Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gut microbiota and inflammation in chronic kidney disease and their roles in the development of cardiovascular disease

Abstract

The health and proper functioning of the cardiovascular and renal systems largely depend on crosstalk in the gut–kidney–heart/vessel triangle. Recent evidence suggests that the gut microbiota has an integral function in this crosstalk. Mounting evidence indicates that the development of chronic kidney and cardiovascular diseases follows chronic inflammatory processes that are affected by the gut microbiota via various immune, metabolic, endocrine, and neurologic pathways. Additionally, deterioration of the function of the cardiovascular and renal systems has been reported to disrupt the original gut microbiota composition, further contributing to the advancement of chronic cardiovascular and renal diseases. Considering the interaction between the gut microbiota and the renal and cardiovascular systems, we can infer that interventions for the gut microbiota through diet and possibly some medications can prevent/stop the vicious cycle between the gut microbiota and the cardiovascular/renal systems, leading to a decrease in chronic cardiovascular and renal diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337–40.

    CAS  Google Scholar 

  2. 2.

    Mahmoodpoor F, Rahbar Saadat Y, Barzegari A, Ardalan M, Zununi Vahed S. The impact of gut microbiota on kidney function and pathogenesis. Biomed Pharmacother. 2017;93:412–9.

    CAS  PubMed  Google Scholar 

  3. 3.

    Tang WH, Kitai T, Hazen SL. Gut microbiota in cardiovascular health and disease. Circ Res. 2017;120:1183–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107–33.

    CAS  PubMed  Google Scholar 

  5. 5.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292:1115–8.

    CAS  PubMed  Google Scholar 

  7. 7.

    Coakley M, Ross RP, Nordgren M, Fitzgerald G, Devery R, Stanton C. Conjugated linoleic acid biosynthesis by human-derived Bifidobacterium species. J Appl Microbiol. 2003;94:138–45.

    CAS  PubMed  Google Scholar 

  8. 8.

    Metges CC. Contribution of microbial amino acids to amino acid homeostasis of the host. J Nutr. 2000;130:1857s–1864s.

    CAS  PubMed  Google Scholar 

  9. 9.

    Burkholder PR, McVeigh I. Synthesis of vitamins by intestinal bacteria. Proc Natl Acad Sci USA. 1942;28:285–9.

    CAS  PubMed  Google Scholar 

  10. 10.

    Fernandez F, Hill MJ. Proceedings: The production of vitamin K by human intestinal bacteria. J Med Microbiol. 1975;8:Pix.

  11. 11.

    Savage DC. Gastrointestinal microflora in mammalian nutrition. Annu Rev Nutr. 1986;6:155–78.

    CAS  PubMed  Google Scholar 

  12. 12.

    Malys MK, Campbell L, Malys N. Symbiotic and antibiotic interactions between gut commensal microbiota and host immune system. Medicinia (Kaunas). 2015;51:69–75.

    Google Scholar 

  13. 13.

    Robijn S, Hoppe B, Vervaet BA, D’Haese PC, Verhulst A. Hyperoxaluria: a gut-kidney axis? Kidney Int. 2011;80:1146–58.

    CAS  PubMed  Google Scholar 

  14. 14.

    Liu H, Hu C, Zhang X, Jia W. Role of gut microbiota, bile acids and their cross-talk in the effects of bariatric surgery on obesity and type 2 diabetes. J Diabetes Investig. 2017;9:13–20.

  15. 15.

    Pluznick JL. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 2016;90:1191–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Sobko T, Huang L, Midtvedt T, Norin E, Gustafsson LE, Norman M, et al. Generation of NO by probiotic bacteria in the gastrointestinal tract. Free Radic Biol Med. 2006;41:985–91.

    CAS  PubMed  Google Scholar 

  17. 17.

    de Andrade JA, Gayer CR, Nogueira NP, Paes MC, Bastos VL, Neto Jda C, et al. The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis. J Inflamm (Lond). 2014;11:11.

    Google Scholar 

  18. 18.

    Nudel BC, Fraile ER. [Selection of bacterial strains for the production of threonine]. Rev Argent Microbiol. 1984;16:209–17.

    CAS  PubMed  Google Scholar 

  19. 19.

    Romano M. Gut microbiota as a trigger of accelerated directional adaptive evolution: acquisition of herbivory in the context of extracellular vesicles, microRNAs and inter-kingdom crosstalk. Front Microbiol. 2017;8:721.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Afsar B, Vaziri ND, Aslan G, Tarim K, Kanbay M. Gut hormones and gut microbiota: implications for kidney function and hypertension. J Am Soc Hypertens. 2016;10:954–61.

    CAS  PubMed  Google Scholar 

  21. 21.

    Lyte M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. Bioessays. 2011;33:574–81.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wang HX, Wang YP. Gut microbiota-brain axis. Chin Med J. 2016;129:2373–80.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Muccioli GG, Naslain D, Backhed F, Reigstad CS, Lambert DM, Delzenne NM, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2013;83:308–15.

    PubMed  Google Scholar 

  25. 25.

    Khoury T, Tzukert K, Abel R, Abu Rmeileh A, Levi R, Ilan Y. The gut-kidney axis in chronic renal failure: a new potential target for therapy. Hemodial Int. 2016;21:323–34.

