Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
권호 표지
DOI QR코드

DOI QR Code

The Gut-Heart Axis: Updated Review for The Roles of Microbiome in Cardiovascular Health

  • Thi Van Anh Bui (Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong) ;
  • Hyesoo Hwangbo (Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong) ;
  • Yimin Lai (Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong) ;
  • Seok Beom Hong (Department of Thoracic and Cardiovascular Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Yeon-Jik Choi (Division of Cardiology, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Hun-Jun Park (Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Kiwon Ban (Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong)
  • Received : 2023.04.25
  • Accepted : 2023.05.19
  • Published : 2023.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

Cardiovascular diseases (CVDs), including coronary artery disease, stroke, heart failure, and hypertension, are the global leading causes of death, accounting for more than 30% of deaths worldwide. Although the risk factors of CVDs have been well understood and various treatment and preventive measures have been established, the mortality rate and the financial burden of CVDs are expected to grow exponentially over time due to the changes in lifestyles and increasing life expectancies of the present generation. Recent advancements in metagenomics and metabolomics analysis have identified gut microbiome and its associated metabolites as potential risk factors for CVDs, suggesting the possibility of developing more effective novel therapeutic strategies against CVD. In addition, increasing evidence has demonstrated the alterations in the ratio of Firmicutes to Bacteroidetes and the imbalance of microbial-dependent metabolites, including short-chain fatty acids and trimethylamine N-oxide, play a crucial role in the pathogenesis of CVD. However, the exact mechanism of action remains undefined to this day. In this review, we focus on the compositional changes in the gut microbiome and its related metabolites in various CVDs. Moreover, the potential treatment and preventive strategies targeting the gut microbiome and its metabolites are discussed.

Keywords

Acknowledgement

This research was supported by Korean Fund for Regenerative Medicine funded by the Ministry of Science and ICT, and the Ministry of Health and Welfare (21A0104L1-11, Republic of Korea). This study was also supported by the Hong Kong Research Grants Council (21100818 to Ban K), CityU Applied Research Grant (ARG to Ban K), and TFBC project fund (Ban K).

