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Almanza-Aguilera E, Martínez-Huélamo M, López-Hernández Y, Guiñón-Fort D, Guadall A, Cruz M, Perez-Cornago A, Rostgaard-Hansen AL, Tjønneland A, Dahm CC, Katzke V, Schulze MB, Masala G, Agnoli C, Tumino R, Ricceri F, Lasheras C, Crous-Bou M, Sánchez MJ, Aizpurua-Atxega A, Guevara M, Tsilidis KK, Chatziioannou AC, Weiderpass E, Travis RC, Wishart DS, Andrés-Lacueva C, Zamora-Ros R. Prediagnostic Plasma Nutrimetabolomics and Prostate Cancer Risk: A Nested Case-Control Analysis Within the EPIC Study. Cancers (Basel) 2024; 16:4116. [PMID: 39682302 PMCID: PMC11639937 DOI: 10.3390/cancers16234116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/29/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
Background and Objective: Nutrimetabolomics may reveal novel insights into early metabolic alterations and the role of dietary exposures on prostate cancer (PCa) risk. We aimed to prospectively investigate the associations between plasma metabolite concentrations and PCa risk, including clinically relevant tumor subtypes. Methods: We used a targeted and large-scale metabolomics approach to analyze plasma samples of 851 matched PCa case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Associations between metabolite concentrations and PCa risk were estimated by multivariate conditional logistic regression analysis. False discovery rate (FDR) was used to control for multiple testing correction. Results: Thirty-one metabolites (predominately derivatives of food intake and microbial metabolism) were associated with overall PCa risk and its clinical subtypes (p < 0.05), but none of the associations exceeded the FDR threshold. The strongest positive and negative associations were for dimethylglycine (OR = 2.13; 95% CI 1.16-3.91) with advanced PCa risk (n = 157) and indole-3-lactic acid (OR = 0.28; 95% CI 0.09-0.87) with fatal PCa risk (n = 57), respectively; however, these associations did not survive correction for multiple testing. Conclusions: The results from the current nutrimetabolomics study suggest that apart from early metabolic deregulations, some biomarkers of food intake might be related to PCa risk, especially advanced and fatal PCa. Further independent and larger studies are needed to validate our results.
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Affiliation(s)
- Enrique Almanza-Aguilera
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (E.A.-A.); (D.G.-F.); (M.C.-B.)
| | - Miriam Martínez-Huélamo
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.M.-H.); (A.G.); (M.C.); (C.A.-L.)
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
| | - Yamilé López-Hernández
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB T6G 1C9, Canada; (Y.L.-H.); (D.S.W.)
- CONAHCyT-Metabolomics and Proteomics Laboratory, Academic Unit of Biological Sciences, Autonomous University of Zacatecas, Zacatecas 98000, Mexico
| | - Daniel Guiñón-Fort
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (E.A.-A.); (D.G.-F.); (M.C.-B.)
| | - Anna Guadall
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.M.-H.); (A.G.); (M.C.); (C.A.-L.)
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
| | - Meryl Cruz
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.M.-H.); (A.G.); (M.C.); (C.A.-L.)
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
| | - Aurora Perez-Cornago
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK (R.C.T.)
| | - Agnetha L. Rostgaard-Hansen
- Danish Cancer Society Research Center, Diet, Cancer and Health, 2100 Copenhagen, Denmark; (A.L.R.-H.); (A.T.)
| | - Anne Tjønneland
- Danish Cancer Society Research Center, Diet, Cancer and Health, 2100 Copenhagen, Denmark; (A.L.R.-H.); (A.T.)
- Department of Public Health, University of Copenhagen, 1353 Copenhagen, Denmark
| | - Christina C. Dahm
- Department of Public Health, Aarhus University, 8000 Aarhus, Denmark;
| | - Verena Katzke
- Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
| | - Matthias B. Schulze
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam Rehbruecke, 14558 Nuthetal, Germany;
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany
| | - Giovanna Masala
- Clinical Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139 Florence, Italy;
| | - Claudia Agnoli
- Department of Research Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, 20133 Milan, Italy;
| | - Rosario Tumino
- Hyblean Association for Epidemiological Research, Associazione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS), 97100 Ragusa, Italy;
| | - Fulvio Ricceri
- Centre for Biostatistics, Epidemiology, and Public Health (C-BEPH, Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, Italy;
| | - Cristina Lasheras
- Department of Functional Biology, Oviedo University, 33003 Oviedo, Spain;
| | - Marta Crous-Bou
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (E.A.-A.); (D.G.-F.); (M.C.-B.)
| | - Maria-Jose Sánchez
- Escuela Andaluza de Salud Pública (EASP), 18011 Granada, Spain;
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain;
| | - Amaia Aizpurua-Atxega
- Sub Directorate for Public Health and Addictions of Gipuzkoa, Ministry of Health of the Basque Government, 20013 San Sebastian, Spain;
- Epidemiology of Chronic and Communicable Diseases Group, Biogipuzkoa (BioDonostia) Health Research Institute, 20014 San Sebastián, Spain
| | - Marcela Guevara
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain;
- Instituto de Salud Pública y Laboral de Navarra, 31003 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
| | - Kostas K. Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary’s Campus, London SW7 2AZ, UK;
| | | | - Elisabete Weiderpass
- International Agency for Research on Cancer (IARC/WHO), 69366 Lyon, France; (A.C.C.); (E.W.)
| | - Ruth C. Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK (R.C.T.)
| | - David S. Wishart
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, AB T6G 1C9, Canada; (Y.L.-H.); (D.S.W.)
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Cristina Andrés-Lacueva
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.M.-H.); (A.G.); (M.C.); (C.A.-L.)
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
| | - Raul Zamora-Ros
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (E.A.-A.); (D.G.-F.); (M.C.-B.)
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
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Li Q, Homilius M, Achilles E, Massey LK, Convey V, Ohlsson Å, Ljungvall I, Häggström J, Boler BV, Steiner P, Day S, MacRae CA, Oyama MA. Metabolic abnormalities and reprogramming in cats with naturally occurring hypertrophic cardiomyopathy. ESC Heart Fail 2024. [PMID: 39499136 DOI: 10.1002/ehf2.15135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/15/2024] [Accepted: 10/05/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND AND AIMS The heart is a metabolic organ rich in mitochondria. The failing heart reprograms to utilize different energy substrates, which increase its oxygen consumption. These adaptive changes contribute to increased oxidative stress. Hypertrophic cardiomyopathy (HCM) is a common heart condition, affecting approximately 15% of the general cat population. Feline HCM shares phenotypical and genotypical similarities with human HCM, but the disease mechanisms for both species are incompletely understood. Our goal was to characterize global changes in metabolome between healthy control cats and cats with different stages of HCM. METHODS Serum samples from 83 cats, the majority (70/83) of which were domestic shorthair and included 23 healthy control cats, 31 and 12 preclinical cats with American College of Veterinary Internal Medicine (ACVIM) stages B1 and B2, respectively, and 17 cats with history of clinical heart failure or arterial thromboembolism (ACVIM stage C), were collected for untargeted metabolomic analysis. Multiple linear regression adjusted for age, sex and body weight was applied to compare between control and across HCM groups. RESULTS Our study identified 1253 metabolites, of which 983 metabolites had known identities. Statistical analysis identified 167 metabolites that were significantly different among groups (adjusted P < 0.1). About half of the differentially identified metabolites were lipids, including glycerophospholipids, sphingolipids and cholesterol. Serum concentrations of free fatty acids, 3-hydroxy fatty acids and acylcarnitines were increased in HCM groups compared with control group. The levels of creatine phosphate and multiple Krebs cycle intermediates, including succinate, aconitate and α-ketoglutarate, also accumulated in the circulation of HCM cats. In addition, serum levels of nicotinamide and tryptophan, precursors for de novo NAD+ biosynthesis, were reduced in HCM groups versus control group. Glutathione metabolism was altered. Serum levels of cystine, the oxidized form of cysteine and cysteine-glutathione disulfide, were elevated in the HCM groups, indicative of heightened oxidative stress. Further, the level of ophthalmate, an endogenous glutathione analog and competitive inhibitor, was increased by more than twofold in HCM groups versus control group. Finally, several uremic toxins, including guanidino compounds and protein bound putrescine, accumulated in the circulation of HCM cats. CONCLUSIONS Our study provided evidence of deranged energy metabolism, altered glutathione homeostasis and impaired renal uremic toxin excretion. Altered lipid metabolism suggested perturbed structure and function of cardiac sarcolemma membrane and lipid signalling.