  26. 26.

    Nagatomo Y, Tang WH. Intersections between microbiome and heart failure: revisiting the gut hypothesis. J Card Fail. 2015;21:973–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kanbay M, Onal EM, Afsar B, Dagel T, Yerlikaya A, Covic A, et al. The crosstalk of gut microbiota and chronic kidney disease: role of inflammation, proteinuria, hypertension, and diabetes mellitus. Int Urol Nephrol. 2018;50:1453–66.

  28. 28.

    Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al. Gut dysbiosis is linked to hypertension. Hypertension. 2015;65:1331–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Xu KY, Xia GH, Lu JQ, Chen MX, Zhen X, Wang S, et al. Impaired renal function and dysbiosis of gut microbiota contribute to increased trimethylamine-N-oxide in chronic kidney disease patients. Sci Rep. 2017;7:1445.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Rossi M, Klein K, Johnson DW, Campbell KL. Pre-, pro-, and synbiotics: do they have a role in reducing uremic toxins? A systematic review and meta-analysis. Int J Nephrol. 2012;2012:673631.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol. 2014;25:1897–907.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Jakobsson HE, Rodriguez-Pineiro AM, Schutte A, Ermund A, Boysen P, Bemark M, et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 2015;16:164–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr. 2011;141:769–76.

    CAS  PubMed  Google Scholar 

  34. 34.

    Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT, et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol. 2006;8:1327–36.

    CAS  PubMed  Google Scholar 

  35. 35.

    Omenetti S, Pizarro TT. The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front Immunol. 2015;6:639.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Ohland CL, Macnaughton WK. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol. 2010;298:G807–819.

    CAS  PubMed  Google Scholar 

  37. 37.

    Watson AJ, Duckworth CA. Gut microbiota control gut permeability through GLP-2. Gastroenterology. 2010;138:779–81.

    PubMed  Google Scholar 

  38. 38.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011;34:794–806.

    CAS  PubMed  Google Scholar 

  40. 40.

    Brandl K, Schnabl B. Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease? Expert Rev Gastroenterol Hepatol. 2015;9:1069–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Poveda J, Sanchez-Nino MD, Glorieux G, Sanz AB, Egido J, Vanholder R, et al. p-cresyl sulphate has pro-inflammatory and cytotoxic actions on human proximal tubular epithelial cells. Nephrol Dial Transplant. 2014;29:56–64.

    CAS  PubMed  Google Scholar 

  42. 42.

    Brunet P, Gondouin B, Duval-Sabatier A, Dou L, Cerini C, Dignat-George F, et al. Does uremia cause vascular dysfunction? Kidney Blood Press Res. 2011;34:284–90.

    CAS  PubMed  Google Scholar 

  43. 43.

    Ito S, Osaka M, Higuchi Y, Nishijima F, Ishii H, Yoshida M. Indoxyl sulfate induces leukocyte-endothelial interactions through up-regulation of E-selectin. J Biol Chem. 2010;285:38869–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Shimizu H, Bolati D, Adijiang A, Muteliefu G, Enomoto A, Nishijima F, et al. NF-kappaB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. Am J Physiol Cell Physiol. 2011;301:C1201–1212.

    CAS  PubMed  Google Scholar 

  45. 45.

    Seldin MM, Meng Y, Qi H, Zhu W, Wang Z, Hazen SL, et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-kappaB. J Am Heart Assoc. 2016;5:e002767.

  46. 46.

    Saemann MD, Bohmig GA, Osterreicher CH, Burtscher H, Parolini O, Diakos C, et al. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J. 2000;14:2380–2.

    CAS  PubMed  Google Scholar 

  47. 47.

    Laroux FS, Pavlick KP, Hines IN, Kawachi S, Harada H, Bharwani S, et al. Role of nitric oxide in inflammation. Acta Physiol Scand. 2001;173:113–8.

    CAS  PubMed  Google Scholar 

  48. 48.

    Knauf F, Asplin JR, Granja I, Schmidt IM, Moeckel GW, David RJ, et al. NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 2013;84:895–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Hatch M. Gut microbiota and oxalate homeostasis. Ann Transl Med. 2017;5:36.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Zhu C, Fuchs CD, Halilbasic E, Trauner M. Bile acids in regulation of inflammation and immunity: friend or foe? Clin Exp Rheumatol. 2016;34:25–31.

    PubMed  Google Scholar 

  51. 51.

    Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai M. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem. 2006;70:926–32.

    CAS  PubMed  Google Scholar 

  52. 52.

    Granados-Soto V, Teran-Rosales F, Rocha-Gonzalez HI, Reyes-Garcia G, Medina-Santillan R, Rodriguez-Silverio J, et al. Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat. Eur J Pharmacol. 2004;492:35–40.

    CAS  PubMed  Google Scholar 

  53. 53.

    Zhang P, Tsuchiya K, Kinoshita T, Kushiyama H, Suidasari S, Hatakeyama M, et al. Vitamin B6 prevents IL-1beta protein production by inhibiting NLRP3 inflammasome activation. J Biol Chem. 2016;291:24517–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Guest J, Bilgin A, Hokin B, Mori TA, Croft KD, Grant R. Novel relationships between B12, folate and markers of inflammation, oxidative stress and NAD(H) levels, systemically and in the CNS of a healthy human cohort. Nutr Neurosci. 2015;18:355–64.