References

  1. Mc Namara K, Alzubaidi H, Jackson JK. Cardiovascular disease as a leading cause of death: how are pharmacists getting involved? Integr Pharm Res Pract 2019;8:1-11.
  2. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 2019;139:e56-528.
  3. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52.
  4. Cho JH. Sudden death and ventricular arrhythmias in heart failure with preserved ejection fraction. Korean Circ J 2022;52:251-64.
  5. Tarride JE, Lim M, DesMeules M, et al. A review of the cost of cardiovascular disease. Can J Cardiol 2009;25:e195-202.
  6. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J 1991;121:293-8.
  7. Dahlof B. Cardiovascular disease risk factors: epidemiology and risk assessment. Am J Cardiol 2010;105:3A-9A.
  8. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007;449:804-10.
  9. Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science 2006;312:1355-9.
  10. Heintz-Buschart A, Wilmes P. Human gut microbiome: function matters. Trends Microbiol 2018;26:563-74.
  11. Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol 2015;31:69-75.
  12. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010;464:59-65.
  13. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90:859-904.
  14. Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 2015;26:26191.
  15. Feng Q, Liu Z, Zhong S, et al. Integrated metabolomics and metagenomics analysis of plasma and urine identified microbial metabolites associated with coronary heart disease. Sci Rep 2016;6:22525.
  16. Razavi AC, Potts KS, Kelly TN, Bazzano LA. Sex, gut microbiome, and cardiovascular disease risk. Biol Sex Differ 2019;10:29.
  17. Chen XF, Chen X, Tang X. Short-chain fatty acid, acylation and cardiovascular diseases. Clin Sci (Lond) 2020;134:657-76.
  18. Yang S, Li X, Yang F, et al. Gut microbiota-dependent marker TMAO in promoting cardiovascular disease: inflammation mechanism, clinical prognostic, and potential as a therapeutic target. Front Pharmacol 2019;10:1360.
  19. Magne F, Gotteland M, Gauthier L, et al. The Firmicutes/Bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients 2020;12:1474.
  20. Poll BG, Cheema MU, Pluznick JL. Gut microbial metabolites and blood pressure regulation: focus on SCFAs and TMAO. Physiology (Bethesda) 2020;35:275-84.
  21. Toya T, Corban MT, Marrietta E, et al. Coronary artery disease is associated with an altered gut microbiome composition. PLoS One 2020;15:e0227147.
  22. Hall AB, Yassour M, Sauk J, et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med 2017;9:103.
  23. Biddle A, Stewart L, Blanchard J, Leschine S. Untangling the genetic basis of fibrolytic specialization by Lachnospiraceae and Ruminococcaceae in diverse gut communities. Diversity (Basel) 2013;5:627-40.
  24. Chen J, Vitetta L. The role of butyrate in attenuating pathobiont-induced hyperinflammation. Immune Netw 2020;20:e15.
  25. Bach Knudsen KE, Laerke HN, Hedemann MS, et al. Impact of diet-modulated butyrate production on intestinal barrier function and inflammation. Nutrients 2018;10:1499.
  26. Emoto T, Yamashita T, Sasaki N, et al. Analysis of gut microbiota in coronary artery disease patients: a possible link between gut microbiota and coronary artery disease. J Atheroscler Thromb 2016;23:908-21.
  27. Luu M, Pautz S, Kohl V, et al. The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 2019;10:760.
  28. Zhu Q, Gao R, Zhang Y, et al. Dysbiosis signatures of gut microbiota in coronary artery disease. Physiol Genomics 2018;50:893-903.
  29. Zheng YY, Wu TT, Liu ZQ, et al. Gut microbiome-based diagnostic model to predict coronary artery disease. J Agric Food Chem 2020;68:3548-57.
  30. Ho KJ, Ramirez JL, Kulkarni R, et al. Plasma gut microbe-derived metabolites associated with peripheral artery disease and major adverse cardiac events. Microorganisms 2022;10:2065.
  31. Xue H, Chen X, Yu C, et al. Gut microbially produced indole-3-propionic acid inhibits atherosclerosis by promoting reverse cholesterol transport and its deficiency is causally related to atherosclerotic cardiovascular disease. Circ Res 2022;131:404-20.