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Affiliation(s)
- Qinghong Li
- Nestlé Purina Research, St. Louis, Missouri, USA
| | - Max Homilius
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Erin Achilles
- Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Laura K Massey
- Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Victoria Convey
- Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Åsa Ohlsson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Ingrid Ljungvall
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Jens Häggström
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | | | | | - Sharlene Day
- Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Calum A MacRae
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mark A Oyama
- Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Lim J, Hong HG, Huang J, Stolzenberg-Solomon R, Mondul AM, Weinstein SJ, Albanes D. Serum Erythritol and Risk of Overall and Cause-Specific Mortality in a Cohort of Men. Nutrients 2024; 16:3099. [PMID: 39339699 PMCID: PMC11434845 DOI: 10.3390/nu16183099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
Erythritol occurs naturally in some fruits and fermented foods, and has also been used as an artificial sweetener since the 1990s. Although there have been questions and some studies regarding its potential adverse health effects, the association between serum erythritol and long-term mortality has not been evaluated. To examine the association between serum erythritol's biochemical status and risk of overall and cause-specific mortality, a prospective cohort analysis was conducted using participants in the ATBC Study (1985-1993) previously selected for metabolomic sub-studies. The analysis included 4468 participants, among whom 3377 deaths occurred during an average of 19.1 years of follow-up. Serum erythritol was assayed using an untargeted, global, high-resolution, accurate-mass platform of ultra-high-performance liquid and gas chromatography. Cause-specific deaths were identified through Statistics Finland and defined by the International Classification of Diseases. After adjustment for potential confounders, serum erythritol was associated with increased risk of overall mortality (HR = 1.50 [95% CI = 1.17-1.92]). We found a positive association between serum erythritol and cardiovascular disease mortality risk (HR = 1.86 [95% CI = 1.18-2.94]), which was stronger for heart disease mortality than for stroke mortality risk (HR = 3.03 [95% CI = 1.00-9.17] and HR = 2.06 [95% CI = 0.72-5.90], respectively). Cancer mortality risk was also positively associated with erythritol (HR = 1.54 [95% CI = 1.09-2.19]). The serum erythritol-overall mortality risk association was stronger in men ≥ 55 years of age and those with diastolic blood pressure ≥ 88 mm Hg (p for interactions 0.045 and 0.01, respectively). Our study suggests that elevated serum erythritol is associated with increased risk of overall, cardiovascular disease, and cancer mortality. Additional studies clarifying the role of endogenous production and dietary/beverage intake of erythritol in human health and mortality are warranted.
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Affiliation(s)
- Jungeun Lim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Epidemiology and Community Health Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hyokyoung G Hong
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jiaqi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Rachael Stolzenberg-Solomon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alison M Mondul
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Andreu‐Sánchez S, Ahmad S, Kurilshikov A, Beekman M, Ghanbari M, van Faassen M, van den Munckhof ICL, Steur M, Harms A, Hankemeier T, Ikram MA, Kavousi M, Voortman T, Kraaij R, Netea MG, Rutten JHW, Riksen NP, Zhernakova A, Kuipers F, Slagboom PE, van Duijn CM, Fu J, Vojinovic D. Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level. IMETA 2024; 3:e183. [PMID: 38898991 PMCID: PMC11183189 DOI: 10.1002/imt2.183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 06/21/2024]
Abstract
Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.
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Affiliation(s)
- Sergio Andreu‐Sánchez
- Department of Genetics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Pediatrics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Shahzad Ahmad
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
- Metabolomics & Analytics Centre, Leiden Academic Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - Alexander Kurilshikov
- Department of Genetics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Marian Beekman
- Molecular Epidemiology, Department of Biomedical Data SciencesLeiden University Medical CenterLeidenThe Netherlands
| | - Mohsen Ghanbari
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Martijn van Faassen
- Department of Laboratory Medicine, University Medical Center GroningenUniversity of GroningenGroningenThe Netherland
| | - Inge C. L. van den Munckhof
- Department of Internal Medicine and Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - Marinka Steur
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Amy Harms
- Metabolomics & Analytics Centre, Leiden Academic Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - Thomas Hankemeier
- Metabolomics & Analytics Centre, Leiden Academic Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
| | - M. Arfan Ikram
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Maryam Kavousi
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Trudy Voortman
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Robert Kraaij
- Department of Internal MedicineErasmus University Medical CenterRotterdamThe Netherlands
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - Joost H. W. Rutten
- Department of Internal Medicine and Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - Niels P. Riksen
- Department of Internal Medicine and Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Laboratory Medicine, University Medical Center GroningenUniversity of GroningenGroningenThe Netherland
- European Institute for the Biology of Ageing, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - P. Eline Slagboom
- Molecular Epidemiology, Department of Biomedical Data SciencesLeiden University Medical CenterLeidenThe Netherlands
| | | | - Jingyuan Fu
- Department of Genetics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Pediatrics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Dina Vojinovic
- Department of EpidemiologyErasmus University Medical CenterRotterdamThe Netherlands
- Molecular Epidemiology, Department of Biomedical Data SciencesLeiden University Medical CenterLeidenThe Netherlands
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Wang M, Tang WW, Li XS, de Oliveira Otto MC, Lee Y, Lemaitre RN, Fretts A, Nemet I, Sotoodehnia N, Sitlani CM, Budoff M, DiDonato JA, Wang Z, Bansal N, Shlipak MG, Psaty BM, Siscovick DS, Sarnak MJ, Mozaffarian D, Hazen SL. The Gut Microbial Metabolite Trimethylamine N -oxide, Incident CKD, and Kidney Function Decline. J Am Soc Nephrol 2024; 35:749-760. [PMID: 38593157 PMCID: PMC11164118 DOI: 10.1681/asn.0000000000000344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/01/2024] [Indexed: 04/11/2024] Open
Abstract
Key Points In community-based US adults, higher plasma trimethylamine N -oxide levels associated with higher risk of incident CKD and greater rate of kidney function decline. Findings from our study support future clinical trials to examine whether lowering plasma trimethylamine N -oxide levels may prevent CKD development and progression. Background Trimethylamine N -oxide (TMAO) is a gut microbiota–derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline. Methods We included 10,564 participants from two community-based, prospective cohorts with eGFR ≥60 ml/min per 1.73 m2 to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and cystatin C were measured up to four times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline ≥30% from baseline and a resulting eGFR <60 ml/min per 1.73 m2. Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels. Results During a median follow-up of 9.4 years (interquartile range, 9.1–11.6 years), 979 incident CKD events occurred. Higher TMAO levels were associated with higher risk of incident CKD (second to fifth versus first quintile hazard ratio [95% confidence interval]=1.65 [1.22 to 2.23], 1.68 [1.26 to 2.25], 2.28 [1.72 to 3.02], and 2.24 [1.68 to 2.98], respectively) and greater annualized eGFR decline (second to fifth versus first quintile annualized eGFR change=−0.21 [−0.32 to −0.09], −0.17 [−0.29 to −0.05], −0.35 [−0.47 to −0.22], and −0.43 [−0.56 to −0.30] ml/min per 1.73 m2, respectively) with monotonic dose–response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors, including diabetes, per 10 mm Hg of higher systolic BP, per 10 years of older age, and Black race. Conclusions In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.
