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• W2948686297 abstract "HomeCirculation ResearchVol. 124, No. 12The Microbiome, Plasma Metabolites, Dietary Habits, and Cardiovascular Risk Unravelling Their Interplay Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Microbiome, Plasma Metabolites, Dietary Habits, and Cardiovascular Risk Unravelling Their Interplay Dariush Mozaffarian Dariush MozaffarianDariush Mozaffarian Correspondence to Dariush Mozaffarian, MD, DrPH, Friedman School of Nutrition Science and Policy, Tufts University, 150 Harrison Ave, Boston, MA 02111. Email E-mail Address: [email protected] From the Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA. Search for more papers by this author Originally published6 Jun 2019https://doi.org/10.1161/CIRCRESAHA.119.315206Circulation Research. 2019;124:1695–1696This article is a commentary on the followingGut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and RiskWhile many scientific topics have experienced boom and bust fads of promise and excitement, it is clear the microbiome is here to stay. A wave of research is documenting the gut microbiome’s critical role in cardiometabolic health, including for obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, and cardiovascular disease (CVD). Multiple microbial species and their metabolites are linked to these outcomes, and changes in microbiome composition and function also appear to mediate much of the powerful health effects of diet.1 Yet, disentangling these relationships can be dizzyingly complex. Our gut contains trillions of gut microorganisms across at least 1000 different species of known bacteria, 100-fold more bacterial genomic variation than in the human genome, and >1000 plasma metabolites in the host that are influenced or even exclusively expressed based on microbial pathways or microbial-host cometabolism, including short-chain fatty acids (eg, propionate, butyrate, and acetate), organic acids, amino acids, vitamins, bile salts, polyphenols, and lipids.2–4Article, see p 1808In this issue, Kurilshikov et al5 use comprehensive metagenomics methods to explore how different gut microbial species and microbial pathways relate to 231 plasma metabolites and other cardiometabolic risk factors in 2 well phenotyped Dutch cohorts, including a community-based (n=978) and clinical obesity (n=297) group. In both groups, fecal microbial species and metabolic pathways were quantified, with analyses focusing on 188 species present in >10% of samples and 562 pathways present in >25% of samples. The 231 plasma metabolites included lipids, lipoproteins, apolipoproteins, cholesterol, glycerides, phospholipids, glycolysis components, fatty acids, inflammation, fluid balance, ketone bodies, and amino acids. The first cohort further assessed inflammatory biomarkers (adipokines and cytokines), dietary habits, short-chain fatty acids; and a metabolite-derived CVD risk score; and the second cohort, carotid intima-media thickness, magnetic resonance imaging-defined body fat distribution, magnetic resonance spectroscopy-defined hepatic fat, and plasma TMAO (trimethylamine N-oxide). Importantly, analyses accounted for multiple comparisons using false discovery rate methods.When associations of microbial species and pathways with plasma metabolites were evaluated, numerous associations were seen in each cohort separately. Adjusting for age, sex, and body mass index, the gut microbiome explained 11.1% and 16.4% of the variation in plasma metabolites in the community and obese cohorts, respectively. Assessing top associations across both cohorts, 16 microbial species-metabolite and 304 microbial pathway-metabolite associations were identified.In the community cohort, 48 microbial pathways but no microbial species were significantly associated with the CVD risk score (false discovery rate <0.05). The top pathways involved GDP (guanosine diphosphate)-mannose biosynthesis; as well as amino acid metabolism including glutamate-related (L-proline, L-arginine, L-histidine, and L-histidine), branched-chain (L-valine), hydrophobic (L-threonine), aromatic (L-phenylalanine and L-tyrosine), and sulfur-containing (L-methionine) amino acids. Most of these pathways were inversely associated with CVD risk, except for L-methionine and L-threonine pathways which were associated with higher risk. Other CVD risk-associated microbial pathways were involved in fermentation and carbohydrate and sugar metabolism. Highlighting complexity, the contribution (abundance) of the top bacterial taxa associated with each of these pathways varied considerably, with some pathways highly correlated with one major taxon, and others with multiple taxa.When these 48 CVD risk score-associated microbial pathways were assessed in relation to plasma cytokines, multiple associations were found