  32. Biscetti F, Nardella E, Cecchini AL, Landolfi R, Flex A. The role of the microbiota in the diabetic peripheral artery disease. Mediators Inflamm 2019;2019:4128682.
  33. Cason CA, Dolan KT, Sharma G, et al. Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. J Vasc Surg 2018;68:1552-1562.e7.
  34. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 2009;6:306-14.
  35. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013;18:666-73.
  36. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 2011;23:255-64, e119.
  37. Gareau MG, Wine E, Rodrigues DM, et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut 2011;60:307-17.
  38. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 2015;28:203-9.
  39. Akhoundzadeh K, Vakili A, Shadnoush M, Sadeghzadeh J. Effects of the oral ingestion of probiotics on brain damage in a transient model of focal cerebral ischemia in mice. Iran J Med Sci 2018;43:32-40.
  40. Liu J, Sun J, Wang F, et al. Neuroprotective effects of Clostridium butyricum against vascular dementia in mice via metabolic butyrate. BioMed Res Int 2015;2015:412946.
  41. Sun J, Wang F, Ling Z, et al. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. Brain Res 2016;1642:180-8.
  42. Rahmati H, Momenabadi S, Vafaei AA, Bandegi AR, Mazaheri Z, Vakili A. Probiotic supplementation attenuates hippocampus injury and spatial learning and memory impairments in a cerebral hypoperfusion mouse model. Mol Biol Rep 2019;46:4985-95.
  43. Wanchao S, Chen M, Zhiguo S, Futang X, Mengmeng S. Protective effect and mechanism of Lactobacillus on cerebral ischemia reperfusion injury in rats. Braz J Med Biol Res 2018;51:e7172.
  44. Wang Z, Xu K, Zhou H. Characteristics of gut virome and microbiome in patients with stroke. Nan Fang Yi Ke Da Xue Xue Bao 2021;41:862-9.
  45. Chen L, Shen Y, Wang C, et al. Megasphaera elsdenii lactate degradation pattern shifts in rumen acidosis models. Front Microbiol 2019;10:162.
  46. Yin J, Liao SX, He Y, et al. Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 2015;4:e002699.
  47. O'Callaghan A, van Sinderen D. Bifidobacteria and their role as members of the human gut microbiota. Front Microbiol 2016;7:925.
  48. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 2008;105:16731-6.
  49. Lopez-Siles M, Enrich-Capo N, Aldeguer X, et al. Alterations in the abundance and co-occurrence of Akkermansia muciniphila and Faecalibacterium prausnitzii in the colonic mucosa of inflammatory bowel disease subjects. Front Cell Infect Microbiol 2018;8:281.
  50. Tan C, Wu Q, Wang H, et al. Dysbiosis of gut microbiota and short-chain fatty acids in acute ischemic stroke and the subsequent risk for poor functional outcomes. JPEN J Parenter Enteral Nutr 2021;45:518-29.
  51. Hayashi T, Yamashita T, Watanabe H, et al. Gut microbiome and plasma microbiome-related metabolites in patients with decompensated and compensated heart failure. Circ J 2018;83:182-92.
  52. Cui X, Ye L, Li J, et al. Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Sci Rep 2018;8:635.
  53. Kamo T, Akazawa H, Suda W, et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLoS One 2017;12:e0174099.
  54. Li J, Zhao F, Wang Y, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 2017;5:14.
  55. Yan Q, Gu Y, Li X, et al. Alterations of the gut microbiome in hypertension. Front Cell Infect Microbiol 2017;7:381.
  56. Kim S, Rigatto K, Gazzana MB, et al. Altered gut microbiome profile in patients with pulmonary arterial hypertension. Hypertension 2020;75:1063-71.
  57. Zhang Z, Zhang H, Chen T, Shi L, Wang D, Tang D. Regulatory role of short-chain fatty acids in inflammatory bowel disease. Cell Commun Signal 2022;20:64.
  58. Nogal A, Valdes AM, Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes 2021;13:1-24.
  59. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012;489:242-9.
  60. Hutchins AP, Diez D, Miranda-Saavedra D. The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. Brief Funct Genomics 2013;12:489-98.
  61. Sun M, Wu W, Liu Z, Cong Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J Gastroenterol 2017;52:1-8.
  62. Rogler G, Rosano G. The heart and the gut. Eur Heart J 2014;35:426-30.