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Affiliation(s)
- Meng Wang
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
| | - W.H. Wilson Tang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, Ohio
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio
| | - Xinmin S. Li
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, Ohio
| | - Marcia C. de Oliveira Otto
- Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Houston, Texas
| | - Yujin Lee
- Department of Food and Nutrition, Myongji University, Yongin, South Korea
| | - Rozenn N. Lemaitre
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Amanda Fretts
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
- Department of Epidemiology, University of Washington, Seattle, Washington
| | - Ina Nemet
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, Ohio
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Colleen M. Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Matthew Budoff
- Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California
| | - Joseph A. DiDonato
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, Ohio
| | - Zeneng Wang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, Ohio
| | - Nisha Bansal
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
| | - Michael G. Shlipak
- Kidney Health Research Collaborative and Department of Medicine, San Francisco Veterans Administration Medical Center and University of California–San Francisco, San Francisco, California
| | - Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
- Department of Epidemiology, University of Washington, Seattle, Washington
- Department of Health Systems and Population Health, University of Washington, Seattle, Washington
| | | | - Mark J. Sarnak
- Department of Medicine (Nephrology), Tufts University School of Medicine, Boston, Massachusetts
| | - Dariush Mozaffarian
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts
| | - Stanley L. Hazen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, Ohio
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland, Ohio
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio
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Toh DWK, Fu AS, Mehta KA, Lam NYL, Haldar S, Henry CJ. Plant-Based Meat Analogs and Their Effects on Cardiometabolic Health: An 8-Week Randomized Controlled Trial Comparing Plant-Based Meat Analogs With Their Corresponding Animal-Based Foods. Am J Clin Nutr 2024; 119:1405-1416. [PMID: 38599522 DOI: 10.1016/j.ajcnut.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/25/2024] [Accepted: 04/02/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND With the growing popularity of plant-based meat analogs (PBMAs), an investigation of their effects on health is warranted in an Asian population. OBJECTIVES This research investigated the impact of consuming an omnivorous animal-based meat diet (ABMD) compared with a PBMAs diet (PBMD) on cardiometabolic health among adults with elevated risk of diabetes in Singapore. METHODS In an 8-wk parallel design randomized controlled trial, participants (n = 89) were instructed to substitute habitual protein-rich foods with fixed quantities of either PBMAs (n = 44) or their corresponding animal-based meats (n = 45; 2.5 servings/d), maintaining intake of other dietary components. Low-density lipoprotein (LDL) cholesterol served as primary outcome, whereas secondary outcomes included other cardiometabolic disease-related risk factors (e.g. glucose and fructosamine), dietary data, and within a subpopulation, ambulatory blood pressure measurements (n = 40) at baseline and postintervention, as well as a 14-d continuous glucose monitor (glucose homeostasis-related outcomes; n = 37). RESULTS Data from 82 participants (ABMD: 42 and PBMD: 40) were examined. Using linear mixed-effects model, there were significant interaction (time × treatment) effects for dietary trans-fat (increased in ABMD), dietary fiber, sodium, and potassium (all increased in PBMD; P-interaction <0.001). There were no significant effects on the lipid-lipoprotein profile, including LDL cholesterol. Diastolic blood pressure (DBP) was lower in the PBMD group (P-interaction=0.041), although the nocturnal DBP dip markedly increased in ABMD (+3.2% mean) and was reduced in PBMD (-2.6%; P-interaction=0.017). Fructosamine (P time=0.035) and homeostatic model assessment for β-cell function were improved at week 8 (P time=0.006) in both groups. Glycemic homeostasis was better regulated in the ABMD than PBMD groups as evidenced by interstitial glucose time in range (ABMD median: 94.1% (Q1:87.2%, Q3:96.7%); PBMD: 86.5% (81.7%, 89.4%); P = 0.041). The intervention had no significant effect on the other outcomes examined. CONCLUSIONS An 8-wk PBMA diet did not show widespread cardiometabolic health benefits compared with a corresponding meat based diet. Nutritional quality is a key factor to be considered for next generation PBMAs. This trial was registered at https://clinicaltrials.gov/as NCT05446753.
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Affiliation(s)
- Darel Wee Kiat Toh
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore.
| | - Amanda Simin Fu
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore
| | - Kervyn Ajay Mehta
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore
| | - Nicole Yi Lin Lam
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore
| | - Sumanto Haldar
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore; Faculty of Health and Social Sciences, Bournemouth University, Bournemouth, United Kingdom
| | - Christiani Jeyakumar Henry
- Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A∗STAR), Singapore, Republic of Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore
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7
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Huang Y, Wu Y, Zhang Y, Bai H, Peng R, Ruan W, Zhang Q, Cai E, Ma M, Zhao Y, Lu Y, Zheng L. Dynamic Changes in Gut Microbiota-Derived Metabolite Trimethylamine-N-Oxide and Risk of Type 2 Diabetes Mellitus: Potential for Dietary Changes in Diabetes Prevention. Nutrients 2024; 16:1711. [PMID: 38892643 PMCID: PMC11174887 DOI: 10.3390/nu16111711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/16/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. METHODS Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. RESULTS During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). CONCLUSION Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.
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Affiliation(s)
- Yuliang Huang
- Department of Acute Communicable Diseases Control and Prevention, Huangpu District Center for Disease Control and Prevention, Shanghai 200023, China;
| | - Yani Wu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Y.W.); (H.B.); (R.P.)
| | - Yao Zhang
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, China;
| | - He Bai
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Y.W.); (H.B.); (R.P.)
| | - Ruiheng Peng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Y.W.); (H.B.); (R.P.)
| | - Wenli Ruan
- Department of Physical and Chemical, Changning District Center for Disease Control and Prevention, Shanghai 200051, China; (W.R.); (E.C.)
| | - Qianlong Zhang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;
| | - Enmao Cai
- Department of Physical and Chemical, Changning District Center for Disease Control and Prevention, Shanghai 200051, China; (W.R.); (E.C.)
| | - Mingfeng Ma
- Department of Cardiovascular Medicine, Fenyang Hospital, Shanxi Medical University, Fenyang 032200, China;
| | - Yueyang Zhao
- Library, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Ying Lu
- Department of Physical and Chemical, Changning District Center for Disease Control and Prevention, Shanghai 200051, China; (W.R.); (E.C.)
| | - Liqiang Zheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (Y.W.); (H.B.); (R.P.)
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;
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Dolkar P, Deyang T, Anand N, Rathipriya AG, Hediyal TA, Chandrasekaran V, Krishnamoorthy NK, Gorantla VR, Bishir M, Rashan L, Chang SL, Sakharkar MK, Yang J, Chidambaram SB. Trimethylamine-N-oxide and cerebral stroke risk: A review. Neurobiol Dis 2024; 192:106423. [PMID: 38286388 DOI: 10.1016/j.nbd.2024.106423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 01/31/2024] Open
Abstract
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono‑oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications.
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Affiliation(s)
- Phurbu Dolkar
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Tenzin Deyang
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Nikhilesh Anand
- Department of Pharmacology, American University of Antigua, College of Medicine, Saint John's, Po Box W-1451, Antigua and Barbuda
| | | | - Tousif Ahmed Hediyal
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Vichitra Chandrasekaran
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Naveen Kumar Krishnamoorthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Vasavi Rakesh Gorantla
- Department of Biomedical sciences, Research Faculty, West Virginia School of Osteopathic Medicine, Lewisburg, WV 24901, USA
| | - Muhammed Bishir
- Institute of NeuroImmune Pharmacology and Department of Biological Sciences, Seton Hall University, South Orange, New Jersey 07079, USA
| | - Luay Rashan
- Biodiversity Research Centre, Dohfar University, Salalah, Sultanate of Oman
| | - Sulie L Chang
- Institute of NeuroImmune Pharmacology and Department of Biological Sciences, Seton Hall University, South Orange, New Jersey 07079, USA
| | - Meena Kishore Sakharkar
- Drug discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Jian Yang
- Drug discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
| | - Saravana Babu Chidambaram
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India.
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Ghosh A, Muley A, Ainapure AS, Deshmane AR, Mahajan A. Exploring the Impact of Optimized Probiotic Supplementation Techniques on Diabetic Nephropathy: Mechanisms and Therapeutic Potential. Cureus 2024; 16:e55149. [PMID: 38558739 PMCID: PMC10979819 DOI: 10.7759/cureus.55149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Worldwide, diabetic nephropathy (DN) is a significant contributor to end-stage renal failure and chronic kidney disease. Probiotic supplementation has recently gained popularity as a potential nutritional therapy in several clinical trials aimed at improving renal function, inflammation, oxidative stress, dyslipidemia, glycemic control, and inflammation. However, they still need to undergo a thorough assessment of DN. It is crucial that the optimal dosage, duration, and combination of probiotic strains administered for the purpose of slowing down the advancement of DN be assessed. Based on the available publications, including relevant randomized controlled trials, systematic reviews, and meta-analysis from 2013-2023 from search engines like MEDLINE (PubMed), Scopus, and Web of Science, a literature review was generated using the keywords "gut microbiota," "gut microbiome," "diabetic kidney disease," "diabetic nephropathy," "probiotic," and "prebiotic." Multiple clinical trials focusing on probiotic administration techniques revealed changes in renal, glucose, and lipid biomarkers. Probiotic supplementation using Bifidobacterium bifidum, Lactobacillus acidophilus, and Streptococcus thermophilus for 12 weeks indicated a reduction in glycosylated hemoglobin, fasting blood glucose, and the microalbuminuria/creatinine ratio. Multispecies as well as single-species probiotic administration containing Lactobacillus, Bifidobacterium, and Streptococcus thermophilus spp. greater than 4*109 colony forming units (CFU)/day for 8-12 weeks in DN patients improves renal metabolic markers and reduces the progression of disease patterns. Optimal supplementation techniques of probiotics in conjunction with prebiotics and synbiotics in DN benefit glycaemic control, renal function, blood lipid profile, inflammation, and oxidative stress. Future randomized controlled trials supplementing specific probiotics coupled with prebiotics and synbiotics, with larger sample sizes and longer follow-up times, will generate more reliable findings for the impact of probiotic supplementation on DN.