    CAS  PubMed  Google Scholar 

  55. 55.

    Osowska S, De Bandt JP, Chaib S, Neveux N, Berard MP, Cynober L. Efficiency of a cysteine-taurine-threonine-serine supplemented parenteral nutrition in an experimental model of acute inflammation. Intensive Care Med. 2003;29:1798–801.

    PubMed  Google Scholar 

  56. 56.

    Filip AT, Balacescu O, Marian C, Anghel A. Microbiota small RNAs in inflammatory bowel disease. J Gastrointest liver Dis. 2016;25:509–16.

    Google Scholar 

  57. 57.

    Lee YS, Park MS, Choung JS, Kim SS, Oh HH, Choi CS, et al. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia. 2012;55:2456–68.

    CAS  PubMed  Google Scholar 

  58. 58.

    Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58:1091–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Vona-Davis L, McFadden DW. PYY and the pancreas: inhibition of tumor growth and inflammation. Peptides. 2007;28:334–8.

    CAS  PubMed  Google Scholar 

  60. 60.

    Duthey B, Hubner A, Diehl S, Boehncke S, Pfeffer J, Boehncke WH. Anti-inflammatory effects of the GABA(B) receptor agonist baclofen in allergic contact dermatitis. Exp Dermatol. 2010;19:661–6.

    CAS  PubMed  Google Scholar 

  61. 61.

    Reyes-Garcia MG, Hernandez-Hernandez F, Hernandez-Tellez B, Garcia-Tamayo F. GABA (A) receptor subunits RNA expression in mice peritoneal macrophages modulate their IL-6/IL-12 production. J Neuroimmunol. 2007;188:64–68.

    CAS  PubMed  Google Scholar 

  62. 62.

    Shajib MS, Khan WI. The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol (Oxf). 2015;213:561–74.

    CAS  Google Scholar 

  63. 63.

    Spengler RN, Chensue SW, Giacherio DA, Blenk N, Kunkel SL. Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. J Immunol. 1994;152:3024–31.

    CAS  PubMed  Google Scholar 

  64. 64.

    Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015;160:62–73.

    CAS  PubMed  Google Scholar 

  65. 65.

    Baez-Pagan CA, Delgado-Velez M, Lasalde-Dominicci JA. Activation of the macrophage alpha7 nicotinic acetylcholine receptor and control of inflammation. J NeuroImmune Pharmacol. 2015;10:468–76.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Chobanyan-Jurgens K, Jordan J. Autonomic nervous system activity and inflammation: good ideas, good treatments, or both? Am J Physiol Heart Circ Physiol. 2015;309:H1999–2001.

    PubMed  Google Scholar 

  67. 67.

    Gabanyi I, Muller PA, Feighery L, Oliveira TY, Costa-Pinto FA, Mucida D. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell. 2016;164:378–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Fernandez-Prado R, Esteras R, Perez-Gomez MV, Gracia-Iguacel C, Gonzalez-Parra E, Sanz AB, et al. Nutrients turned into toxins: microbiota modulation of nutrient properties in chronic kidney disease. Nutrients 2017;9:E489.

  69. 69.

    Moraes C, Fouque D, Amaral AC, Mafra D. Trimethylamine N-oxide from gut microbiota in chronic kidney disease patients: focus on diet. J Ren Nutr. 2015;25:459–65.

    CAS  PubMed  Google Scholar 

  70. 70.

    Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio. 2015;6:e02481.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    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;39:230–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Pogribna M, Freeman JP, Paine D, Boudreau MD. Effect of Aloe vera whole leaf extract on short chain fatty acids production by Bacteroides fragilis, Bifidobacterium infantis and Eubacterium limosum. Lett Appl Microbiol. 2008;46:575–80.

    CAS  PubMed  Google Scholar 

  73. 73.

    Barcenilla A, Pryde SE, Martin JC, Duncan SH, Stewart CS, Henderson C, et al. Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol. 2000;66:1654–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Duncan SH, Hold GL, Barcenilla A, Stewart CS, Flint HJ. Roseburia intestinalis sp. nov., a novel saccharolytic, butyrate-producing bacterium from human faeces. Int J Syst Evol Microbiol. 2002;52:1615–20.

    CAS  PubMed  Google Scholar 

  75. 75.

    Tsukahara T, Koyama H, Okada M, Ushida K. Stimulation of butyrate production by gluconic acid in batch culture of pig cecal digesta and identification of butyrate-producing bacteria. J Nutr. 2002;132:2229–34.

    CAS  PubMed  Google Scholar 

  76. 76.

    Everard A, Cani PD. Gut microbiota and GLP-1. Rev Endocr Metab Disord. 2014;15:189–96.

    CAS  PubMed  Google Scholar 

  77. 77.

    Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA. 2008;105:16767–72.

    CAS  PubMed  Google Scholar 

  78. 78.

    Simon MC, Strassburger K, Nowotny B, Kolb H, Nowotny P, Burkart V, et al. Intake of Lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans: a proof of concept. Diabetes Care. 2015;38:1827–34.