  63. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409-39.
  64. Lee YS, Jun HS. Anti-inflammatory effects of GLP-1-based therapies beyond glucose control. Mediators Inflamm 2016;2016:3094642.
  65. Bui TV, Hwang JW, Lee JH, Park HJ, Ban K. Challenges and limitations of strategies to promote therapeutic potential of human mesenchymal stem cells for cell-based cardiac repair. Korean Circ J 2021;51:97-113.
  66. Usami M, Kishimoto K, Ohata A, et al. Butyrate and trichostatin A attenuate nuclear factor κB activation and tumor necrosis factor α secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. Nutr Res 2008;28:321-8.
  67. Li M, van Esch BC, Wagenaar GT, Garssen J, Folkerts G, Henricks PA. Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. Eur J Pharmacol 2018;831:52-9.
  68. Coutinho-Wolino KS, de F Cardozo LF, de Oliveira Leal V, Mafra D, Stockler-Pinto MB. Can diet modulate trimethylamine N-oxide (TMAO) production? What do we know so far? Eur J Nutr 2021;60:3567-84.
  69. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57-63.
  70. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol 2006;26:1702-11.
  71. Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575-84.
  72. Lee HY, Lim S, Park S. Role of inflammation in arterial calcification. Korean Circ J 2021;51:114-25.
  73. Mohammadi A, Gholamhoseyniannajar A, Yaghoobi MM, Jahani Y, Vahabzadeh Z. Expression levels of heat shock protein 60 and glucose-regulated protein 78 in response to trimethylamine-N-oxide treatment in murine macrophage J774A.1 cell line. Cell Mol Biol (Noisy-le-grand) 2015;61:94-100.
  74. Mohammadi A, Vahabzadeh Z, Jamalzadeh S, Khalili T. Trimethylamine-N-oxide, as a risk factor for atherosclerosis, induces stress in J774A.1 murine macrophages. Adv Med Sci 2018;63:57-63.
  75. Kim HL, Weber T. Pulsatile hemodynamics and coronary artery disease. Korean Circ J 2021;51:881-98.
  76. Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GR. IL-1㬡 and IL-18: inflammatory markers or mediators of hypertension? Br J Pharmacol 2014;171:5589-602.
  77. Seldin MM, Meng Y, Qi H, et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J Am Heart Assoc 2016;5:e002767.
  78. Kim HK, Tantry US, Park HW, et al. Ethnic difference of thrombogenicity in patients with cardiovascular disease: a pandora box to explain prognostic differences. Korean Circ J 2021;51:202-21.
  79. Qiu L, Yang D, Tao X, Yu J, Xiong H, Wei H. Enterobacter aerogenes ZDY01 attenuates choline-induced trimethylamine N-oxide levels by remodeling gut microbiota in mice. J Microbiol Biotechnol 2017;27:1491-9.
  80. Qiu L, Tao X, Xiong H, Yu J, Wei H. Lactobacillus plantarum ZDY04 exhibits a strain-specific property of lowering TMAO via the modulation of gut microbiota in mice. Food Funct 2018;9:4299-309.
  81. Vasu S, Zhou J, Chen J, Johnston PV, Kim DH. Biomaterials-based approaches for cardiac regeneration. Korean Circ J 2021;51:943-60.
  82. Gupta S, Allen-Vercoe E, Petrof EO. Fecal microbiota transplantation: in perspective. Therap Adv Gastroenterol 2016;9:229-39.
  83. Quraishi MN, Widlak M, Bhala N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther 2017;46:479-93.
  84. Hu XF, Zhang WY, Wen Q, et al. Fecal microbiota transplantation alleviates myocardial damage in myocarditis by restoring the microbiota composition. Pharmacol Res 2019;139:412-21.
  85. Toral M, Robles-Vera I, de la Visitacion N, et al. Critical role of the interaction gut microbiota - sympathetic nervous system in the regulation of blood pressure. Front Physiol 2019;10:231.
  86. Kim TT, Parajuli N, Sung MM, et al. Fecal transplant from resveratrol-fed donors improves glycaemia and cardiovascular features of the metabolic syndrome in mice. Am J Physiol Endocrinol Metab 2018;315:E511-9.
  87. Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214.
  88. Kim ES, Yoon BH, Lee SM, et al. Fecal microbiota transplantation ameliorates atherosclerosis in mice with C1q/TNF-related protein 9 genetic deficiency. Exp Mol Med 2022;54:103-14.
  89. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143:913-916.e7.