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Affiliation(s)
- Anindita Ghosh
- Nutrition and Dietetics, Symbiosis Institute of Health Sciences, Symbiosis International (Deemed University), Pune, IND
- Beauty Wellness and Nutrition, Symbiosis Skills and Professional University, Pune, IND
| | - Arti Muley
- Nutrition and Dietetics, Symbiosis Institute of Health Sciences, Symbiosis International (Deemed University), Pune, IND
| | - Archana S Ainapure
- Beauty Wellness and Nutrition, Symbiosis Skills and Professional University, Pune, IND
| | - Aditi R Deshmane
- Clinical Nutrition, Indian Institute of Food Science and Technology, Aurangabad, IND
- Nutrition and Dietetics, Symbiosis Institute of Health Sciences, Symbiosis International (Deemed University), Pune, IND
| | - Anu Mahajan
- Nutrition and Dietetics, Symbiosis Institute of Health Sciences, Symbiosis International (Deemed University), Pune, IND
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Prince N, Liang D, Tan Y, Alshawabkeh A, Angel EE, Busgang SA, Chu SH, Cordero JF, Curtin P, Dunlop AL, Gilbert-Diamond D, Giulivi C, Hoen AG, Karagas MR, Kirchner D, Litonjua AA, Manjourides J, McRitchie S, Meeker JD, Pathmasiri W, Perng W, Schmidt RJ, Watkins DJ, Weiss ST, Zens MS, Zhu Y, Lasky-Su JA, Kelly RS. Metabolomic data presents challenges for epidemiological meta-analysis: a case study of childhood body mass index from the ECHO consortium. Metabolomics 2024; 20:16. [PMID: 38267770 PMCID: PMC11099615 DOI: 10.1007/s11306-023-02082-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 12/12/2023] [Indexed: 01/26/2024]
Abstract
INTRODUCTION Meta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility. OBJECTIVE The objective of this study was to identify maternal blood metabolites during pregnancy (> 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework. METHODS We used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother-child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini-Hochberg procedure. RESULTS Only 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P < 0.05) with offspring BMI z-scores at age 2 years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10-3), guanidinoacetate (Coefmeta = - 0.28 [- 0.54, - 0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = - 0.18 [- 0.33, - 0.04], Pmeta = 0.011), serine (Coefmeta = - 0.18 [- 0.36, - 0.01], Pmeta = 0.034), and lysine (Coefmeta = - 0.16 [- 0.32, - 0.01], Pmeta = 0.044). No associations were robust to multiple testing correction. CONCLUSIONS Despite including three cohorts with large sample sizes (N > 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology.
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Affiliation(s)
- Nicole Prince
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Donghai Liang
- Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA
| | - Youran Tan
- Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA
| | - Akram Alshawabkeh
- Department of Civil and Environmental Engineering, Northeastern University, Boston, MA, USA
| | - Elizabeth Esther Angel
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, 95616, USA
| | - Stefanie A Busgang
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Su H Chu
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - José F Cordero
- Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA
| | - Paul Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Anne L Dunlop
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Diane Gilbert-Diamond
- Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA
- Department of Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA
- Department of Pediatrics, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, 95616, USA
| | - Anne G Hoen
- Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA
| | - Margaret R Karagas
- Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA
| | - David Kirchner
- Department of Nutrition, Gillings School of Global Public Health, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA
| | - Augusto A Litonjua
- Division of Pediatric Pulmonary Medicine, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Susan McRitchie
- Department of Nutrition, Gillings School of Global Public Health, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA
| | - John D Meeker
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Wimal Pathmasiri
- Department of Nutrition, Gillings School of Global Public Health, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA
| | - Wei Perng
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rebecca J Schmidt
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, 95616, USA
- MIND Institute, School of Medicine, University of California Davis, Davis, CA, 95616, USA
| | - Deborah J Watkins
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Michael S Zens
- Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon, NH, USA
| | - Yeyi Zhu
- Kaiser Permanente Northern California Division of Research, Oakland, CA, USA
| | - Jessica A Lasky-Su
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Rachel S Kelly
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.
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Yuan L, Li Y, Chen M, Xue L, Wang J, Ding Y, Gu Q, Zhang J, Zhao H, Xie X, Wu Q. Therapeutic applications of gut microbes in cardiometabolic diseases: current state and perspectives. Appl Microbiol Biotechnol 2024; 108:156. [PMID: 38244075 PMCID: PMC10799778 DOI: 10.1007/s00253-024-13007-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 12/21/2023] [Accepted: 01/08/2024] [Indexed: 01/22/2024]
Abstract
Cardiometabolic disease (CMD) encompasses a range of diseases such as hypertension, atherosclerosis, heart failure, obesity, and type 2 diabetes. Recent findings about CMD's interaction with gut microbiota have broadened our understanding of how diet and nutrition drive microbes to influence CMD. However, the translation of basic research into the clinic has not been smooth, and dietary nutrition and probiotic supplementation have yet to show significant evidence of the therapeutic benefits of CMD. In addition, the published reviews do not suggest the core microbiota or metabolite classes that influence CMD, and systematically elucidate the causal relationship between host disease phenotypes-microbiome. The aim of this review is to highlight the complex interaction of the gut microbiota and their metabolites with CMD progression and to further centralize and conceptualize the mechanisms of action between microbial and host disease phenotypes. We also discuss the potential of targeting modulations of gut microbes and metabolites as new targets for prevention and treatment of CMD, including the use of emerging technologies such as fecal microbiota transplantation and nanomedicine. KEY POINTS: • To highlight the complex interaction of the gut microbiota and their metabolites with CMD progression and to further centralize and conceptualize the mechanisms of action between microbial and host disease phenotypes. • We also discuss the potential of targeting modulations of gut microbes and metabolites as new targets for prevention and treatment of CMD, including the use of emerging technologies such as FMT and nanomedicine. • Our study provides insight into identification-specific microbiomes and metabolites involved in CMD, and microbial-host changes and physiological factors as disease phenotypes develop, which will help to map the microbiome individually and capture pathogenic mechanisms as a whole.
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Affiliation(s)
- Lin Yuan
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, China
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Ying Li
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Moutong Chen
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Liang Xue
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Juan Wang
- College of Food Science, South China Agricultural University, Guangzhou, 510642, China
| | - Yu Ding
- Department of Food Science and Engineering, Institute of Food Safety and Nutrition, College of Science & Engineering, Jinan University, Guangzhou, 510632, China
| | - Qihui Gu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Jumei Zhang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Hui Zhao
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China
| | - Xinqiang Xie
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China.
| | - Qingping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, Guangdong Academy of Sciences, Guangzhou, 510070, China.
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Shea JW, Jacobs DR, Howard AG, Lulla A, Lloyd-Jones DM, Murthy VL, Shah RV, Trujillo-Gonzalez I, Gordon-Larsen P, Meyer KA. Choline metabolites and incident cardiovascular disease in a prospective cohort of adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Clin Nutr 2024; 119:29-38. [PMID: 37865185 PMCID: PMC10808833 DOI: 10.1016/j.ajcnut.2023.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/06/2023] [Accepted: 10/16/2023] [Indexed: 10/23/2023] Open
Abstract
BACKGROUND The potential role for choline metabolite trimethylamine N-oxide (TMAO) in cardiovascular disease (CVD) has garnered much attention, but there have been limited data from diverse population-based cohorts. Furthermore, few studies have included circulating choline and betaine, which can serve as precursors to TMAO and may independently influence CVD. OBJECTIVE We quantified prospective associations between 3 choline metabolites and 19-y incident CVD in a population-based cohort and tested effect modification of metabolite-CVD associations by kidney function. METHODS Data were from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort with recruitment from 4 US urban centers (year 0: 1985-1986, n = 5115, ages 18-30). The analytic sample included 3444 White and Black males and females, aged 33 to 45, who attended the year 15 follow-up exam and did not have prevalent CVD. TMAO, choline, and betaine were quantitated from stored plasma (-70°C) using liquid-chromatography mass-spectrometry. Nineteen-year incident CVD events (n = 221), including coronary heart disease and stroke, were identified through adjudicated hospitalization records and linkage with the National Death Register. RESULTS Plasma choline was positively associated with CVD in Cox proportional hazards regression analysis adjusted for demographics, health behaviors, CVD risk factors, and metabolites (hazard ratio: 1.24; 95% CI: 1.09, 1.40 per standard deviation-unit choline). TMAO and betaine were not associated with CVD in an identically adjusted analysis. There was statistical evidence for effect modification by kidney function with CVD positively associated with TMAO and negatively associated with betaine at lower values of estimated glomerular filtration rate (interaction P values: 0.0046 and 0.020, respectively). CONCLUSIONS Our findings are consistent with a positive association between plasma choline and incident CVD. Among participants with lower kidney function, TMAO was positively, and betaine negatively, associated with CVD. These results further our understanding of the potential role for choline metabolism on CVD risk.