    CAS  PubMed  Google Scholar 

  79. 79.

    Holzer P, Farzi A. Neuropeptides and the microbiota-gut-brain axis. Adv Exp Med Biol. 2014;817:195–219.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Gordon Cooke JB, Costello M. Newly identified vitamin K-producing bacteria isolated from the neonatal faecal flora. Microb Ecol Health Dis. 2006;18:133–8.

    Google Scholar 

  81. 81.

    LeBlanc JG, Laino JE, del Valle MJ, Vannini V, van Sinderen D, Taranto MP, et al. B-group vitamin production by lactic acid bacteria--current knowledge and potential applications. J Appl Microbiol. 2011;111:1297–309.

    CAS  PubMed  Google Scholar 

  82. 82.

    Sathyanarayanan Jayashree KJ, Kalaichelvan Gurumurthy. Isolation, screening and characterization of riboflavin producing lactic acid bacteria from Katpadi, Vellore District. Recent Res Sci Technol. 2010;2:83–88.

    Google Scholar 

  83. 83.

    Kuipers F, Claudel T, Sturm E, Staels B. The Farnesoid X Receptor (FXR) as modulator of bile acid metabolism. Rev Endocr Metab Disord. 2004;5:319–26.

    CAS  PubMed  Google Scholar 

  84. 84.

    Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–59.

    CAS  PubMed  Google Scholar 

  85. 85.

    Hu Z, Ren L, Wang C, Liu B, Song G. Effect of chenodeoxycholic acid on fibrosis, inflammation and oxidative stress in kidney in high-fructose-fed Wistar rats. Kidney Blood Press Res. 2012;36:85–97.

    CAS  PubMed  Google Scholar 

  86. 86.

    Carbonero F, Gaskins HR. Sulfate-reducing bacteria in the human gut microbiome. In: Nelson KE, editor. Encyclopedia of metagenomics. New York, NY: Springer New York; 2013. p. 1–3.

  87. 87.

    Aminzadeh MA, Vaziri ND. Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease. Nephrol Dial Transplant. 2012;27:498–504.

    CAS  PubMed  Google Scholar 

  88. 88.

    Song K, Wang F, Li Q, Shi YB, Zheng HF, Peng H, et al. Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int. 2014;85:1318–29.

    CAS  PubMed  Google Scholar 

  89. 89.

    Perna AF, Lanza D, Sepe I, Raiola I, Capasso R, De Santo NG, et al. Hydrogen sulfide, a toxic gas with cardiovascular properties in uremia: how harmful is it? Blood Purif. 2011;31:102–6.

    CAS  PubMed  Google Scholar 

  90. 90.

    Tanida M, Yamano T, Maeda K, Okumura N, Fukushima Y, Nagai K. Effects of intraduodenal injection of Lactobacillus johnsonii La1 on renal sympathetic nerve activity and blood pressure in urethane-anesthetized rats. Neurosci Lett. 2005;389:109–14.

    CAS  PubMed  Google Scholar 

  91. 91.

    Ait-Belgnaoui A, Han W, Lamine F, Eutamene H, Fioramonti J, Bueno L, et al. Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction. Gut. 2006;55:1090–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23:1132–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    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 USA. 2011;108:16050–5.

    CAS  PubMed  Google Scholar 

  94. 94.

    Eutamene H, Lamine F, Chabo C, Theodorou V, Rochat F, Bergonzelli GE, et al. Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats. J Nutr. 2007;137:1901–7.

    CAS  PubMed  Google Scholar 

  95. 95.

    Ma X, Mao YK, Wang B, Huizinga JD, Bienenstock J, Kunze W. Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli. Am J Physiol Gastrointest Liver Physiol. 2009;296:G868–75.

    CAS  PubMed  Google Scholar 

  96. 96.

    Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007;13:35–37.

    CAS  PubMed  Google Scholar 

  97. 97.

    Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.

    CAS  PubMed  Google Scholar 

  98. 98.

    Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA. 2011;108:8030–5.

    CAS  PubMed  Google Scholar 

  99. 99.

    McCafferty DM, Wallace JL, Sharkey KA. Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat. Am J Physiol. 1997;272:G272–280.

    CAS  PubMed  Google Scholar 

  100. 100.

    Schicho R, Krueger D, Zeller F, Von Weyhern CW, Frieling T, Kimura H, et al. Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon. Gastroenterology. 2006;131:1542–52.

    CAS  PubMed  Google Scholar 

  101. 101.

    Evenepoel P, Poesen R, Meijers B. The gut-kidney axis. Pediatr Nephrol. 2016;32:2005–14.

  102. 102.

    Felizardo RJ, Castoldi A, Andrade-Oliveira V, Camara NO. The microbiota and chronic kidney diseases: a double-edged sword. Clin Transl Immunol. 2016;5:e86.

    Google Scholar 

  103. 103.

    Kikuchi M, Ueno M, Itoh Y, Suda W, Hattori M. Uremic toxin-producing gut microbiota in rats with chronic kidney disease. Nephron. 2017;135:51–60.

    CAS  PubMed  Google Scholar 

  104. 104.

