren JP (2022) A secondary metabolite drives intraspecies antagonism in a gut symbiont that is inhibited by cell-wall acetylation. Cell host & microbe 30((6)):824-835.e6 · Pubmed · DOI

    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.

  • Debédat J, Le Roy T, Voland L, Belda E, Alili R, Adriouch S, Bel Lassen P, Kasahara K, Hutchison E, Genser L, Torres L, Gamblin C, Rouault C, Zucker JD, Kapel N, Poitou C, Marcelin G, Rey FE, Aron-Wisnewsky J, Clément K (2022) The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass. Gut microbes 14((1)):2050635 PMC9037437 · Pubmed · DOI

    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 Phocaeicola dorei, Bacteroides fragilis , and Bacteroides caecimuris . 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.

  • An R, Robbins D, Rey FE, Thibeault SL (2022) Vocal fold mucus layer: Comparison of histological protocols for visualization in mice. Laryngoscope investigative otolaryngology 7((2)):444-453 PMC9008169 · Pubmed · DOI

    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.

  • Thorstenson JC, Heston MB, Zarbock KR, Carlsson CM, Engelman CD, Deming Y, Johnson SC, Ulland TK, Asthana S, Kollmorgen G, Suridjan I, Blennow K, Zetterberg H, Chin NA, Rey FE, Bendlin BB (2022) Diet and APOE as moderators of the relationship between trimethylamine N-oxide and biomarkers of Alzheimer's disease and glial activation. Alzheimer's & dementia : the journal of the Alzheimer's Association 17 Suppl 3:e051827 · Pubmed · DOI

    No abstract available.

  • Feng J, Qian Y, Zhou Z, Ertmer S, Vivas EI, Lan F, Hamilton JJ, Rey FE, Anantharaman K, Venturelli OS (2022) Polysaccharide utilization loci in Bacteroides determine population fitness and community-level interactions. Cell host & microbe 30((2)):200-215.e12 PMC9060796 · Pubmed · DOI

    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.

  • Buffa JA, Romano KA, Copeland MF, Cody DB, Zhu W, Galvez R, Fu X, Ward K, Ferrell M, Dai HJ, Skye S, Hu P, Li L, Parlov M, McMillan A, Wei X, Nemet I, Koeth RA, Li XS, Wang Z, Sangwan N, Hajjar AM, Dwidar M, Weeks TL, Bergeron N, Krauss RM, Tang WHW, Rey FE, DiDonato JA, Gogonea V, Gerberick GF, Garcia-Garcia JC, Hazen SL (2021) The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism. Nature microbiology 7((1)):73-86 PMC8732312 · Pubmed · DOI

    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.

  • Lobo AK, Traeger LL, Keller MP, Attie AD, Rey FE, Broman KW (2021) Identification of sample mix-ups and mixtures in microbiome data in Diversity Outbred mice. G3 (Bethesda, Md.) 11((11)): PMC8527510 · Pubmed · DOI

    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.

  • Lucas LN, Barrett K, Kerby RL, Zhang Q, Cattaneo LE, Stevenson D, Rey FE, Amador-Noguez D (2021) Dominant Bacterial Phyla from the Human Gut Show Widespread Ability To Transform and Conjugate Bile Acids. mSystems :e0080521 · Pubmed · DOI

    Gut bacteria influence human physiology by chemically modifying host-synthesized primary bile acids. These modified bile acids, known as secondary bile acids, can act as signaling molecules that modulate host lipid, glucose, and energy metabolism and affect gut microbiota composition via selective antimicrobial properties. However, knowledge regarding the bile acid-transforming capabilities of individual gut microbes remains limited. To help address this knowledge gap, we screened 72 bacterial isolates, spanning seven major phyla commonly found in the human gut, for their ability to chemically modify unconjugated bile acids. We found that 43 isolates, representing 41 species, were capable of in vitro modification of one or more of the three most abundant unconjugated bile acids in humans: cholic acid, chenodeoxycholic acid, and deoxycholic acid. Of these, 32 species have not been previously described as bile acid transformers. The most prevalent bile acid transformations detected were oxidation of 3α-, 7α-, or 12α-hydroxyl groups on the steroid core, a reaction catalyzed by hydroxysteroid dehydrogenases. In addition, we found 7α-dehydroxylation activity to be distributed across various bacterial genera, and we observed several other complex bile acid transformations. Finally, our screen revealed widespread bacterial conjugation of primary and secondary bile acids to glycine, a process that was thought to only occur in the liver, and to 15 other amino acids, resulting in the discovery of 44 novel microbially conjugated bile acids. IMPORTANCE Our current knowledge regarding microbial bile acid transformations comes primarily from biochemical studies on a relatively small number of species or from bioinformatic predictions that rely on homology to known bile acid-transforming enzyme sequences. Therefore, much remains to be learned regarding the variety of bile acid transformations and their representation across gut microbial species. By carrying out a systematic investigation of bacterial species commonly found in the human intestinal tract, this study helps better define the gut bacteria that impact composition of the bile acid pool, which has implications in the context of metabolic disorders and cancers of the digestive tract. Our results greatly expand upon the list of bacterial species known to perform different types of bile acid transformations. This knowledge will be vital for assessing the causal connections between the microbiome, bile acid pool composition, and human health.