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Affiliation(s)
- Jonathan W Shea
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC, United States
| | - David R Jacobs
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States
| | - Annie Green Howard
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States; Carolina Population Center, University of North Carolina, Chapel Hill, NC, United States
| | - Anju Lulla
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC, United States
| | - Donald M Lloyd-Jones
- Department of Preventive Medicine, Northwestern University, Chicago, IL, United States
| | - Venkatesh L Murthy
- Department of Medicine and Radiology, University of Michigan, Ann Arbor, MI, United States
| | - Ravi V Shah
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Isis Trujillo-Gonzalez
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC, United States; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
| | - Penny Gordon-Larsen
- Carolina Population Center, University of North Carolina, Chapel Hill, NC, United States; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
| | - Katie A Meyer
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC, United States; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States.
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13
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Wang AYM, Mallamaci F, Zoccali C. What is central to renal nutrition: protein or sodium intake? Clin Kidney J 2023; 16:1824-1833. [PMID: 37915942 PMCID: PMC10616450 DOI: 10.1093/ckj/sfad151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Indexed: 11/03/2023] Open
Abstract
Historically, nutrition intervention has been primarily focused on limiting kidney injury, reducing generation of uraemic metabolites, as well as maintaining nutrition status and preventing protein-energy wasting in patients with chronic kidney disease (CKD). This forms an important rationale for prescribing restricted protein diet and restricted salt diet in patients with CKD. However, evidence supporting a specific protein intake threshold or salt intake threshold remains far from compelling. Some international or national guidelines organizations have provided strong or 'level 1' recommendations for restricted protein diet and restricted salt diet in CKD. However, it is uncertain whether salt or protein restriction plays a more central role in renal nutrition management. A key challenge in successful implementation or wide acceptance of a restricted protein diet and a restricted salt diet is patients' long-term dietary adherence. These challenges also explain the practical difficulties in conducting randomized trials that evaluate the impact of dietary therapy on patients' outcomes. It is increasingly recognized that successful implementation of a restricted dietary prescription or nutrition intervention requires a highly personalized, holistic care approach with support and input from a dedicated multidisciplinary team that provides regular support, counselling and close monitoring of patients. With the advent of novel drug therapies for CKD management such as sodium-glucose cotransporter-2 inhibitors or non-steroidal mineralocorticoid receptor antagonist, it is uncertain whether restricted protein diet and restricted salt diet may still be necessary and have incremental benefits. Powered randomized controlled trials with novel design are clearly indicated to inform clinical practice on recommended dietary protein and salt intake threshold for CKD in this new era.
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Affiliation(s)
- Angela Yee-Moon Wang
- University Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, SAR, China
| | - Francesca Mallamaci
- Nefrologia and CNR Unit, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renal (IPNET), Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
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14
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Witkowska AM, Salem JE. Pharmacological and Nutritional Modulation of Metabolome and Metagenome in Cardiometabolic Disorders. Biomolecules 2023; 13:1340. [PMID: 37759740 PMCID: PMC10526920 DOI: 10.3390/biom13091340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Cardiometabolic disorders are major causes of morbidity and mortality worldwide. A growing body of research indicates that the gut microbiota, whether it interacts favorably or not, plays an important role in host metabolism. Elucidating metabolic pathways may be crucial in preventing and treating cardiometabolic diseases, and omics methods are key to studying the interaction between the fecal microbiota and host metabolism. This review summarizes available studies that combine metabolomic and metagenomic approaches to describe the effects of drugs, diet, nutrients, and specific foods on cardiometabolic health and to identify potential targets for future research.
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Affiliation(s)
- Anna Maria Witkowska
- Department of Food Biotechnology, Faculty of Health Sciences, Medical University of Bialystok, Szpitalna 37, 15-295 Białystok, Poland
| | - Joe-Elie Salem
- Department of Pharmacology, Pitié-Salpêtrière Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center (CIC-1901), Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, 75013 Paris, France;
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15
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Yu CT, Farhat Z, Livinski AA, Loftfield E, Zanetti KA. Characteristics of Cancer Epidemiology Studies That Employ Metabolomics: A Scoping Review. Cancer Epidemiol Biomarkers Prev 2023; 32:1130-1145. [PMID: 37410086 PMCID: PMC10472112 DOI: 10.1158/1055-9965.epi-23-0045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 04/26/2023] [Accepted: 06/28/2023] [Indexed: 07/07/2023] Open
Abstract
An increasing number of cancer epidemiology studies use metabolomics assays. This scoping review characterizes trends in the literature in terms of study design, population characteristics, and metabolomics approaches and identifies opportunities for future growth and improvement. We searched PubMed/MEDLINE, Embase, Scopus, and Web of Science: Core Collection databases and included research articles that used metabolomics to primarily study cancer, contained a minimum of 100 cases in each main analysis stratum, used an epidemiologic study design, and were published in English from 1998 to June 2021. A total of 2,048 articles were screened, of which 314 full texts were further assessed resulting in 77 included articles. The most well-studied cancers were colorectal (19.5%), prostate (19.5%), and breast (19.5%). Most studies used a nested case-control design to estimate associations between individual metabolites and cancer risk and a liquid chromatography-tandem mass spectrometry untargeted or semi-targeted approach to measure metabolites in blood. Studies were geographically diverse, including countries in Asia, Europe, and North America; 27.3% of studies reported on participant race, the majority reporting White participants. Most studies (70.2%) included fewer than 300 cancer cases in their main analysis. This scoping review identified key areas for improvement, including needs for standardized race and ethnicity reporting, more diverse study populations, and larger studies.
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Affiliation(s)
- Catherine T. Yu
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland
| | - Zeinab Farhat
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Alicia A. Livinski
- National Institutes of Health Library, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, Maryland
| | - Erikka Loftfield
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Krista A. Zanetti
- Office of Nutrition Research, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the Director, National Institutes of Health, Bethesda, Maryland
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16
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Tate BN, Van Guilder GP, Aly M, Spence LA, Diaz-Rubio ME, Le HH, Johnson EL, McFadden JW, Perry CA. Changes in Choline Metabolites and Ceramides in Response to a DASH-Style Diet in Older Adults. Nutrients 2023; 15:3687. [PMID: 37686719 PMCID: PMC10489641 DOI: 10.3390/nu15173687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
This feeding trial evaluated the impact of the Dietary Approaches to Stop Hypertension diet on changes in plasma choline, choline metabolites, and ceramides in obese older adults; 28 adults consumed 3oz (n = 15) or 6oz (n = 13) of beef within a standardized DASH diet for 12 weeks. Plasma choline, betaine, methionine, dimethylglycine (DMG), phosphatidylcholine (PC), lysophosphotidylcholine (LPC), sphingomyelin, trimethylamine-N-oxide (TMAO), L-carnitine, ceramide, and triglycerides were measured in fasted blood samples. Plasma LPC, sphingomyelin, and ceramide species were also quantified. In response to the study diet, with beef intake groups combined, plasma choline decreased by 9.6% (p = 0.012); DMG decreased by 10% (p = 0.042); PC decreased by 51% (p < 0.001); total LPC increased by 281% (p < 0.001); TMAO increased by 26.5% (p < 0.001); total ceramide decreased by 22.1% (p < 0.001); and triglycerides decreased by 18% (p = 0.021). All 20 LPC species measured increased (p < 0.01) with LPC 16:0 having the greatest response. Sphingomyelin 16:0, 18:0, and 18:1 increased (all p < 0.001) by 10.4%, 22.5%, and 24%, respectively. In contrast, we observed that sphingomyelin 24:0 significantly decreased by 10%. Ceramide 22:0 and 24:0 decreased by 27.6% and 10.9% (p < 0.001), respectively, and ceramide 24:1 increased by 36.8% (p = 0.013). Changes in choline and choline metabolites were in association with anthropometric and cardiometabolic outcomes. These findings show the impact of the DASH diet on choline metabolism in older adults and demonstrate the influence of diet to modify circulating LPC, sphingomyelin, and ceramide species.