    Sampaio-Maia B, Simoes-Silva L, Pestana M, Araujo R, Soares-Silva IJ. The role of the gut microbiome on chronic kidney disease. Adv Appl Microbiol. 2016;96:65–94.

    CAS  PubMed  Google Scholar 

  105. 105.

    Vianna HR, Soares CM, Tavares MS, Teixeira MM, Silva AC. [Inflammation in chronic kidney disease: the role of cytokines]. J Bras Nefrol. 2011;33:351–64.

    PubMed  Google Scholar 

  106. 106.

    Amdur RL, Feldman HI, Gupta J, Yang W, Kanetsky P, Shlipak M, et al. Inflammation and progression of CKD: the CRIC study. Clin J Am Soc Nephrol. 2016;11:1546–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Stephenson M, Rowatt E. The production of acetylcholine by a strain of Lactobacillus plantarum. J Gen Microbiol. 1947;1:279–98.

    CAS  PubMed  Google Scholar 

  108. 108.

    Truong LD, Trostel J, Garcia GE. Absence of nicotinic acetylcholine receptor alpha7 subunit amplifies inflammation and accelerates onset of fibrosis: an inflammatory kidney model. FASEB J. 2015;29:3558–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Kobayashi M, Mikami D, Kimura H, Kamiyama K, Morikawa Y, Yokoi S, et al. Short-chain fatty acids, GPR41 and GPR43 ligands, inhibit TNF-alpha-induced MCP-1 expression by modulating p38 and JNK signaling pathways in human renal cortical epithelial cells. Biochem Biophys Res Commun. 2017;486:499–505.

    CAS  PubMed  Google Scholar 

  110. 110.

    Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C. gamma-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol. 2012;113:411–7.

    CAS  PubMed  Google Scholar 

  111. 111.

    Salman IM, Sarma Kandukuri D, Harrison JL, Hildreth CM, Phillips JK. Direct conscious telemetry recordings demonstrate increased renal sympathetic nerve activity in rats with chronic kidney disease. Front Physiol. 2015;6:218.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Chen CH, Yang WC, Hsiao YH, Huang SC, Huang YC. High homocysteine, low vitamin B-6, and increased oxidative stress are independently associated with the risk of chronic kidney disease. Nutrition. 2016;32:236–41.

    CAS  PubMed  Google Scholar 

  113. 113.

    Streja E, Kovesdy CP, Streja DA, Moradi H, Kalantar-Zadeh K, Kashyap ML. Niacin and progression of CKD. Am J Kidney Dis. 2015;65:785–98.

    CAS  PubMed  Google Scholar 

  114. 114.

    Pastore A, Noce A, Di Giovamberardino G, De Stefano A, Calla C, Zenobi R, et al. Homocysteine, cysteine, folate and vitamin B(1)(2) status in type 2 diabetic patients with chronic kidney disease. J Nephrol. 2015;28:571–6.

    CAS  PubMed  Google Scholar 

  115. 115.

    Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int. 2000;58:1261–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Pal GK, Pal P, Nanda N, Amudharaj D, Adithan C. Cardiovascular dysfunctions and sympathovagal imbalance in hypertension and prehypertension: physiological perspectives. Future Cardiol. 2013;9:53–69.

    CAS  PubMed  Google Scholar 

  117. 117.

    Fujimura S, Shimakage H, Tanioka H, Yoshida M, Suzuki-Kusaba M, Hisa H, et al. Effects of GABA on noradrenaline release and vasoconstriction induced by renal nerve stimulation in isolated perfused rat kidney. Br J Pharmacol. 1999;127:109–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Wierema TK, Houben AJ, de Leeuw PW. Acetylcholine-induced vasodilatation in the human hypertensive kidney: inhibition by muscarinic receptor antagonism. J Hypertens. 1997;15:1649–51.

    CAS  PubMed  Google Scholar 

  119. 119.

    Skov J. Effects of GLP-1 in the kidney. Rev Endocr Metab Disord. 2014;15:197–207.

    CAS  PubMed  Google Scholar 

  120. 120.

    Skov J, Dejgaard A, Frokiaer J, Holst JJ, Jonassen T, Rittig S, et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J Clin Endocrinol Metab. 2013;98:E664–671.

    CAS  PubMed  Google Scholar 

  121. 121.

    Bischoff A, Avramidis P, Erdbrugger W, Munter K, Michel MC. Receptor subtypes Y1 and Y5 are involved in the renal effects of neuropeptide Y. Br J Pharmacol. 1997;120:1335–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci USA. 2013;110:4410–5.

    CAS  PubMed  Google Scholar 

  123. 123.

    Natarajan N, Hori D, Flavahan S, Steppan J, Flavahan NA, Berkowitz DE, et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G-protein coupled receptor 41. Physiol Genomics 2016;48:826–34.

  124. 124.

    Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes. 2014;5:202–7.

    PubMed  Google Scholar 

  125. 125.

    Parekh N, Dobrowolski L, Zou AP, Steinhausen M. Nitric oxide modulates angiotensin II- and norepinephrine-dependent vasoconstriction in rat kidney. Am J Physiol. 1996;270:R630–635.

    CAS  PubMed  Google Scholar 

  126. 126.