with interleukins previously associated with CVD risk, including for microbial pathways relevant to bacterial amino acid biosynthesis (proline, ornithine, threonine, citrulline, tyrosine, and arginine), GDP-mannose metabolism glycolysis, and homolactic fermentation. In addition, the bacterial glycolysis pathway positively associated with host plasma adiponectin.Highlighting the important role of diet, 34 different dietary factors associated with these 48 CVD risk score-associated microbial pathways. These included higher intakes of fruits, vegetables, nuts, fish, tea, and red wine, and a protein-rich or gluten-free diet (each linked to microbial pathways associated with lower CVD risk scores) and higher intakes of carbohydrates, total fat, total calories, sweetened drinks, bread, and dairy products (each linked to microbial pathways associated with higher CVD risk scores). Plasma, but not stool, levels of short-chain fatty acids (produced by fermentation of fiber-rich minimally processed foods) were associated with a lower CVD risk score as well as with 29 of the 48 CVD risk score-associated microbial pathways.In the smaller obese cohort (N=297), a higher abundance of Ruminococcus sp_5_1_39BFAA positively associated with hepatic fat; and a higher abundance of bacterial L-methionine biosynthesis, with carotid plaque and maximum stenosis.This investigation has several strengths, particularly the comprehensive nature of the host and microbiome profiling and analyses, the correction for multiple comparisons, and the exploration of both microbial species and microbial metabolic pathways. Main limitations include the smaller sample size of the obese cohort, which likely limited statistical power to detect certain associations (eg, for TMAO or body fat); and the cross-sectional nature of the analysis, which prevents assessment of temporality of the associations (ie, are changes in the microbiome driving the host phenotype, or changes in the host phenotype driving the microbiome?).One key strength is the assessment of diet. While dietary habits are inevitably measured with some error, which may falsely attenuate findings toward the null and underestimate the true associations, diet is perhaps the strongest and most rapid environmental determinant of the gut microbiome.6–8 While thousands of prior research studies have been funded by US government agencies to study the gut microbiome in both humans and animal models, only a small number of these studies have addressed the impact of diet.9 Microbial fermentation of less digestible carbohydrates, such as from minimally processed foods like fruits, nuts, beans, and vegetables, gives rise to short-chain fatty acids and succinate, which may have benefits against obesity, nonalcoholic fatty liver disease, diabetes mellitus, and CVD.7,10 These dietary-microbiome interactions likely at least partly explain why different aspects of carbohydrate quality and food processing, such as fiber content, whole grain content, and glycemic responses, influence cardiometabolic outcomes.11 Phenolics, proteins, fats, and probiotics in these and other foods are also likely important for microbial health.6–8 Overall, a healthy, well-fed microbiome appears crucial for human metabolic health, while a hungry, malnourished microbiome appears to create metabolic havoc for its host. Indeed, many of the foods we consider being protective or harmful for us may, to a large extent, be first directly protective or harmful for our gut bacteria.In summary, this new investigation by Kurilshikov et al5 provides additional robust evidence for the role of gut microbial composition and function in cardiometabolic health and the important role of diet. The microbiome explained 11% to 16% of the variation in 231 major plasma metabolites, highlighting its powerful impact on the host. Microbial metabolic pathways linked to a CVD risk profile in the host included pathways related to GDP-mannose, multiple amino acids, fermentation, and carbohydrate and sugar metabolism. Many of these same pathways were associated with biomarkers of systemic inflammation; and specific dietary factors were positively or inversely associated with these CVD risk associated microbial metabolic pathways and in directions consistent with the known relationships of these dietary factors with human cardiometabolic health. As with most complex science, this new investigation also raises many questions for the future, pointing to new directions to advance our knowledge of the multidimensional interplay between our gut bacteria, their functional pathways, our diets, and our health.Sources of FundingThis work was supported by the National Heart, Lung, and Blood Institute (1R01-HL135920), National Institutes of Health.DisclosuresDr Mozaffarian has received personal fees from GOED, Nutrition Impact, Pollock Communications, Bunge, Indigo Agriculture, Amarin, Acasti Pharma, Cleveland Clinic Foundation, America’s Test Kitchen, and Danone; scientific advisory board for Elysium Health (with stock options), Omada Health, and DayTwo; and chapter royalties from UpToDate; all outside the submitted work.