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Affiliation(s)
- Brianna N. Tate
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA; (B.N.T.); (J.W.M.)
| | - Gary P. Van Guilder
- High Altitude Exercise Physiology Department, Western Colorado University, Gunnison, CO 81231, USA;
| | - Marwa Aly
- Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN 47405, USA; (M.A.); (L.A.S.)
| | - Lisa A. Spence
- Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN 47405, USA; (M.A.); (L.A.S.)
| | - M. Elena Diaz-Rubio
- Proteomic and Metabolomics Facility, Cornell University, Ithaca, NY 14853, USA;
| | - Henry H. Le
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; (H.H.L.); (E.L.J.)
| | - Elizabeth L. Johnson
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; (H.H.L.); (E.L.J.)
| | - Joseph W. McFadden
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA; (B.N.T.); (J.W.M.)
| | - Cydne A. Perry
- Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN 47405, USA; (M.A.); (L.A.S.)
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17
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Najjar RS. The Impacts of Animal-Based Diets in Cardiovascular Disease Development: A Cellular and Physiological Overview. J Cardiovasc Dev Dis 2023; 10:282. [PMID: 37504538 PMCID: PMC10380617 DOI: 10.3390/jcdd10070282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/29/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death in the United States, and diet plays an instrumental role in CVD development. Plant-based diets have been strongly tied to a reduction in CVD incidence. In contrast, animal food consumption may increase CVD risk. While increased serum low-density lipoprotein (LDL) cholesterol concentrations are an established risk factor which may partially explain the positive association with animal foods and CVD, numerous other biochemical factors are also at play. Thus, the aim of this review is to summarize the major cellular and molecular effects of animal food consumption in relation to CVD development. Animal-food-centered diets may (1) increase cardiovascular toll-like receptor (TLR) signaling, due to increased serum endotoxins and oxidized LDL cholesterol, (2) increase cardiovascular lipotoxicity, (3) increase renin-angiotensin system components and subsequent angiotensin II type-1 receptor (AT1R) signaling and (4) increase serum trimethylamine-N-oxide concentrations. These nutritionally mediated factors independently increase cardiovascular oxidative stress and inflammation and are all independently tied to CVD development. Public policy efforts should continue to advocate for the consumption of a mostly plant-based diet, with the minimization of animal-based foods.
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Affiliation(s)
- Rami Salim Najjar
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA
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18
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Grant WB, van Amerongen BM, Boucher BJ. Periodontal Disease and Other Adverse Health Outcomes Share Risk Factors, including Dietary Factors and Vitamin D Status. Nutrients 2023; 15:2787. [PMID: 37375691 DOI: 10.3390/nu15122787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/09/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
For nearly a century, researchers have associated periodontal disease (PD) with risks of other adverse health outcomes such as cardiovascular disease, diabetes mellitus, and respiratory diseases, as well as adverse pregnancy outcomes. Those findings have led to the hypothesis that PD causes those adverse health outcomes either by increasing systemic inflammation or by the action of periodontopathic bacteria. However, experiments largely failed to support that hypothesis. Instead, the association is casual, not causal, and is due to shared underlying modifiable risk factors, including smoking, diet, obesity, low levels of physical activity, and low vitamin D status. Diabetes mellitus is also considered a risk factor for PD, whereas red and processed meat are the most important dietary risk factors for diabetes. Because PD generally develops before other adverse health outcomes, a diagnosis of PD can alert patients that they could reduce the risk of adverse health outcomes with lifestyle changes. In addition, type 2 diabetes mellitus can often be reversed rapidly by adopting an anti-inflammatory, nonhyperinsulinemic diet that emphasizes healthful, whole plant-based foods. This review describes the evidence that proinflammatory and prohyperinsulinemia diets and low vitamin D status are important risk factors for PD and other adverse health outcomes. We also make recommendations regarding dietary patterns, food groups, and serum 25-hydroxyvitamin D concentrations. Oral health professionals should routinely inform patients with PD that they could reduce their risk of severe PD as well as the risks of many other adverse health outcomes by making appropriate lifestyle changes.
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Affiliation(s)
- William B Grant
- Sunlight, Nutrition and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
| | | | - Barbara J Boucher
- The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
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19
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Grant WB, Blake SM. Diet's Role in Modifying Risk of Alzheimer's Disease: History and Present Understanding. J Alzheimers Dis 2023; 96:1353-1382. [PMID: 37955087 PMCID: PMC10741367 DOI: 10.3233/jad-230418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2023] [Indexed: 11/14/2023]
Abstract
Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.
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Affiliation(s)
- William B. Grant
- Sunlight, Nutrition, and Health Research Center, San Francisco, CA, USA
| | - Steven M. Blake
- Nutritional Neuroscience, Maui Memory Clinic, Wailuku, HI, USA
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20
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Wang M, Wang Z, Lee Y, Lai HTM, de Oliveira Otto MC, Lemaitre RN, Fretts A, Sotoodehnia N, Budoff M, DiDonato JA, McKnight B, Tang WHW, Psaty BM, Siscovick DS, Hazen SL, Mozaffarian D. Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2022; 42:e273-e288. [PMID: 35912635 PMCID: PMC9420768 DOI: 10.1161/atvbaha.121.316533] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 05/24/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways. METHODS Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways. RESULTS After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association. CONCLUSIONS In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.
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Affiliation(s)
- Meng Wang
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
| | - Zeneng Wang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Yujin Lee
- Department of Food and Nutrition, Myongji University, Yongin, South Korea 17055
| | - Heidi TM Lai
- Imperial College London, Department of Primary Care and Public Health, London, SW7 2AZ, UK
| | - Marcia C. de Oliveira Otto
- Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth) School of Public Health, Houston, TX
| | - Rozenn N. Lemaitre
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
| | - Amanda Fretts
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
- Department of Epidemiology, University of Washington, Seattle, WA
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
| | - Matthew Budoff
- Los Angeles BioMedical Research Institute, Harbor UCLA Medical Center, CA
| | - Joseph A. DiDonato
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Barbara McKnight
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
- Department of Biostatistics, University of Washington, Seattle, WA
| | - W. H. Wilson Tang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
| | - Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA
- Department of Epidemiology, University of Washington, Seattle, WA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA
| | | | - Stanley L. Hazen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
| | - Dariush Mozaffarian
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
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21
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Associations of Diet with Urinary Trimethylamine-N-Oxide (TMAO) and Its Precursors among Free-Living 10-Year-Old Children: Data from SMBCS. Nutrients 2022; 14:nu14163419. [PMID: 36014922 PMCID: PMC9413070 DOI: 10.3390/nu14163419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/02/2022] Open
Abstract
Trimethylamine-N-oxide (TMAO), a diet-derived cometabolite linked to cardiometabolic disease, has been associated with elevated dietary status, particularly in people with kidney failure and adults with dietary modulations. However, the influence of the current diet on TMAO levels in free-living children has not been adequately described. This study was to explore associations of food compositions and dietary diversity with urinary TMAO and its precursor concentrations. Urinary TMAO and its precursor concentrations of 474 healthy children from the Sheyang Mini Birth Cohort were quantified by ultra-performance liquid chromatography−Q Exactive high-resolution mass spectrometer (UPLC-Q Exactive HRMS). Individual food compositions from 24 h dietary recall data were classified into 20 groups and diversity scores were calculated according to the guidelines of the Food and Agriculture Organization of the United Nations (FAO). Associations of urinary TMAO and its precursors with food compositions and dietary diversity scores were assessed by generalized linear regression models. In models adjusted for potential confounders, urinary TMAO was significantly associated with intakes of fish (β, regression coefficient = 0.155, p < 0.05) and vegetables (β = 0.120, p < 0.05). Eggs intake showed positive associations with TMAO’s precursors (trimethylamine: β = 0.179, p < 0.05; choline: β = 0.181, p < 0.05). No association between meat intake and TMAO was observed, whereas meat and poultry intakes were related to the levels of acetyl-L-carnitine and L-carnitine (β: 0.134 to 0.293, p < 0.05). The indicators of dietary diversity were positively correlated to TMAO concentration (β: 0.027 to 0.091, p < 0.05). In this free-living children-based study, dietary factors were related to urinary TMAO and its precursors, especially fish, meat, and eggs. As such, dietary diversity was positively related to the level of TMAO.