    O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015;277:32–48.

    PubMed  Google Scholar 

  127. 127.

    Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Takahashi T, Hisa H, Satoh S. Serotonin-induced renin release in the dog kidney. Eur J Pharmacol. 1991;193:315–20.

    CAS  PubMed  Google Scholar 

  129. 129.

    Li T, Croce K, Winquist RJ. Vasoconstrictor and vasodilator effects of serotonin in the isolated rabbit kidney. J Pharmacol Exp Ther. 1992;263:928–32.

    CAS  PubMed  Google Scholar 

  130. 130.

    Tuncer M, Vanhoutte PM. Serotonin releases a vasoconstrictor prostanoid in the kidney of the aging spontaneously hypertensive rat. Blood Press. 1993;2:142–5.

    CAS  PubMed  Google Scholar 

  131. 131.

    Dean C, Kampine JP. A role for serotonin in the elaboration of a differential pattern of activity in sympathetic nerves to kidney and skeletal muscle vasculature. J Auton Nerv Syst. 1993;44:207–15.

    CAS  PubMed  Google Scholar 

  132. 132.

    Mitani S, Yabuki A, Taniguchi K, Yamato O. Association between the intrarenal renin-angiotensin system and renal injury in chronic kidney disease of dogs and cats. J Vet Med Sci. 2013;75:127–33.

    CAS  PubMed  Google Scholar 

  133. 133.

    Malekmakan L, Malekmakan A, Daneshian A, Pakfetrat M, Roosbeh J. Hypertension and diabetes remain the main causes of chronic renal failure in Fars Province, Iran 2013. Saudi J Kidney Dis Transplant. 2016;27:423–4.

    Google Scholar 

  134. 134.

    Cook PR, Malmqvist LA, Bengtsson M, Tryggvason B, Lofstrom JB. Vagal and sympathetic activity during spinal analgesia. Acta Anaesthesiol Scand. 1990;34:271–5.

    CAS  PubMed  Google Scholar 

  135. 135.

    Reimann M, Hamer M, Schlaich MP, Malan NT, Ruediger H, Ziemssen T, et al. Greater cardiovascular reactivity to a cold stimulus is due to higher cold pain perception in black Africans: the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. J Hypertens. 2012;30:2416–24.

    CAS  PubMed  Google Scholar 

  136. 136.

    Narita K, Murata T, Hamada T, Takahashi T, Omori M, Suganuma N, et al. Interactions among higher trait anxiety, sympathetic activity, and endothelial function in the elderly. J Psychiatr Res. 2007;41:418–27.

    PubMed  Google Scholar 

  137. 137.

    Moynes DM, Lucas GH, Beyak MJ, Lomax AE. Effects of inflammation on the innervation of the colon. Toxicol Pathol. 2014;42:111–7.

    PubMed  Google Scholar 

  138. 138.

    Kiuchi MG, Chen S. Improvement of renal function after renal sympathetic denervation in CKD patients with controlled vs. uncontrolled hypertension. Int J Cardiol. 2016;223:494–6.

    PubMed  Google Scholar 

  139. 139.

    Lau WL, Vaziri ND. Urea, a true uremic toxin: the empire strikes back. Clin Sci (Lond). 2017;131:3–12.

    CAS  Google Scholar 

  140. 140.

    Kobori H, Ohashi N, Katsurada A, Miyata K, Satou R, Saito T, et al. Urinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases. J Am Soc Hypertens. 2008;2:349–54.

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Anguiano L, Riera M, Pascual J, Valdivielso JM, Barrios C, Betriu A, et al. Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease. Nephrol Dial Transplant. 2015;30:1176–85.

    CAS  PubMed  Google Scholar 

  142. 142.

    Panjeta M, Tahirovic I, Sofic E, Coric J, Dervisevic A. Interpretation of erythropoietin and haemoglobin levels in patients with various stages of chronic kidney disease. J Med Biochem. 2017;36:145–52.

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011;6:913–21.

    CAS  PubMed  Google Scholar 

  144. 144.

    Liu TJ, Shi YY, Wang EB, Zhu T, Zhao Q. AT1R blocker losartan attenuates intestinal epithelial cell apoptosis in a mouse model of Crohn’s disease. Mol Med Rep. 2016;13:1156–62.

    CAS  PubMed  Google Scholar 

  145. 145.

    Kim S, Wang G, Lobaton G, Li E, Yang T, Raizada M. Os 05-10 the microbial metabolite, butyrate attenuates angiotensin II-induced hypertension and dysbiosis. J Hypertens. 2016;34:e60–1.

    Google Scholar 

  146. 146.

    Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect. 2013;15:866–73.

    CAS  PubMed  Google Scholar 

  147. 147.

    Shiou SR, Yu Y, Chen S, Ciancio MJ, Petrof EO, Sun J, et al. Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis. J Biol Chem. 2011;286:12123–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Dimitrov V, White JH. Vitamin D signaling in intestinal innate immunity and homeostasis. Mol Cell Endocrinol 2017;453:68–78.

  149. 149.

    Serino M, Blasco-Baque V, Nicolas S, Burcelin R. Far from the eyes, close to the heart: dysbiosis of gut microbiota and cardiovascular consequences. Curr Cardiol Rep. 2014;16:540.

