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Nutri(meta)genetics and Cardiovascular Disease: Novel Concepts in the Interaction of Diet and Genomic Variation

  • Genetics (AJ Marian, Section Editor)
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Abstract

In addition to the interaction of nutrition and genetic variation on the genesis and natural history of cardiovascular disease, recent studies have revealed an entire new genome that resides in the trillions of microbes that exist in various human habitats, predominantly in the gut, that may also contribute to the pathogenesis of cardiovascular disease. This microbial genome and the proteins for which it codes have important functions in homeostatic adaptations to the past and present changes in diet and environment accompanying human civilization. Both preclinical and clinical investigations suggest the role of commensal microbiota in promoting adverse cardiovascular risk. Specifically, microbial metabolism of methylated amines leads to direct pro-atherogenic effects in humans. Further investigations are needed to understand the complex relationships among nutritional status, genetic variation, and the microbial genome, which may explain the recent negative results of clinical trials of nutritional interventions such as B vitamin therapy to lower plasma homocysteine levels. The results of such contemporary genomic investigations would allow us to utilize personalized nutritional interventions to reduce cardiovascular risk.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–8.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012; 486:207–14.

  5. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science. 2009;326:1694–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4578–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4554–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449:804–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hehemann JH, Correc G, Barbeyron T, Helbert W, Czjzek M, Michel G. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature. 2010;464:908–12.

    Article  CAS  PubMed  Google Scholar 

  10. Martin FP, Dumas ME, Wang Y, Legido-Quigley C, Yap IK, Tang H, et al. A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model. Mol Syst Biol. 2007;3:112.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen UT, et al. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS One. 2011;6:e25482.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science. 2010;330:1768–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MA, et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science. 2009;325:617–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Sokol H, Seksik P, Rigottier-Gois L, Lay C, Lepage P, Podglajen I, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis. 2006;12:106–11.

    Article  PubMed  Google Scholar 

  16. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474:298–306.

    Article  CAS  PubMed  Google Scholar 

  17. Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K, Rutgeerts P, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60:631–7.

    Article  PubMed  Google Scholar 

  18. Russell SL, Gold MJ, Hartmann M, Willing BP, Thorson L, Wlodarska M, et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO Rep. 2012;13:440–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011;108:16050–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Wostmann BS, Bruckner-Kardoss E, Knight Jr PL. Cecal enlargement, cardiac output, and O2 consumption in germfree rats. Proc Soc Exp Biol Med. 1968;128:137–41.

    Article  CAS  PubMed  Google Scholar 

  21. Bruckner-Kardoss E, Wostmann BS. Oxygen consumption of germfree and conventional mice. Lab Anim Sci. 1978;28:282–6.

    CAS  PubMed  Google Scholar 

  22. Wostmann BS, Bruckner-Kardoss E, Pleasants JR. Oxygen consumption and thyroid hormones in germfree mice fed glucose-amino acid liquid diet. J Nutr. 1982;112:552–9.

    CAS  PubMed  Google Scholar 

  23. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.

    Article  PubMed  Google Scholar 

  24. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718–23.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102:11070–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

    Article  PubMed  Google Scholar 

  27. Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011;5:82–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455:1109–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99–103.

    Article  CAS  PubMed  Google Scholar 

  30. Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am J Clin Nutr. 2010;91:535–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Saturated fatty acids and risk of coronary heart disease: modulation by replacement nutrients. Curr Atheroscler Rep. 2010;12:384–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Karlsson FH, Fak F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun. 2012;3:1245.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63. This “bedside to bench” study utilized metabolomics approaches to identify a plasma metabolite associated with increased cardiovascular risk, and, subsequently, using germ-free mice, demonstrated that the metabolite trimethylamine oxide was derived from metabolism of phosphatidyl choline, a common dietary component, by gut microbiota, and promoted atherosclerosis.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–84. This seminal human study demonstrated that human gut microbiota were crucial in generating trimethylamine oxide from dietary phosphatidylcholine. This report also showed the association of elevated plasma levels of trimethylamine oxide with the risk of cardiovascular events.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85. This original report demonstrated that omnivorous humans generated more trimethylamine from dietary carnitine compared to vegans and that gut microbiota were crucial to this effect. Using a mouse model, the investigators also showed the interaction of dietary carnitine and gut microbiota in promoting atherosclerosis. This study demonstrated the role of microbiota in the link between consumption of red meat and the risk of atherosclerosis.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Zhu Y, Jameson E, Crosatti M, Schafer H, Rajakumar K, Bugg TD, et al. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc Natl Acad Sci U S A. 2014;111:4268–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998;7:839–45.

    Article  CAS  PubMed  Google Scholar 

  38. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17:49–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Lambert DM, Mamer OA, Akerman BR, Choiniere L, Gaudet D, Hamet P, et al. In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene. Mol Genet Metab. 2001;73:224–9.

    Article  CAS  PubMed  Google Scholar 

  40. Loscalzo J. Lipid metabolism by gut microbes and atherosclerosis. Circ Res. 2011;109:127–9.

    Article  CAS  PubMed  Google Scholar 

  41. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969;56:111–28.

  42. Joseph J, Handy DE, Loscalzo J. Quo vadis: whither homocysteine research? Cardiovasc Toxicol. 2009;9:53–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Joseph J, Loscalzo J. Methoxistasis: integrating the roles of homocysteine and folic acid in cardiovascular pathobiology. Nutrients. 2013;5:3235–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Cotlarciuc I, Andrew T, Dew T, Clement G, Gill R, Surdulescu G, et al. The basis of differential responses to folic acid supplementation. J Nutrigenet Nutrigenomics. 2011;4:99–109.

    Article  CAS  PubMed  Google Scholar 

  45. Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, Koeth RA, et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J. 2014;35:904–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Valentini L, Pinto A, Bourdel-Marchasson I, Ostan R, Brigidi P, Turroni S, A et al. Impact of personalized diet and probiotic supplementation on inflammation, nutritional parameters and intestinal microbiota—the “RISTOMED project”: randomized controlled trial in healthy older people. Clin Nutr. 2014.

  47. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A. 2010;107:14691–6.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500:585–8.

    Article  CAS  PubMed  Google Scholar 

  49. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104:979–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Wang D, Xia M, Yan X, Li D, Wang L, Xu Y, et al. Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circ Res. 2012;111:967–81.

    Article  CAS  PubMed  Google Scholar 

  51. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010;328:228–31.

    Article  CAS  PubMed  Google Scholar 

  52. Hartiala J, Bennett BJ, Tang WH, Wang Z, Stewart AF, Roberts R, et al. Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscl Thromb Vasc Biol. 2014;34:1307–13.

    Article  CAS  PubMed  Google Scholar 

  53. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457:480–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013; 341:1241214-1-10.

  55. Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot JL, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59:3049–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60.

    Article  CAS  PubMed  Google Scholar 

  57. Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12:56–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Borenstein E. Computational systems biology and in silico modeling of the human microbiome. Brief Bionform. 2012;13:769–80.

    Article  Google Scholar 

  59. Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci U S A. 2012;109:594–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIH grants R37 HL 061795, U01 HG007690, and HL048743.

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Conflict of Interest

Jacob Joseph and Joseph Loscalzo declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Joseph Loscalzo.

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This article is part of the Topical Collection on Genetics

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Joseph, J., Loscalzo, J. Nutri(meta)genetics and Cardiovascular Disease: Novel Concepts in the Interaction of Diet and Genomic Variation. Curr Atheroscler Rep 17, 29 (2015). https://doi.org/10.1007/s11883-015-0505-x

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