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22
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Li SY, Chen S, Lu XT, Fang AP, Chen YM, Huang RZ, Lin XL, Huang ZH, Ma JF, Huang BX, Zhu HL. Serum trimethylamine-N-oxide is associated with incident type 2 diabetes in middle-aged and older adults: a prospective cohort study. Lab Invest 2022; 20:374. [PMID: 35982495 PMCID: PMC9389664 DOI: 10.1186/s12967-022-03581-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/07/2022] [Indexed: 11/17/2022]
Abstract
Background The role of trimethylamine-N-oxide (TMAO) in the development of diabetes remains controversial, and prospective data are few. We aimed to investigate the association between serum TMAO and incident type 2 diabetes in middle-aged and older adults. Methods This study was based on the Guangzhou Nutrition and Health Study (GNHS), a community-based prospective cohort study in China. A total of 2088 diabetes-free participants aged 40–75 years were included from 2008 to 2010. Incident type 2 diabetes was ascertained during follow-up visits. Baseline serum TMAO was measured by high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for diabetes across tertiles of serum TMAO were calculated using Cox proportional hazard models. Prospective associations of serum TMAO with changes in glycemic traits (fasting glucose, HbA1c, insulin, HOMA-IR) over time were estimated using linear mixed-effects models (LMEMs). Results We ascertained 254 incident type 2 diabetes cases during a median follow-up of 8.9 years. The median (interquartile range) of serum TMAO was 1.54 (0.86–2.91) μmol/L. From the first to the third tertile of serum TMAO, the multivariable-adjusted HRs for diabetes were 1.00 (reference), 1.17 (95% CI: 0.84–1.61), and 1.42 (95% CI: 1.03–1.96) (P-trend = 0.031). LMEMs showed that the estimated yearly change in fasting glucose was 0.011 (0.001–0.022) mmol/L/y in the highest tertile of serum TMAO, compared with the lowest tertile (P-interaction = 0.044). Serum TMAO was not associated with longitudinal changes in HbA1c, insulin or HOMA-IR. Conclusions Our findings suggested that higher serum TMAO was associated with a higher risk of type 2 diabetes and an increase in fasting glucose among middle-aged and older Chinese adults. Trial registration: NCT03179657. https://clinicaltrials.gov/ct2/show/NCT03179657?term=NCT03179657&draw=2&rank=1 Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03581-7.
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Affiliation(s)
- Shu-Yi Li
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Si Chen
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Xiao-Ting Lu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Ai-Ping Fang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yu-Ming Chen
- Department of Medical Statistics & Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Rong-Zhu Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Xin-Lei Lin
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zi-Hui Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Jing-Fei Ma
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Bi-Xia Huang
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.
| | - Hui-Lian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China. .,Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China.
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23
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Liu Y, Zheng G, Jin X, Fan T, Chen Z, Sheng X. Influence of Gut Microbiota and Trimethylamine N-Oxide in Patients with Coronary Heart Disease. Int Heart J 2022; 63:683-691. [PMID: 35831155 DOI: 10.1536/ihj.22-070] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the current study, the gut microbiota of patients with and without coronary heart disease was compared and the relationship between gut microbiota distribution, intending to reveal the role of gut microbiota in the coronary atherosclerosis process, was investigated.This study included 50 patients diagnosed with coronary heart disease (CHD) who received conventional coronary angiography or computed tomography angiography and 50 patients with CHD at Changshu No. 2 People's Hospital, Suzhou, China, from May 2020 to January 2021. Trimethylamine N-oxide (TMAO) level was tested and feces were collected, the DNA of the gut microbiota was extracted, and the distribution by 16SrRNA gene sequencing was obtained from the two groups of patients.Plasma TMAO concentrations were significantly higher in patients with CHD (P < 0.001). In the CHD group, 22 patients with multivessel disease had a higher level of TMAO compared with the 28 patients who had the single-vessel disease (P < 0.001). No difference in the gut microbiota diversity was noted between the two groups (P < 0.001). Patients with CHD had a significantly lower proportion of Bacteroidetes phyla and more proportion of Epsilonbacteraeota phyla. At the genus level, patients with CHD had an increased abundance of Enterococcus, whereas healthy controls had significantly higher levels of Streptococcus. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 analysis found that, in the KEGG ORTHOLOGY, the level of choline trimethylamine-lyase gene expression correlated with TMAO production was higher in the fecal microbiome of the CHD group (P < 0.05).Gut microbiota and its product were expected to become a diagnostic marker and a new target for preventing CHD.
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Affiliation(s)
- Yanqi Liu
- Department of Cardiology, The Second People's Hospital of Changshu
| | - Guanqun Zheng
- Department of Cardiology, The Second People's Hospital of Changshu
| | - Xiaoqi Jin
- Department of Cardiology, The Second People's Hospital of Changshu
| | - Tao Fan
- Department of Cardiology, The Second People's Hospital of Changshu
| | - Zhixian Chen
- Department of Cardiology, The Second People's Hospital of Changshu
| | - Xiaodong Sheng
- Department of Cardiology, The Second People's Hospital of Changshu
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Gut Microbial Signatures of Distinct Trimethylamine N-Oxide Response to Raspberry Consumption. Nutrients 2022; 14:nu14081656. [PMID: 35458219 PMCID: PMC9027468 DOI: 10.3390/nu14081656] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023] Open
Abstract
The aim of this exploratory study was to evaluate the gut microbial signatures of distinct trimethylamine N-oxide (TMAO) responses following raspberry consumption. Investigations were carried out in 24 subjects at risk of developing metabolic syndrome who received 280 g/day of frozen raspberries for 8 weeks. Blood and stool samples were collected at weeks 0 and 8. Inter-individual variability in plasma TMAO levels was analyzed, 7 subjects were excluded due to noninformative signals and 17 subjects were kept for analysis and further stratified according to their TMAO response. Whole-metagenome shotgun sequencing analysis was used to determine the impact of raspberry consumption on gut microbial composition. Before the intervention, the relative abundance of Actinobacteriota was significantly higher in participants whose TMAO levels increased after the intervention (p = 0.03). The delta TMAO (absolute differences of baseline and week 8 levels) was positively associated with the abundance of gut bacteria such as Bilophila wadsworthia (p = 0.02; r2 = 0.37), from the genus Granulicatella (p = 0.03; r2 = 0.48) or the Erysipelotrichia class (p = 0.03; r2 = 0.45). Changes in the gut microbial ecology induced by raspberry consumption over an 8-week period presumably impacted quaternary amines-utilizing activity and thus plasma TMAO levels.