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling S, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007;50:1561–9.

    CAS  PubMed  Google Scholar 

  151. 151.

    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.

    PubMed  PubMed Central  Google Scholar 

  152. 152.

    Koren O, Spor A, Felin J, Fak F, Stombaugh J, Tremaroli V, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci USA. 2011;108(Suppl 1):4592–8.

    CAS  PubMed  Google Scholar 

  153. 153.

    Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017;5:14.

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    Kamo T, Akazawa H, Suda W, Saqa-Kamo A, Shimizu Y, Yaqi H, et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLoS ONE. 2017;12:e0174099

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Adnan S, Nelson JW, Ajami NJ, Venna VR, Petrosino JF, Bryan RM, et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genom. 2017;49:96–104.

    CAS  Google Scholar 

  156. 156.

    Al Khodor S, Reichert B, Shatat IF. The microbiome and blood pressure: can microbes regulate our blood pressure? Front Pediatr. 2017;5:138.

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Lopez-Candales A, Hernandez Burgos PM, Hernandez-Suarez DF, Harris D. Linking chronic inflammation with cardiovascular disease: from normal aging to the metabolic syndrome. J Nat Sci. 2017;3:e341.

  158. 158.

    Org E, Mehrabian M, Lusis AJ. Unraveling the environmental and genetic interactions in atherosclerosis: central role of the gut microbiota. Atherosclerosis. 2015;241:387–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Rogler G, Rosano G. The heart and the gut. Eur Heart J. 2014;35:426–30.

    PubMed  Google Scholar 

  160. 160.

    Pucino V, Bombardieri M, Pitzalis C, Mauro C. Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Eur J Immunol. 2017;47:14–21.

    CAS  PubMed  Google Scholar 

  161. 161.

    Juraschek SP, Bower JK, Selvin E, Subash Shantha GP, Hoogeveen RC, Ballantyne CM, et al. Plasma lactate and incident hypertension in the atherosclerosis risk in communities study. Am J Hypertens. 2015;28:216–24.

    CAS  PubMed  Google Scholar 

  162. 162.

    Solak Y, Afsar B, Vaziri ND, Aslan G, Yalcin CE, Covic A, et al. Hypertension as an autoimmune and inflammatory disease. Hypertens Res. 2016;39:567–73.

    CAS  PubMed  Google Scholar 

  163. 163.

    Guo J, Lu L, Hua Y, Huang K, Wang I, Huang L, et al. Vasculopathy in the setting of cardiorenal syndrome: roles of protein-bound uremic toxins. Am J Physiol Heart Circ Physiol. 2017;313:H1–13.

    PubMed  Google Scholar 

  164. 164.

    Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124:4204–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, Gregory JC, et al. gamma-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 2014;20:799–812.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Goldsmith JR, Sartor RB. The role of diet on intestinal microbiota metabolism: downstream impacts on host immune function and health, and therapeutic implications. J Gastroenterol. 2014;49:785–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Wei SG, Yu Y, Zhang ZH, Felder RB. Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat. Hypertension. 1979;2015:1126–33.

    Google Scholar 

  168. 168.

    Li DP, Pan HL. Role of gamma-aminobutyric acid (GABA)A and GABAB receptors in paraventricular nucleus in control of sympathetic vasomotor tone in hypertension. J Pharmacol Exp Ther. 2007;320:615–26.

    CAS  PubMed  Google Scholar 

  169. 169.

    Marcil V, Delvin E, Seidman E, Poitras L, Zoltowska M, Garofalo C, et al. Modulation of lipid synthesis, apolipoprotein biogenesis, and lipoprotein assembly by butyrate. Am J Physiol Gastrointest Liver Physiol. 2002;283:G340–6.

    CAS  PubMed  Google Scholar 

  170. 170.

    Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701–12.

    CAS  Google Scholar 

  171. 171.

    Nichols CD. Serotonin 5-HT(2A) receptor function as a contributing factor to both neuropsychiatric and cardiovascular diseases. Cardiovasc Psychiatry Neurol. 2009;2009:475108.

    PubMed  PubMed Central  Google Scholar 

  172. 172.

    Penesova A, Radikova Z, Cizmarova E, Kvetnansky R, Blazicek P, Vlcek M, et al. The role of norepinephrine and insulin resistance in an early stage of hypertension. Ann NY Acad Sci. 2008;1148:490–4.

    CAS  PubMed  Google Scholar 

  173. 173.

    Liu S, Li Y, Zhang Z, Xie F, Xu Q, Huang X, et al. alpha1-Adrenergic receptors mediate combined signals initiated by mechanical stretch stress and norepinephrine leading to accelerated mouse vein graft atherosclerosis. J Vasc Surg. 2013;57:1645–56, 1656.e1641–3

    PubMed  Google Scholar 

  174. 174.

    Cuevas S, Villar VA, Jose PA, Armando I. Renal dopamine receptors, oxidative stress, and hypertension. Int J Mol Sci. 2013;14:17553–72.

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Yasunari K, Kohno M, Kano H, Yokokawa K, Minami M, Yoshikawa J. Vascular dopamine-I receptors and atherosclerosis. J Atheroscler Thromb. 1997;4:59–64.

