Abstract
Recent years have brought interesting insights into the human gut microbiota and have highlighted its increasingly recognized impact on cardiovascular (CV) diseases, including heart failure (HF). Changes in composition of gut microbiota, called dysbiosis, can trigger systemic inflammation, which is known to be involved in the pathophysiology of HF. Trimethylamine N-oxide (TMAO), which is derived from gut microbiota metabolites of specific dietary nutrients, has emerged as a key contributor to cardiovascular disease pathogenesis. Elevated TMAO levels have been reported to be associated with poor outcomes in patients with both HF and chronic kidney disease (CKD). Dysbiosis of gut microbiota can contribute to higher levels of TMAO and the generation of uremic toxins, progressing to both HF and CKD. Therefore, this bidirectional relationship between HF and CKD through gut microbiota may be a novel therapeutic target for the cardiorenal syndrome. However, the mechanisms by which gut microbiota could influence the development of heart failure are still unknown, and there are still some questions regarding the causative effects of TMAO and the underlying mechanistic link that explains how TMAO might directly or indirectly promote CV diseases including HF. Further studies are warranted to clarify the function of TMAO on the pathophysiology of cardiorenal syndrome and the handling of TMAO levels by the kidneys.
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Cani PD, Lecourt E, Dewulf EM, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr. 2009;90(5):1236–43.
Arora T, Anastasovska J, Gibson G, et al. Effect of Lactobacillus acidophilus NCDC 13 supplementation on the progression of obesity in diet-induced obese mice. Br J Nutr. 2012;108(8):1382–9.
Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63. This landmark paper described the contribution of gut microbiota-derived TMAO production and atherogenesis in mouse models as well as in humans.
Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–84.
Tang WH, Wang Z, Fan Y, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol. 2014;64(18):1908–14.
Tang WH, Wang Z, Kennedy DJ, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res. 2015;116(3):448–55.
Tang WH, Wang Z, Shrestha K, et al. Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail. 2015;21(2):91–6.
Bonnet M, Buc E, Sauvanet P, et al. Colonization of the human gut by E. coli and colorectal cancer risk. Clin Cancer Res. 2014;20(4):859–67.
Gerasimidis K, Bertz M, Hanske L, et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn's disease during enteral nutrition. Inflamm Bowel Dis. 2014;20(5):861–71.
Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85.
Parnell JA, Reimer RA. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr. 2009;89(6):1751–9.
Carroll IM, Threadgill DW, Threadgill DS. The gastrointestinal microbiome: a malleable, third genome of mammals. Mamm Genome. 2009;20(7):395–403.
Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–8.
Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327–36.
Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489(7415):242–9.
Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–73.
Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250–4.
Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A. 2008;105(39):15064–9.
Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–72.
Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470–81.
Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–3.
Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55–60.
Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58(8):1091–103.
Kumar A, Brar R, Wang P, et al. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol. 1999;276(1 Pt 2):R265–276.
Charalambous BM, Stephens RC, Feavers IM, Montgomery HE. Role of bacterial endotoxin in chronic heart failure: the gut of the matter. Shock. 2007;28(1):15–23.
Sandek A, Rauchhaus M, Anker SD, von Haehling S. The emerging role of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care. 2008;11(5):632–9.
Krack A, Richartz BM, Gastmann A, et al. Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure. Eur J Heart Fail. 2004;6(4):403–7.
Sandek A, Bjarnason I, Volk HD, et al. Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure. Int J Cardiol. 2012;157(1):80–5.
Sandek A, Bauditz J, Swidsinski A, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007;50(16):1561–9. This is an elegant mechanistic study linking altered intestinal function to patients with heart failure.
Arutyunov GP, Kostyukevich OI, Serov RA, Rylova NV, Bylova NA. Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure. Int J Cardiol. 2008;125(2):240–5.
Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.
Wang F, Li Q, He Q, et al. Temporal variations of the ileal microbiota in intestinal ischemia and reperfusion. Shock. 2013;39(1):96–103.
Llamas MA, Aller MA, Marquina D, Nava MP, Arias J. Bacterial translocation to mesenteric lymph nodes increases in chronic portal hypertensive rats. Dig Dis Sci. 2010;55(8):2244–54.
Sandek A, Springer J, Habedank D, Brunkhorst F, Anker SD. Procalcitonin-guided antibiotic treatment in heart failure. Lancet. 2004;363(9420):1555. author reply 1555-1556.
Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323(4):236–41.
Maeda K, Tsutamoto T, Wada A, et al. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol. 2000;36(5):1587–93.
Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol. 1998;31(2):391–8.
Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353(9167):1838–42. This is a classic study demonstrating the potential contribution of microbiota and bacterial translocation leading to endotoxin and immunactivation in the setting of heart failure.
Sandek A, Swidsinski A, Schroedl W, et al. Intestinal blood flow in patients with chronic heart failure: a link with bacterial growth, gastrointestinal symptoms, and cachexia. J Am Coll Cardiol. 2014;64(11):1092–102.
Bennion BJ, Daggett V. Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: a chemical chaperone at atomic resolution. Proc Natl Acad Sci U S A. 2004;101(17):6433–8.