  • Zhu W, Romano KA, Li L, Buffa JA, Sangwan N, Prakash P, Tittle AN, Li XS, Fu X, Androjna C, DiDonato AJ, Brinson K, Trapp BD, Fischbach MA, Rey FE, Hajjar AM, DiDonato JA, Hazen SL (2021) Gut microbes impact stroke severity via the trimethylamine N-oxide pathway. Cell host & microbe 29((7)):1199-1208.e5 PMC8288076 · Pubmed · DOI

    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.

  • Murga-Garrido SM, Hong Q, Cross TL, Hutchison ER, Han J, Thomas SP, Vivas EI, Denu J, Ceschin DG, Tang ZZ, Rey FE (2021) Gut microbiome variation modulates the effects of dietary fiber on host metabolism. Microbiome 9((1)):117 PMC8138933 · Pubmed · DOI

    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.

  • Rodriguez-Castaño GP, Rey FE, Caro-Quintero A, Acosta-González A (2020) Gut-derived Flavonifractor species variants are differentially enriched during in vitro incubation with quercetin. PloS one 15((12)):e0227724 PMC7710108 · Pubmed · DOI

    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.

  • An R, Gowda M, Rey FE, Thibeault SL (2020) Selective Bacterial Colonization of the Murine Larynx in a Gnotobiotic Model. Frontiers in microbiology 11:594617 PMC7676279 · Pubmed · DOI

    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.

  • Sublette MG, Cross TL, Korcarz CE, Hansen KM, Murga-Garrido SM, Hazen SL, Wang Z, Oguss MK, Rey FE, Stein JH (2020) Effects of Smoking and Smoking Cessation on the Intestinal Microbiota. Journal of clinical medicine 9((9)): PMC7564179 · Pubmed · DOI

    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, p = 0.008) and Cyanobacteria correlated with CO levels (rho = 0.39, p = 0.021). After 12 weeks, relative abundances of the phylum Bacteroidetes increased ( p = 0.048) and Firmicutes decreased ( p = 0.036) among abstainers compared to continuing smokers. Increases in alpha-diversity were associated with heart rates (rho = -0.59, p = 0.037), systolic blood pressures (rho = -0.58, p = 0.043), and C-reactive protein (rho = -0.60, p = 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.

  • Liu R, Wei P, Keller C, Orefice NS, Shi Y, Li Z, Huang J, Cui Y, Frost DC, Han S, Cross TL, Rey FE, Li L (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. Analytical chemistry 92((20)):14021-14030 PMC7577927 · Pubmed · DOI

    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 p -value of

  • Keller C, Wei P, Wancewicz B, Cross TL, Rey FE, Li L (2020) Extraction optimization for combined metabolomics, peptidomics, and proteomics analysis of gut microbiota samples. Journal of mass spectrometry : JMS 56((4)):e4625 PMC7855350 · Pubmed · DOI

    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.

  • Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, Funabashi M, Ramer-Tait AE, Naga Prasad SV, Fiehn O, Rey FE, Tang WHW, Fischbach MA, DiDonato JA, Hazen SL (2020) A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. Cell 180((5)):862-877.e22 PMC7402401 · Pubmed · DOI

    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.

  • Kasahara K, Rey FE (2019) The emerging role of gut microbial metabolism on cardiovascular disease. Current opinion in microbiology 50:64-70 · Pubmed · DOI

    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.

  • Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, Schell M, Sandoval-Espinola WJ, Tao J, Sha B, Graham M, Crooke R, Kleinridders A, Balskus EP, Rey FE, Morris AJ, Biddinger SB (2019) Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell metabolism 30((6)):1141-1151.e5 · Pubmed · DOI

    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.

  • Kemis JH, Linke V, Barrett KL, Boehm FJ, Traeger LL, Keller MP, Rabaglia ME, Schueler KL, Stapleton DS, Gatti DM, Churchill GA, Amador-Noguez D, Russell JD, Yandell BS, Broman KW, Coon JJ, Attie AD, Rey FE (2019) Genetic determinants of gut microbiota composition and bile acid profiles in mice. PLoS genetics 15((8)):e1008073 PMC6715156 · Pubmed · DOI

    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.