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25
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Dhakal S, Moazzami Z, Perry C, Dey M. Effects of Lean Pork on Microbiota and Microbial-Metabolite Trimethylamine-N-Oxide: A Randomized Controlled Non-Inferiority Feeding Trial Based on the Dietary Guidelines for Americans. Mol Nutr Food Res 2022; 66:e2101136. [PMID: 35182101 DOI: 10.1002/mnfr.202101136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/19/2022] [Indexed: 11/09/2022]
Abstract
SCOPE Trimethylamine-N-oxide (TMAO) is a microbiota-dependent and primarily animal-protein-derived proatherogenic metabolite. The ecological impact of pork-the most popular animal protein worldwide-on the human microbiome, and in the physiological context of TMAO and other biogenic amines, remains unclear. Poultry being the recommended heart-healthier animal protein, we inquired-if pork intake results in inferior-to-chicken TMAO-response while consuming a US. Dietary Guidelines (DGA)-diet? METHODS AND RESULTS In a randomized, controlled, all-food-provided, crossover, feeding trial, healthy adults consumed 156 g/day of lean-pork or chicken (active-control) as primary proteins. Mixed-effect modeling shows pork as noninferior to chicken for circulating TMAO response and microbiota-generated essential TMAO-precursor-trimethylamine (97.5% CI, n = 36/protein). Markers of lipid metabolism, inflammation and oxidative stress, serum levels of betaine, choline, L-carnitine, composition and functional-capability of the microbiota, and association of baseline TMAO-levels with TMAO-response (both, r>0.6, p = 0.0001) were nondistinguishable between the protein groups. TMAO reduction and similar shifts in microbiota and biogenic-amine signatures postdiet in both groups indicate a background DGA-effect. CONCLUSIONS Unlike extrapolating negative results, we present noninferiority-testing based evidence that consuming pork as a predominant protein within an omnivorous DGA-diet does not exacerbate TMAO-response. Results highlight the importance of understanding protein-TMAO interactions within dietary patterns. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Samitinjaya Dhakal
- Department of Health and Nutritional Sciences, South Dakota State University, Box 2275A, Brookings, SD, 57007
| | - Zahra Moazzami
- Department of Health and Nutritional Sciences, South Dakota State University, Box 2275A, Brookings, SD, 57007.,Food Science and Nutrition, University of Minnesota, St. Paul, MN, 55108
| | - Cydne Perry
- Department of Health and Nutritional Sciences, South Dakota State University, Box 2275A, Brookings, SD, 57007.,Applied Health Science, Indiana University, Bloomington, IN, 47405
| | - Moul Dey
- Department of Health and Nutritional Sciences, South Dakota State University, Box 2275A, Brookings, SD, 57007
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26
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The Influence of Animal- or Plant-Based Diets on Blood and Urine Trimethylamine-N-Oxide (TMAO) Levels in Humans. Curr Nutr Rep 2022; 11:56-68. [PMID: 34990005 DOI: 10.1007/s13668-021-00387-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE OF REVIEW The aim of the review was to evaluate which diets are associated with higher TMAO levels. RECENT FINDINGS Several studies have shown that plasma and urinary levels of trimethylamine N-oxide (TMAO) are a reliable indicator of cardiovascular disease risk. Diet certainly has a strong influence on TMAO levels, but there is still uncertainty about which diet is the most effective in reducing this risk factor. PubMed, Web of Science and Scopus were searched for studies that were published up until July 1, 2021 using specific keywords. In total, 447 studies were evaluated, of which papers on individual foods or supplements, or conducted in children, in vitro or in animal model studies were excluded. Twenty-five studies were included in this review. Three studies showed that caloric restriction and (visceral) weight loss improve TMAO levels. Six out of eight studies revealed beneficial effects of plant-based diets on plasma or urinary TMAO concentrations. Most of the studies demonstrated that a diet high in protein, particularly of animal origin, such as diets rich in fish or red meat, have negative effects on TMAO levels. Most studies that have evaluated the relationship between diet and plasma or urinary concentrations of TMAO seem to indicate that plant-based diets (Mediterranean, vegetarian and vegan) are effective in improving TMAO levels, while animal-based diets appear to have the opposite effect. Further long-term studies are needed to assess whether vegetarian or vegan diets are more effective than the Mediterranean diet in reducing TMAO levels.
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27
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Wang B, Qiu J, Lian J, Yang X, Zhou J. Gut Metabolite Trimethylamine-N-Oxide in Atherosclerosis: From Mechanism to Therapy. Front Cardiovasc Med 2021; 8:723886. [PMID: 34888358 PMCID: PMC8650703 DOI: 10.3389/fcvm.2021.723886] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis is associated with various pathological manifestations, such as ischemic heart disease, ischemic stroke, and peripheral arterial disease, and remains a leading cause of public health concern. Atherosclerosis is an inflammatory disease characterized by endothelial dysfunction; vascular inflammation; and the deposition of lipids, cholesterol, calcium, and cellular debris within the vessel wall intima. In-depth studies of gut flora in recent years have shown that bacterial translocation and the existence of bacterial active products in blood circulation can affect the inflammatory state of the whole blood vessel. The gut flora is considered to be a large “secretory organ,” which produces trimethylamine-N-oxide (TMAO), short-chain fatty acids and secondary bile acids by breaking down the ingested food. Studies have shown that TMAO is an independent risk factor for the occurrence of malignant adverse cardiovascular events, but whether it is harmful or beneficial to patients with cardiovascular diseases with mild or no clinical manifestations remains controversial. We review the relationship between TMAO and its precursor (L-carnitine) and coronary atherosclerosis and summarize the potential molecular mechanism and therapeutic measures of TMAO on coronary atherosclerosis.
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Affiliation(s)
- BingYu Wang
- Department of Cardiology Vascular Internal Medicine, Ningbo Medical Center LiHuiLi Hospital, Ningbo University, Ningbo, China
| | - Jun Qiu
- Department of Cardiology Vascular Internal Medicine, Ningbo Medical Center LiHuiLi Hospital, Ningbo University, Ningbo, China
| | - JiangFang Lian
- Department of Cardiology Vascular Internal Medicine, Ningbo Medical Center LiHuiLi Hospital, Ningbo University, Ningbo, China.,Central Laboratory, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
| | - Xi Yang
- Central Laboratory, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
| | - JianQing Zhou
- Department of Cardiology Vascular Internal Medicine, Ningbo Medical Center LiHuiLi Hospital, Ningbo University, Ningbo, China.,Central Laboratory, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
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28
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Barone M, D'Amico F, Fabbrini M, Rampelli S, Brigidi P, Turroni S. Over-feeding the gut microbiome: A scoping review on health implications and therapeutic perspectives. World J Gastroenterol 2021; 27:7041-7064. [PMID: 34887627 PMCID: PMC8613651 DOI: 10.3748/wjg.v27.i41.7041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/02/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
The human gut microbiome has gained increasing attention over the past two decades. Several findings have shown that this complex and dynamic microbial ecosystem can contribute to the maintenance of host health or, when subject to imbalances, to the pathogenesis of various enteric and non-enteric diseases. This scoping review summarizes the current knowledge on how the gut microbiota and microbially-derived compounds affect host metabolism, especially in the context of obesity and related disorders. Examples of microbiome-based targeted intervention strategies that aim to restore and maintain an eubiotic layout are then discussed. Adjuvant therapeutic interventions to alleviate obesity and associated comorbidities are traditionally based on diet modulation and the supplementation of prebiotics, probiotics and synbiotics. However, these approaches have shown only moderate ability to induce sustained changes in the gut microbial ecosystem, making the development of innovative and tailored microbiome-based intervention strategies of utmost importance in clinical practice. In this regard, the administration of next-generation probiotics and engineered microbiomes has shown promising results, together with more radical intervention strategies based on the replacement of the dysbiotic ecosystem by means of fecal microbiota transplantation from healthy donors or with the introduction of synthetic communities specifically designed to achieve the desired therapeutic outcome. Finally, we provide a perspective for future translational investigations through the implementation of bioinformatics approaches, including machine and deep learning, to predict health risks and therapeutic outcomes.
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Affiliation(s)
- Monica Barone
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Federica D'Amico
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Fabbrini
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Simone Rampelli
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Patrizia Brigidi
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
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29
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Pan XF, Yang JJ, Shu XO, Moore SC, Palmer ND, Guasch-Ferré M, Herrington DM, Harada S, Eliassen H, Wang TJ, Gerszten RE, Albanes D, Tzoulaki I, Karaman I, Elliott P, Zhu H, Wagenknecht LE, Zheng W, Cai H, Cai Q, Matthews CE, Menni C, Meyer KA, Lipworth LP, Ose J, Fornage M, Ulrich CM, Yu D. Associations of circulating choline and its related metabolites with cardiometabolic biomarkers: an international pooled analysis. Am J Clin Nutr 2021; 114:893-906. [PMID: 34020444 PMCID: PMC8408854 DOI: 10.1093/ajcn/nqab152] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/09/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear. OBJECTIVE We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants. METHODS The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (β) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant. RESULTS We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [β (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (β = 0.076; 95% CI: 0.042, 0.109), homocysteine (β = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (β = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (β = 0.068; 95% CI: 0.023, 0.114), insulin (β = 0.068; 95% CI: 0.043, 0.093), and IL-6 (β = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (β = -0.146; 95% CI: -0.188, -0.104), insulin (β = -0.106; 95% CI: -0.130, -0.082), homocysteine (β = -0.097; 95% CI: -0.149, -0.045), and total cholesterol (β = -0.074; 95% CI: -0.102, -0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [β = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [β = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites. CONCLUSIONS Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events.
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Affiliation(s)
- Xiong-Fei Pan
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jae Jeong Yang
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Steven C Moore
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Nicholette D Palmer
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Marta Guasch-Ferré
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - David M Herrington
- Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Sei Harada
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Heather Eliassen
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Thomas J Wang
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Robert E Gerszten
- Broad Institute of Harvard and Massachusetts Institute of Technology and Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Ioanna Tzoulaki
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- Dementia Research Institute, Imperial College London, London, United Kingdom
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
| | - Ibrahim Karaman
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- Dementia Research Institute, Imperial College London, London, United Kingdom
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
- Dementia Research Institute, Imperial College London, London, United Kingdom
| | - Huilian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Lynne E Wagenknecht
- Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Hui Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Charles E Matthews
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Cristina Menni
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Katie A Meyer
- Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA
| | - Loren P Lipworth
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jennifer Ose
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
- Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Cornelia M Ulrich
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
- Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Danxia Yu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
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