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Dariush Mozaffarian, MD, DrPH, Friedman School of Nutrition Science and Policy, Tufts University, 150 Harrison Ave, Boston, MA 02111. Email dariush.[email protected]eduReferences1. Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review.Circulation. 2016; 133:187–225. doi: 10.1161/CIRCULATIONAHA.115.018585LinkGoogle Scholar2. Vernocchi P, Del Chierico F, Putignani L. Gut microbiota profiling: metabolomics based approach to unravel compounds affecting human health.Front Microbiol. 2016; 7:1144. doi: 10.3389/fmicb.2016.01144CrossrefMedlineGoogle Scholar3. Thursby E, Juge N. Introduction to the human gut microbiota.Biochem J. 2017; 474:1823–1836. doi: 10.1042/BCJ20160510CrossrefMedlineGoogle Scholar4. Sridharan GV, Choi K, Klemashevich C, Wu C, Prabakaran D, Pan LB, Steinmeyer S, Mueller C, Yousofshahi M, Alaniz RC, Lee K, Jayaraman A. Prediction and quantification of bioactive microbiota metabolites in the mouse gut.Nat Commun. 2014; 5:5492. doi: 10.1038/ncomms6492CrossrefMedlineGoogle Scholar5. Kurilshikov A, van den Munckhof ICL, Chen L, et al; LifeLines DEEP Cohort Study; BBMRI Metabolomics Consortium. Gut microbial associations to plasma metabolites linked to cardiovascular phenotypes and risk: a cross-sectional study.Circ Res. 2019; 124:1808–1820. doi: 10.1161/CIRCRESAHA.118.314642LinkGoogle Scholar6. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome.Nature. 2014; 505:559–563. doi: 10.1038/nature12820CrossrefMedlineGoogle Scholar7. Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, Abrouk M, Farahnik B, Nakamura M, Zhu TH, Bhutani T, Liao W. Influence of diet on the gut microbiome and implications for human health.J Transl Med. 2017; 15:73. doi: 10.1186/s12967-017-1175-yCrossrefMedlineGoogle Scholar8. Reese AT, Carmody RN. Thinking outside the cereal box: noncarbohydrate routes for dietary manipulation of the gut microbiota.Appl Environ Microbiol. 2019; 85:e02246-18. doi: 10.1128/AEM.02246-18CrossrefMedlineGoogle Scholar9. Klurfeld DM, Davis CD, Karp RW, et al. Considerations for best practices in studies of fiber or other dietary components and the intestinal microbiome.Am J Physiol Endocrinol Metab. 2018; 315:E1087–E1097. doi: 10.1152/ajpendo.00058.2018CrossrefMedlineGoogle Scholar10. Canfora EE, Meex RCR, Venema K, Blaak EE. Gut microbial metabolites in obesity, NAFLD and T2DM.Nat Rev Endocrinol. 2019; 15:261–273. doi: 10.1038/s41574-019-0156-zCrossrefMedlineGoogle Scholar11. Reynolds A, Mann J, Cummings J, Winter N, Mete E, Te Morenga L. Carbohydrate quality and human health: a series of systematic reviews and meta-analyses.Lancet. 2019; 393:434–445. doi: 10.1016/S0140-6736(18)31809-9CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jang H, Kim E, Kim M, Kim S, Kim Y, Sohn M and Kim K (2022) Metabolomic profiling revealed altered lipid metabolite levels in childhood food allergy, Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2021.10.034, 149:5, (1722-1731.e9), Online publication date: 1-May-2022. Liu J, Zhao F, Xu Y, Qiu J and Qian Y (2021) Gut Flora-Mediated Metabolic Health, the Risk Produced by Dietary Exposure to Acetamiprid and Tebuconazole, Foods, 10.3390/foods10040835, 10:4, (835) Zhang L, Yu J, Liu Y, Guo W, Li Y and Hu W (2021) Effect of Yishenjiangyafang on Plasma Metabolomics in Senile Spontaneously Hypertensive Rats, Evidence-Based Complementary and Alternative Medicine, 10.1155/2021/8868267, 2021, (1-14), Online publication date: 8-Apr-2021. Loong C, Tay M and Loke W (2020) Assessment of Dietary, Physical Activity and Sedentary Behaviours of Singapore Schooling Youths, Current Research in Nutrition and Food Science Journal, 10.12944/CRNFSJ.8.3.05, 8:3, (715-726), Online publication date: 30-Dec-2021. Ross C (2019) Letter by Ross Regarding Article, “The Microbiome, Plasma Metabolites, Dietary Habits, and Cardiovascular Risk Unravelling Their Interplay”, Circulation Research, 125:5, (e27-e27), Online publication date: 16-Aug-2019.Related articlesGut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and RiskAlexander Kurilshikov, et al. Circulation Research. 2019;124:1808-1820 June 7, 2019Vol 124, Issue 12 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.119.315206PMID: 31170040 Originally publishedJune 6, 2019 KeywordsEditorialmetabolomicscardiovascular diseasesobesityliver diseasediabetes mellitusPDF download Advertisement SubjectsDiet and NutritionInflammationMetabolismOmicsProteomicsRisk Factors" @default.
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