  • Rodriguez-Castaño GP, Dorris MR, Liu X, Bolling BW, Acosta-Gonzalez A, Rey FE (2019) Bacteroides thetaiotaomicron Starch Utilization Promotes Quercetin Degradation and Butyrate Production by Eubacterium ramulus . Frontiers in microbiology 10:1145 PMC6548854 · Pubmed · DOI

    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 Eubacterium ramulus is dependent on interspecies cross-feeding interactions when starch is the only energy source available. E. ramulus can degrade quercetin in the presence of glucose but is unable to use starch for growth or quercetin degradation. However, the starch-metabolizing bacterium Bacteroides thetaiotaomicron , which does not metabolize quercetin, stimulates degradation of quercetin and butyrate production by E. ramulus 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.

  • Bresciani L, Angelino D, Vivas EI, Kerby RL, García-Viguera C, Del Rio D, Rey FE, Mena P (2019) Differential Catabolism of an Anthocyanin-Rich Elderberry Extract by Three Gut Microbiota Bacterial Species. Journal of agricultural and food chemistry 68((7)):1837-1843 · Pubmed · DOI

    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 ( Enterobacter cancerogenous , Bifidobacterium dentium , and Dorea longicatena ) 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 in vitro 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.

  • Miller IJ, Rees ER, Ross J, Miller I, Baxa J, Lopera J, Kerby RL, Rey FE, Kwan JC (2019) Autometa: automated extraction of microbial genomes from individual shotgun metagenomes. Nucleic acids research 47((10)):e57 PMC6547426 · Pubmed · DOI

    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).

  • Moriano-Gutierrez S, Koch EJ, Bussan H, Romano K, Belcaid M, Rey FE, Ruby EG, McFall-Ngai MJ (2019) Critical symbiont signals drive both local and systemic changes in diel and developmental host gene expression. Proceedings of the National Academy of Sciences of the United States of America 116((16)):7990-7999 PMC6475425 · Pubmed · DOI

    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 Euprymna scolopes and its luminous bacterial partner, Vibrio fischeri , to define the impact of colonization on transcriptomic networks in the host. A night-active predator, E. scolopes 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 V. fischeri -specifically, deletion of the lux 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.

  • Dill-McFarland KA, Tang ZZ, Kemis JH, Kerby RL, Chen G, Palloni A, Sorenson T, Rey FE, Herd P (2019) Close social relationships correlate with human gut microbiota composition. Scientific reports 9((1)):703 PMC6345772 · Pubmed · DOI

    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.

  • Tang TWH, Chen HC, Chen CY, Yen CYT, Lin CJ, Prajnamitra RP, Chen LL, Ruan SC, Lin JH, Lin PJ, Lu HH, Kuo CW, Chang CM, Hall AD, Vivas EI, Shui JW, Chen P, Hacker TA, Rey FE, Kamp TJ, Hsieh PCH (2018) Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair. Circulation 139((5)):647-659 · Pubmed · DOI

    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.

  • Vogt NM, Romano KA, Darst BF, Engelman CD, Johnson SC, Carlsson CM, Asthana S, Blennow K, Zetterberg H, Bendlin BB, Rey FE (2018) The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer's disease. Alzheimer's research & therapy 10((1)):124 PMC6303862 · Pubmed · DOI

    No abstract available.

  • Pei R, Martin DA, Valdez JC, Liu J, Kerby RL, Rey FE, Smyth JA, Liu Z, Bolling BW (2018) Dietary Prevention of Colitis by Aronia Berry is Mediated Through Increased Th17 and Treg. Molecular nutrition & food research 63((5)):e1800985 · Pubmed · DOI

    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.

  • Bratburd JR, Keller C, Vivas E, Gemperline E, Li L, Rey FE, Currie CR (2018) Gut Microbial and Metabolic Responses to Salmonella enterica Serovar Typhimurium and Candida albicans. mBio 9((6)): PMC6222126 · Pubmed · DOI

    No abstract available.

  • Kasahara K, Krautkramer KA, Org E, Romano KA, Kerby RL, Vivas EI, Mehrabian M, Denu JM, Bäckhed F, Lusis AJ, Rey FE (2018) Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nature microbiology 3((12)):1461-1471 PMC6280189 · Pubmed · DOI

    No abstract available.

  • Skye SM, Zhu W, Romano KA, Guo CJ, Wang Z, Jia X, Kirsop J, Haag B, Lang JM, DiDonato JA, Tang WHW, Lusis AJ, Rey FE, Fischbach MA, Hazen SL (2018) Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circulation research 123((10)):1164-1176 PMC6223262 · Pubmed · DOI

    No abstract available.

  • Romano KA, Rey FE (2018) Is maternal microbial metabolism an early-life determinant of health? Lab animal 47((9)):239-243 · Pubmed · DOI

    No abstract available.

  • Cross TL, Kasahara K, Rey FE (2018) Sexual dimorphism of cardiometabolic dysfunction: Gut microbiome in the play? Molecular metabolism 15:70-81 PMC6066746 · Pubmed · DOI

    No abstract available.