Wang Z, Tang WH, Buffa JA, et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J. 2014;35(14):904–10.
Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52(19):1527–39.
Simenhoff ML, Saukkonen JJ, Burke JF, Wesson Jr LG, Schaedler RW, Gordon SJ. Bacterial populations of the small intestine in uremia. Nephron. 1978;22(1-3):63–8.
Vaziri ND, Wong J, Pahl M, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2013;83(2):308–15.
Wong J, Piceno YM, Desantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 2014;39(3):230–7.
Szeto CC, Kwan BC, Chow KM, et al. Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clin J Am Soc Nephrol. 2008;3(2):431–6.
McIntyre CW, Harrison LE, Eldehni MT, et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(1):133–41.
Vaziri ND, Yuan J, Nazertehrani S, Ni Z, Liu S. Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction. Am J Nephrol. 2013;38(2):99–103.
Shi K, Wang F, Jiang H, et al. Gut bacterial translocation may aggravate microinflammation in hemodialysis patients. Dig Dis Sci. 2014;59(9):2109–17.
Evenepoel P, Meijers BK, Bammens BR, Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney Int Suppl. 2009;114:S12–19.
Wang CP, Lu LF, Yu TH, et al. Serum levels of total p-cresylsulphate are associated with angiographic coronary atherosclerosis severity in stable angina patients with early stage of renal failure. Atherosclerosis. 2010;211(2):579–83.
Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int. 2003;63(5):1671–80.
Schepers E, Meert N, Glorieux G, Goeman J, Van der Eycken J, Vanholder R. P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transplant. 2007;22(2):592–6.
Bell JD, Lee JA, Lee HA, Sadler PJ, Wilkie DR, Woodham RH. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide. Biochim Biophys Acta. 1991;1096(2):101–7.
Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 2013;83(6):1010–6.
Vitetta L, Gobe G. Uremia and chronic kidney disease: the role of the gut microflora and therapies with pro- and prebiotics. Mol Nutr Food Res. 2013;57(5):824–32.
Doucet C, Dutheil D, Petit I, et al. Influence of colloid, preservation medium and trimetazidine on renal medulla injury. Biochim Biophys Acta. 2004;1673(3):105–14.
Wang A, Bolen DW. A naturally occurring protective system in urea-rich cells: mechanism of osmolyte protection of proteins against urea denaturation. Biochemistry. 1997;36(30):9101–8.
Rhee EP, Souza A, Farrell L, et al. Metabolite profiling identifies markers of uremia. J Am Soc Nephrol. 2010;21(6):1041–51.
Al-Waiz M, Mitchell SC, Idle JR, Smith RL. The metabolism of 14C-labelled trimethylamine and its N-oxide in man. Xenobiotica. 1987;17(5):551–8.
Stubbs JR, House JA, Ocque AJ, et al. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol. 2015;30:2014111063.
Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105–8.
Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80.
David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559–63.
Almoosawi S, Winter J, Prynne CJ, Hardy R, Stephen AM. Daily profiles of energy and nutrient intakes: are eating profiles changing over time? Eur J Clin Nutr. 2012;66(6):678–86.
Trichopoulou A, Kouris-Blazos A, Wahlqvist ML, et al. Diet and overall survival in elderly people. BMJ. 1995;311(7018):1457–60.
Mekki K, Bouzidi-bekada N, Kaddous A, Bouchenak M. Mediterranean diet improves dyslipidemia and biomarkers in chronic renal failure patients. Food Funct. 2010;1(1):110–5.
Ojetti V, Lauritano EC, Barbaro F, et al. Rifaximin pharmacology and clinical implications. Expert Opin Drug Metab Toxicol. 2009;5(6):675–82.
Simenhoff ML, Dunn SR, Zollner GP, et al. Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus. Miner Electrolyte Metab. 1996;22(1-3):92–6.
Ranganathan N, Ranganathan P, Friedman EA, et al. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Adv Ther. 2010;27(9):634–47.
Broekaert WF, Courtin CM, Verbeke K, Van de Wiele T, Verstraete W, Delcour JA. Prebiotic and other health-related effects of cereal-derived arabinoxylans, arabinoxylan-oligosaccharides, and xylooligosaccharides. Crit Rev Food Sci Nutr. 2011;51(2):178–94.
Everard A, Lazarevic V, Derrien M, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes. 2011;60(11):2775–86.
Acknowledgments
Dr. Tang is supported by research grants from the National Institutes of Health (R01HL103931, P20HL113452, R01DK106000).
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Takeshi Kitai declares that he has no conflict of interest.
Jennifer Kirsop and W.H. Wilson Tang have received grants from the National Institutes of Health during the conduct of the study.
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This article is part of the Topical Collection on Biomarkers of Heart Failure
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Kitai, T., Kirsop, J. & Tang, W.H.W. Exploring the Microbiome in Heart Failure. Curr Heart Fail Rep 13, 103–109 (2016). https://doi.org/10.1007/s11897-016-0285-9
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DOI: https://doi.org/10.1007/s11897-016-0285-9