  90. Smits LP, Kootte RS, Levin E, et al. Effect of vegan fecal microbiota transplantation on carnitine- and choline-derived trimethylamine-N-oxide production and vascular inflammation in patients with metabolic syndrome. J Am Heart Assoc 2018;7:e008342.
  91. Fan L, Ren J, Chen Y, et al. Effect of fecal microbiota transplantation on primary hypertension and the underlying mechanism of gut microbiome restoration: protocol of a randomized, blinded, placebo-controlled study. Trials 2022;23:178.
  92. Zhong HJ, Zeng HL, Cai YL, et al. Washed microbiota transplantation lowers blood pressure in patients with hypertension. Front Cell Infect Microbiol 2021;11:679624.
  93. Qian B, Zhang K, Li Y, Sun K. Update on gut microbiota in cardiovascular diseases. Front Cell Infect Microbiol 2022;12:1059349.
  94. Wu H, Chiou J. Potential benefits of probiotics and prebiotics for coronary heart disease and stroke. Nutrients 2021;13:2878.
  95. Oniszczuk A, Oniszczuk T, Gancarz M, Szymanska J. Role of gut microbiota, probiotics and prebiotics in the cardiovascular diseases. Molecules 2021;26:1172.
  96. Kaye DM, Shihata WA, Jama HA, et al. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease. Circulation 2020;141:1393-403.
  97. Rault-Nania MH, Gueux E, Demougeot C, Demigne C, Rock E, Mazur A. Inulin attenuates atherosclerosis in apolipoprotein E-deficient mice. Br J Nutr 2006;96:840-4.
  98. Lim SH. Larch arabinogalactan attenuates myocardial injury by inhibiting apoptotic cascades in a rat model of ischemia-reperfusion. J Med Food 2017;20:691-9.
  99. Queenan KM, Stewart ML, Smith KN, Thomas W, Fulcher RG, Slavin JL. Concentrated oat beta-glucan, a fermentable fiber, lowers serum cholesterol in hypercholesterolemic adults in a randomized controlled trial. Nutr J 2007;6:6.
  100. Tai ES, Fok AC, Chu R, Tan CE. A study to assess the effect of dietary supplementation with soluble fibre (Minolest) on lipid levels in normal subjects with hypercholesterolaemia. Ann Acad Med Singapore 1999;28:209-13.
  101. Jiang T, Xing X, Zhang L, Liu Z, Zhao J, Liu X. Chitosan oligosaccharides show protective effects in coronary heart disease by improving antioxidant capacity via the increase in intestinal probiotics. Oxid Med Cell Longev 2019;2019:7658052.
  102. Moludi J, Khedmatgozar H, Nachvak SM, Abdollahzad H, Moradinazar M, Sadeghpour Tabaei A. The effects of co-administration of probiotics and prebiotics on chronic inflammation, and depression symptoms in patients with coronary artery diseases: a randomized clinical trial. Nutr Neurosci 2022;25:1659-68.
  103. Tajabadi-Ebrahimi M, Sharifi N, Farrokhian A, et al. A randomized controlled clinical trial investigating the effect of synbiotic administration on markers of insulin metabolism and lipid profiles in overweight type 2 diabetic patients with coronary heart disease. Exp Clin Endocrinol Diabetes 2017;125:21-7.
  104. Raygan F, Ostadmohammadi V, Asemi Z. The effects of probiotic and selenium co-supplementation on mental health parameters and metabolic profiles in type 2 diabetic patients with coronary heart disease: a randomized, double-blind, placebo-controlled trial. Clin Nutr 2019;38:1594-8.
  105. Liu Y, Feng J, Pan H, Zhang X, Zhang Y. Genetically engineered bacterium: principles, practices, and prospects. Front Microbiol 2022;13:997587.
  106. Steidler L, Hans W, Schotte L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000;289:1352-5.
  107. Yang G, Jiang Y, Yang W, et al. Effective treatment of hypertension by recombinant Lactobacillus plantarum expressing angiotensin converting enzyme inhibitory peptide. Microb Cell Fact 2015;14:202.
  108. Muller M, Hernandez MA, Goossens GH, et al. Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans. Sci Rep 2019;9:12515.
  109. Shubitowski TB, Poll BG, Natarajan N, Pluznick JL. Short-chain fatty acid delivery: assessing exogenous administration of the microbiome metabolite acetate in mice. Physiol Rep 2019;7:e14005.
  110. Krokowicz L, Stojcev Z, Kaczmarek BF, et al. Microencapsulated sodium butyrate administered to patients with diverticulosis decreases incidence of diverticulitis--a prospective randomized study. Int J Colorectal Dis 2014;29:387-93.