  • Yang H, Wang W, Romano KA, Gu M, Sanidad KZ, Kim D, Yang J, Schmidt B, Panigrahy D, Pei R, Martin DA, Ozay EI, Wang Y, Song M, Bolling BW, Xiao H, Minter LM, Yang GY, Liu Z, Rey FE, Zhang G (2018) A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice. Science translational medicine 10((443)): PMC6343133 · Pubmed · DOI

    No abstract available.

  • Romano KA, Dill-McFarland KA, Kasahara K, Kerby RL, Vivas EI, Amador-Noguez D, Herd P, Rey FE (2018) Fecal Aliquot Straw Technique (FAST) allows for easy and reproducible subsampling: assessing interpersonal variation in trimethylamine-N-oxide (TMAO) accumulation. Microbiome 6((1)):91 PMC5960144 · Pubmed · DOI

    No abstract available.

  • Li XS, Wang Z, Cajka T, Buffa JA, Nemet I, Hurd AG, Gu X, Skye SM, Roberts AB, Wu Y, Li L, Shahen CJ, Wagner MA, Hartiala JA, Kerby RL, Romano KA, Han Y, Obeid S, Lüscher TF, Allayee H, Rey FE, DiDonato JA, Fiehn O, Tang WHW, Hazen SL (2018) Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk. JCI insight 3((6)): PMC5926943 · Pubmed · DOI

    No abstract available.

  • Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE (2017) Gut microbiome alterations in Alzheimer's disease. Scientific reports 7((1)):13537 PMC5648830 · Pubmed · DOI

    No abstract available.

  • Romano KA, Martinez-Del Campo A, Kasahara K, Chittim CL, Vivas EI, Amador-Noguez D, Balskus EP, Rey FE (2017) Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption. Cell host & microbe 22((3)):279-290.e7 PMC5599363 · Pubmed · DOI

    No abstract available.

  • Krautkramer KA, Rey FE, Denu JM (2017) Chemical signaling between gut microbiota and host chromatin: What is your gut really saying? The Journal of biological chemistry 292((21)):8582-8593 PMC5448088 · Pubmed · DOI

    No abstract available.

  • Kreznar JH, Keller MP, Traeger LL, Rabaglia ME, Schueler KL, Stapleton DS, Zhao W, Vivas EI, Yandell BS, Broman AT, Hagenbuch B, Attie AD, Rey FE (2017) Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes. Cell reports 18((7)):1739-1750 PMC5325228 · Pubmed · DOI

    No abstract available.

  • Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, Keller MP, Attie AD, Rey FE, Denu JM (2016) Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues. Mol. Cell 64(5):982-992 (PMC5227652) · Pubmed

    Histone-modifying enzymes regulate transcription and are sensitive to availability of endogenous small-molecule metabolites, allowing chromatin to respond to changes in environment. The gut microbiota produces a myriad of metabolites that affect host physiology and susceptibility to disease; however, the underlying molecular events remain largely unknown. Here we demonstrate that microbial colonization regulates global histone acetylation and methylation in multiple host tissues in a diet-dependent manner: consumption of a "Western-type" diet prevents many of the microbiota-dependent chromatin changes that occur in a polysaccharide-rich diet. Finally, we demonstrate that supplementation of germ-free mice with short-chain fatty acids, major products of gut bacterial fermentation, is sufficient to recapitulate chromatin modification states and transcriptional responses associated with colonization. These findings have profound implications for understanding the complex functional interactions between diet, gut microbiota, and host health.

  • Martínez-Del Campo A, Romano KA, Rey FE, Balskus EP (2016) The Plot Thickens: Diet Microbe Interactions May Modulate Thrombosis Risk. Cell Metab. 23(4):573-5 · Pubmed

    Thrombosis plays an important role in cardiovascular disease (CVD). Platelet activation is an essential step in the genesis and propagation of atherothrombotic complications. In a recent publication, Zhu and colleagues report that gut microbe-derived TMAO enhances platelet responsiveness and thrombosis, providing a novel mechanistic connection between microbes and CVD (Zhu et al., 2016).

  • Romano KA, Vivas EI, Amador-Noguez D, Rey FE (2015) Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio 6(2):e02481 (PMC4453578) · Pubmed

    Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans. Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases.

  • Seedorf H, Griffin NW, Ridaura VK, Reyes A, Cheng J, Rey FE, Smith MI, Simon GM, Scheffrahn RH, Woebken D, Spormann AM, Van Treuren W, Ursell LK, Pirrung M, Robbins-Pianka A, Cantarel BL, Lombard V, Henrissat B, Knight R, Gordon JI (2014) Bacteria from diverse habitats colonize and compete in the mouse gut. Cell 159(2):253-66 (PMC4194163) · Pubmed

    To study how microbes establish themselves in a mammalian gut environment, we colonized germ-free mice with microbial communities from human, zebrafish, and termite guts, human skin and tongue, soil, and estuarine microbial mats. Bacteria from these foreign environments colonized and persisted in the mouse gut; their capacity to metabolize dietary and host carbohydrates and bile acids correlated with colonization success. Cohousing mice harboring these xenomicrobiota or a mouse cecal microbiota, along with germ-free "bystanders," revealed the success of particular bacterial taxa in invading guts with established communities and empty gut habitats. Unanticipated patterns of ecological succession were observed; for example, a soil-derived bacterium dominated even in the presence of bacteria from other gut communities (zebrafish and termite), and human-derived bacteria colonized germ-free bystander mice before mouse-derived organisms. This approach can be generalized to address a variety of mechanistic questions about succession, including succession in the context of microbiota-directed therapeutics.

  • Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI (2013) Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341(6150):1241214 (PMC3829625) · Pubmed

    The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the U.S. diet. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes, were transmissible with uncultured fecal communities and with their corresponding fecal bacterial culture collections. Cohousing mice harboring an obese twin's microbiota (Ob) with mice containing the lean co-twin's microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cage mates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota and was diet-dependent. These findings reveal transmissible, rapid, and modifiable effects of diet-by-microbiota interactions.

  • Rey FE, Gonzalez MD, Cheng J, Wu M, Ahern PP, Gordon JI (2013) Metabolic niche of a prominent sulfate-reducing human gut bacterium. Proc. Natl. Acad. Sci. U.S.A. 110(33):13582-7 (PMC3746858) · Pubmed

    Sulfate-reducing bacteria (SRB) colonize the guts of ∼50% of humans. We used genome-wide transposon mutagenesis and insertion-site sequencing, RNA-Seq, plus mass spectrometry to characterize genetic and environmental factors that impact the niche of Desulfovibrio piger, the most common SRB in a surveyed cohort of healthy US adults. Gnotobiotic mice were colonized with an assemblage of sequenced human gut bacterial species with or without D. piger and fed diets with different levels and types of carbohydrates and sulfur sources. Diet was a major determinant of functions expressed by this artificial nine-member community and of the genes that impact D. piger fitness; the latter includes high- and low-affinity systems for using ammonia, a limiting resource for D. piger in mice consuming a polysaccharide-rich diet. Although genes involved in hydrogen consumption and sulfate reduction are necessary for its colonization, varying dietary-free sulfate levels did not significantly alter levels of D. piger, which can obtain sulfate from the host in part via cross-feeding mediated by Bacteroides-encoded sulfatases. Chondroitin sulfate, a common dietary supplement, increased D. piger and H2S levels without compromising gut barrier integrity. A chondroitin sulfate-supplemented diet together with D. piger impacted the assemblage's substrate utilization preferences, allowing consumption of more reduced carbon sources and increasing the abundance of the H2-producing Actinobacterium, Collinsella aerofaciens. Our findings provide genetic and metabolic details of how this H2-consuming SRB shapes the responses of a microbiota to diet ingredients and a framework for examining how individuals lacking D. piger differ from those who harbor it.

  • Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI (2012) Human gut microbiome viewed across age and geography. Nature 486(7402):222-7 (PMC3376388) · Pubmed

    Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.

  • Wei X, Yang Z, Rey FE, Ridaura VK, Davidson NO, Gordon JI, Semenkovich CF (2012) Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin 2. Cell Host Microbe 11(2):140-52 (PMC3285413) · Pubmed

    No abstract available.

  • Faith JJ, McNulty NP, Rey FE, Gordon JI (2011) Predicting a human gut microbiota's response to diet in gnotobiotic mice. Science 333(6038):101-4 (PMC3303606) · Pubmed

    The interrelationships between our diets and the structure and operations of our gut microbial communities are poorly understood. A model community of 10 sequenced human gut bacteria was introduced into gnotobiotic mice, and changes in species abundance and microbial gene expression were measured in response to randomized perturbations of four defined ingredients in the host diet. From the responses, we developed a statistical model that predicted over 60% of the variation in species abundance evoked by diet perturbations, and we were able to identify which factors in the diet best explained changes seen for each community member. The approach is generally applicable, as shown by a follow-up study involving diets containing various mixtures of pureed human baby foods.

  • Hansen EE, Lozupone CA, Rey FE, Wu M, Guruge JL, Narra A, Goodfellow J, Zaneveld JR, McDonald DT, Goodrich JA, Heath AC, Knight R, Gordon JI (2011) Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii, studied in twins. Proc. Natl. Acad. Sci. U.S.A. 108 Suppl :4599-606 (PMC3063581) · Pubmed

    The human gut microbiota harbors three main groups of H(2)-consuming microbes: methanogens including the dominant archaeon, Methanobrevibacter smithii, a polyphyletic group of acetogens, and sulfate-reducing bacteria. Defining their roles in the gut is important for understanding how hydrogen metabolism affects the efficiency of fermentation of dietary components. We quantified methanogens in fecal samples from 40 healthy adult female monozygotic (MZ) and 28 dizygotic (DZ) twin pairs, analyzed bacterial 16S rRNA datasets generated from their fecal samples to identify taxa that co-occur with methanogens, sequenced the genomes of 20 M. smithii strains isolated from families of MZ and DZ twins, and performed RNA-Seq of a subset of strains to identify their responses to varied formate concentrations. The concordance rate for methanogen carriage was significantly higher for MZ versus DZ twin pairs. Co-occurrence analysis revealed 22 bacterial species-level taxa positively correlated with methanogens: all but two were members of the Clostridiales, with several being, or related to, known hydrogen-producing and -consuming bacteria. The M. smithii pan-genome contains 987 genes conserved in all strains, and 1,860 variably represented genes. Strains from MZ and DZ twin pairs had a similar degree of shared genes and SNPs, and were significantly more similar than strains isolated from mothers or members of other families. The 101 adhesin-like proteins (ALPs) in the pan-genome (45 ± 6 per strain) exhibit strain-specific differences in expression and responsiveness to formate. We hypothesize that M. smithii strains use their different repertoires of ALPs to create diversity in their metabolic niches, by allowing them to establish syntrophic relationships with bacterial partners with differing metabolic capabilities and patterns of co-occurrence.

  • Faith JJ, Rey FE, O'Donnell D, Karlsson M, McNulty NP, Kallstrom G, Goodman AL, Gordon JI (2010) Creating and characterizing communities of human gut microbes in gnotobiotic mice. ISME J 4(9):1094-8 (PMC2927777) · Pubmed

    No abstract available.

  • Rey FE, Faith JJ, Bain J, Muehlbauer MJ, Stevens RD, Newgard CB, Gordon JI (2010) Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285(29):22082-90 (PMC2903421) · Pubmed

    Fermenting microbial communities generate hydrogen; its removal through the production of acetate, methane, or hydrogen sulfide modulates the efficiency of energy extraction from available nutrients in many ecosystems. We noted that pathway components for acetogenesis are more abundantly and consistently represented in the gut microbiomes of monozygotic twins and their mothers than components for methanogenesis or sulfate reduction and subsequently analyzed the metabolic potential of two sequenced human gut acetogens, Blautia hydrogenotrophica and Marvinbryantia formatexigens in vitro and in the intestines of gnotobiotic mice harboring a prominent saccharolytic bacterium. To do so, we developed a generally applicable method for multiplex sequencing of expressed microbial mRNAs (microbial RNA-Seq) and, together with mass spectrometry of metabolites, showed that these organisms have distinct patterns of substrate utilization. B. hydrogenotrophica targets aliphatic and aromatic amino acids. It increases the efficiency of fermentation by consuming reducing equivalents, thereby maintaining a high NAD(+)/NADH ratio and boosting acetate production. In contrast, M. formatexigens consumes oligosaccharides, does not impact the redox state of the gut, and boosts the yield of succinate. These findings have strategic implications for those who wish to manipulate the hydrogen economy of gut microbial communities in ways that modulate energy harvest.

  • Rey FE, Harwood CS (2010) FixK, a global regulator of microaerobic growth, controls photosynthesis in Rhodopseudomonas palustris. Mol. Microbiol. 75(4):1007-20 · Pubmed

    Purple non-sulphur phototrophic bacteria (PNSB) are excellent models for analysing the co-ordination of major metabolisms, including oxidative phosphorylation, photophosphorylation, carbon dioxide fixation and nitrogen fixation. In species studied to date, a two-component system called RegBA controls these functions and it has been thought that this redox sensing regulatory system is essential for co-ordinating electron flow and cannot be easily replaced. Here we show that this is not the case for all PNSB and that the oxygen-sensing FixLJ-K system, initially described in rhizobia, controls microaerobic respiration, photophosphorylation and other major metabolic traits in Rhodopseudomonas palustris. A R. palustris fixK mutant grew normally aerobically but was impaired in microaerobic growth. It was also severely impaired in photosynthetic growth. Transcriptome analyses indicated that FixK positively regulates haem and bacteriochlorophyll biosynthesis, cbb3 oxidase and NADH dehydrogenase genes, as well as genes for autotrophy and aromatic compound degradation. Purified FixK interacted with the promoters of a bacteriochlorophyll biosynthesis operon, a bacteriophytochrome-histidine kinase gene and the fnr-type regulatory gene, aadR. A FixK-AadR hierarchy mediates the transition from microaerobic to anaerobic growth. These results underscore that physiologically similar bacteria can use very different regulatory strategies to control common major metabolisms.

  • Rey FE, Harwood CS (2010) FixK, a global regulator of microaerobic growth, controls photosynthesis in Rhodopseudomonas palustris. Mol. Microbiol. : · Pubmed

    No abstract available.

  • Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1(6):6ra14 (PMC2894525) · Pubmed

    Diet and nutritional status are among the most important modifiable determinants of human health. The nutritional value of food is influenced in part by a person's gut microbial community (microbiota) and its component genes (microbiome). Unraveling the interrelations among diet, the structure and operations of the gut microbiota, and nutrient and energy harvest is confounded by variations in human environmental exposures, microbial ecology, and genotype. To help overcome these problems, we created a well-defined, representative animal model of the human gut ecosystem by transplanting fresh or frozen adult human fecal microbial communities into germ-free C57BL/6J mice. Culture-independent metagenomic analysis of the temporal, spatial, and intergenerational patterns of bacterial colonization showed that these humanized mice were stably and heritably colonized and reproduced much of the bacterial diversity of the donor's microbiota. Switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar "Western" diet shifted the structure of the microbiota within a single day, changed the representation of metabolic pathways in the microbiome, and altered microbiome gene expression. Reciprocal transplants involving various combinations of donor and recipient diets revealed that colonization history influences the initial structure of the microbial community but that these effects can be rapidly altered by diet. Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation. Humanized gnotobiotic mice will be useful for conducting proof-of-principle "clinical trials" that test the effects of environmental and genetic factors on the gut microbiota and host physiology. Nearly full-length 16S rRNA gene sequences are deposited in GenBank under the accession numbers GQ491120 to GQ493997.

  • Mahowald MA, Rey FE, Seedorf H, Turnbaugh PJ, Fulton RS, Wollam A, Shah N, Wang C, Magrini V, Wilson RK, Cantarel BL, Coutinho PM, Henrissat B, Crock LW, Russell A, Verberkmoes NC, Hettich RL, Gordon JI (2009) Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc. Natl. Acad. Sci. U.S.A. 106(14):5859-64 (PMC2660063) · Pubmed

    The adult human distal gut microbial community is typically dominated by 2 bacterial phyla (divisions), the Firmicutes and the Bacteroidetes. Little is known about the factors that govern the interactions between their members. Here, we examine the niches of representatives of both phyla in vivo. Finished genome sequences were generated from Eubacterium rectale and E. eligens, which belong to Clostridium Cluster XIVa, one of the most common gut Firmicute clades. Comparison of these and 25 other gut Firmicutes and Bacteroidetes indicated that the Firmicutes possess smaller genomes and a disproportionately smaller number of glycan-degrading enzymes. Germ-free mice were then colonized with E. rectale and/or a prominent human gut Bacteroidetes, Bacteroides thetaiotaomicron, followed by whole-genome transcriptional profiling, high-resolution proteomic analysis, and biochemical assays of microbial-microbial and microbial-host interactions. B. thetaiotaomicron adapts to E. rectale by up-regulating expression of a variety of polysaccharide utilization loci encoding numerous glycoside hydrolases, and by signaling the host to produce mucosal glycans that it, but not E. rectale, can access. E. rectale adapts to B. thetaiotaomicron by decreasing production of its glycan-degrading enzymes, increasing expression of selected amino acid and sugar transporters, and facilitating glycolysis by reducing levels of NADH, in part via generation of butyrate from acetate, which in turn is used by the gut epithelium. This simplified model of the human gut microbiota illustrates niche specialization and functional redundancy within members of its major bacterial phyla, and the importance of host glycans as a nutrient foundation that ensures ecosystem stability.

  • Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI (2008) Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. U.S.A. 105(43):16767-72 (PMC2569967) · Pubmed

    The distal human intestine harbors trillions of microbes that allow us to extract calories from otherwise indigestible dietary polysaccharides. The products of polysaccharide fermentation include short-chain fatty acids that are ligands for Gpr41, a G protein-coupled receptor expressed by a subset of enteroendocrine cells in the gut epithelium. To examine the contribution of Gpr41 to energy balance, we compared Gpr41-/- and Gpr41+/+ mice that were either conventionally-raised with a complete gut microbiota or were reared germ-free and then cocolonized as young adults with two prominent members of the human distal gut microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic archaeon, Methanobrevibacter smithii. Both conventionally-raised and gnotobiotic Gpr41-/- mice colonized with the model fermentative community are significantly leaner and weigh less than their WT (+/+) littermates, despite similar levels of chow consumption. These differences are not evident when germ-free WT and germ-free Gpr41 knockout animals are compared. Functional genomic, biochemical, and physiologic studies of germ-free and cocolonized Gpr41-/- and +/+ littermates disclosed that Gpr41-deficiency is associated with reduced expression of PYY, an enteroendocrine cell-derived hormone that normally inhibits gut motility, increased intestinal transit rate, and reduced harvest of energy (short-chain fatty acids) from the diet. These results reveal that Gpr41 is a regulator of host energy balance through effects that are dependent upon the gut microbiota.

  • Rey FE, Heiniger EK, Harwood CS (2007) Redirection of metabolism for biological hydrogen production. Appl. Environ. Microbiol. 73(5):1665-71 (PMC1828789) · Pubmed

    No abstract available.

  • Gosse JL, Engel BJ, Rey FE, Harwood CS, Scriven LE, Flickinger MC (2007) Hydrogen production by photoreactive nanoporous latex coatings of nongrowing Rhodopseudomonas palustris CGA009. Biotechnol. Prog. 23(1):124-30 · Pubmed

    No abstract available.

  • Rey FE, Oda Y, Harwood CS (2006) Regulation of uptake hydrogenase and effects of hydrogen utilization on gene expression in Rhodopseudomonas palustris. J. Bacteriol. 188(17):6143-52 (PMC1595397) · Pubmed

    Rhodopseudomonas palustris is a purple, facultatively phototrophic bacterium that uses hydrogen gas as an electron donor for carbon dioxide fixation during photoautotrophic growth or for ammonia synthesis during nitrogen fixation. It also uses hydrogen as an electron supplement to enable the complete assimilation of oxidized carbon compounds, such as malate, into cell material during photoheterotrophic growth. The R. palustris genome predicts a membrane-bound nickel-iron uptake hydrogenase and several regulatory proteins to control hydrogenase synthesis. There is also a novel sensor kinase gene (RPA0981) directly adjacent to the hydrogenase gene cluster. Here we show that the R. palustris regulatory sensor hydrogenase HupUV acts in conjunction with the sensor kinase-response regulator protein pair HoxJ-HoxA to activate hydrogenase expression in response to hydrogen gas. Transcriptome analysis indicated that the HupUV-HoxJA regulatory system also controls the expression of genes encoding a predicted dicarboxylic acid transport system, a putative formate transporter, and a glutamine synthetase. RPA0981 had a small effect in repressing hydrogenase synthesis. We also determined that the two-component system RegS-RegR repressed expression of the uptake hydrogenase, probably in response to changes in intracellular redox status. Transcriptome analysis indicated that about 30 genes were differentially expressed in R. palustris cells that utilized hydrogen when growing photoheterotrophically on malate under nitrogen-fixing conditions compared to a mutant strain that lacked uptake hydrogenase. From this it appears that the recycling of reductant in the form of hydrogen does not have extensive nonspecific effects on gene expression in R. palustris.

  • Oda Y, Samanta SK, Rey FE, Wu L, Liu X, Yan T, Zhou J, Harwood CS (2005) Functional genomic analysis of three nitrogenase isozymes in the photosynthetic bacterium Rhodopseudomonas palustris. J. Bacteriol. 187(22):7784-94 (PMC1280311) · Pubmed

    The photosynthetic bacterium Rhodopseudomonas palustris is one of just a few prokaryotes described so far that has vnf and anf genes for alternative vanadium cofactor (V) and iron cofactor (Fe) nitrogenases in addition to nif genes for a molybdenum cofactor (Mo) nitrogenase. Transcriptome data indicated that the 32 genes in the nif gene cluster, but not the anf or vnf genes, were induced in wild-type and Mo nitrogenase-expressing strains grown under nitrogen-fixing conditions in Mo-containing medium. Strains that were unable to express a functional Mo nitrogenase due to mutations in Mo nitrogenase structural genes synthesized functional V and Fe nitrogenases and expressed vnf and anf genes in nitrogen-fixing growth media that contained Mo and V at concentrations far in excess of those that repress alternative nitrogenase gene expression in other bacteria. Thus, not only does R. palustris have multiple enzymatic options for nitrogen fixation, but in contrast to reports on other nitrogen-fixing bacteria, the expression of its alternative nitrogenases is not repressed by transition metals. Between 95 and 295 genes that are not directly associated with nitrogenase synthesis and assembly were induced under nitrogen-fixing conditions, depending on which nitrogenase was being used by R. palustris. Genes for nitrogen acquisition were expressed at particularly high levels during alternative nitrogenase-dependent growth. This suggests that alternative nitrogenase-expressing cells are relatively starved for nitrogen and raises the possibility that fixed nitrogen availability may be the primary signal that controls the synthesis of the V and Fe nitrogenases.

  • Rey FE, Pagano PJ (2002) The reactive adventitia: fibroblast oxidase in vascular function. Arterioscler. Thromb. Vasc. Biol. 22(12):1962-71 · Pubmed

    No abstract available.

  • Rey FE, Li XC, Carretero OA, Garvin JL, Pagano PJ (2002) Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation: role of gp91(phox). Circulation 106(19):2497-502 · Pubmed

    No abstract available.

  • Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ (2001) Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ. Res. 89(5):408-14 · Pubmed

    No abstract available.

  • Cifuentes ME, Rey FE, Carretero OA, Pagano PJ (2000) Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin II-infused mice. Am. J. Physiol. Heart Circ. Physiol. 279(5):H2234-40 · Pubmed

    No abstract available.

  • Hsich E, Segal BH, Pagano PJ, Rey FE, Paigen B, Deleonardis J, Hoyt RF, Holland SM, Finkel T (2000) Vascular effects following homozygous disruption of p47(phox) : An essential component of NADPH oxidase. Circulation 101(11):1234-6 · Pubmed

    No abstract available.