    CAS  PubMed  Google Scholar 

  176. 176.

    Tjeerdsma G, van Wijk LM, Molhoek GP, Boomsma F, Haaksma J, van Veldhuisen DJ. Autonomic and hemodynamic effects of a new selective dopamine agonist, CHF1035, in patients with chronic heart failure. Cardiovasc Drugs Ther. 2001;15:139–45.

    CAS  PubMed  Google Scholar 

  177. 177.

    Li J, Zheng J, Wang S, Lau HK, Fathi A, Wang Q. Cardiovascular benefits of native GLP-1 and its metabolites: an indicator for GLP-1-therapy strategies. Front Physiol. 2017;8:15.

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Angelone T, Filice E, Quintieri AM, Imbrogno S, Amodio N, Pasqua T, et al. Receptor identification and physiological characterisation of glucagon-like peptide-2 in the rat heart. Nutr Metab Cardiovasc Dis. 2012;22:486–94.

    CAS  PubMed  Google Scholar 

  179. 179.

    Lutz TA, Osto E. Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism. Curr Opin Lipidol. 2016;27:257–63.

    CAS  PubMed  Google Scholar 

  180. 180.

    Ansar S, Koska J, Reaven PD. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc Diabetol. 2011;10:61.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Smith RM, Klein R, Kruzliak P, Zulli A. Role of peptide YY in blood vessel function and atherosclerosis in a rabbit model. Clin Exp Pharmacol Physiol. 2015;42:648–52.

    CAS  PubMed  Google Scholar 

  182. 182.

    Zhu X, Gillespie DG, Jackson EKNPY1-36. and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4. Am J Physiol Heart Circ Physiol. 2015;309:H1528–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Grassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. J Am Soc Hypertens. 2016;10:457–66.

    CAS  PubMed  Google Scholar 

  184. 184.

    Gregorio PC, Favretto G, Sassaki GL, Cunha RS, Becker-Finco A, Pecoits-Filho R, et al. Sevelamer reduces endothelial inflammatory response to advanced glycation end products. Clin Kidney J. 2018;11:89–98.

    PubMed  Google Scholar 

  185. 185.

    Liu J, Huang K, Cai GY, Chen XM, Yang JR, Lin LR, et al. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell Signal. 2014;26:110–21.

    PubMed  Google Scholar 

  186. 186.

    Stinghen AE, Massy ZA, Vlassara H, Striker GE, Boullier A. Uremic toxicity of advanced glycation end products in CKD. J Am Soc Nephrol. 2016;27:354–70.

    CAS  PubMed  Google Scholar 

  187. 187.

    Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA. 1994;91:11704–8.

    CAS  PubMed  Google Scholar 

  188. 188.

    Thomas MC, Woodward M, Neal B, Li Q, Pickering R, Marre M, et al. Relationship between levels of advanced glycation end products and their soluble receptor and adverse outcomes in adults with type 2 diabetes. Diabetes Care. 2015;38:1891–7.

    CAS  PubMed  Google Scholar 

  189. 189.

    Hartog JW, Voors AA, Bakker SJ, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications. Eur J Heart Fail. 2007;9:1146–55.

    CAS  PubMed  Google Scholar 

  190. 190.

    Campbell DJ, Somaratne JB, Jenkins AJ, Prior DL, Yii M, Kenny JF, et al. Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease. Cardiovasc Diabetol. 2011;10:80.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Donaldson C, Taatjes DJ, Zile M, Palmer B, VanBuren P, Spinale F, et al. Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium. Histochem Cell Biol. 2010;134:23–30.

    CAS  PubMed  Google Scholar 

  192. 192.

    Faist V, Erbersdobler HF. Metabolic transit and in vivo effects of melanoidins and precursor compounds deriving from the Maillard reaction. Ann Nutr Metab. 2001;45:1–12.

    CAS  PubMed  Google Scholar 

  193. 193.

    Kellow NJ, Coughlan MT. Effect of diet-derived advanced glycation end products on inflammation. Nutr Rev. 2015;73:737–59.

    PubMed  Google Scholar 

  194. 194.

    Ames JM, Wynne A, Hofmann A, Plos S, Gibson GR. The effect of a model melanoidin mixture on faecal bacterial populations in vitro. Br J Nutr. 1999;82:489–95.

    CAS  PubMed  Google Scholar 

  195. 195.

    Yacoub R, Nugent M, Cai W, Nadkarni GN, Chaves LD, Abyad S, et al. Advanced glycation end products dietary restriction effects on bacterial gut microbiota in peritoneal dialysis patients; a randomized open label controlled trial. PLoS ONE. 2017;12:e0184789.

    PubMed  PubMed Central  Google Scholar 

  196. 196.

    Ou J, Huang J, Zhao D, Du B, Wang M. Protective effect of rosmarinic acid and carnosic acid against streptozotocin-induced oxidation, glycation, inflammation and microbiota imbalance in diabetic rats. Food Funct. 2018;9:851–60.

    CAS  PubMed  Google Scholar 

  197. 197.

    Battson ML, Lee DM, Jarrell DK, Hou S, Ecton KE, Weir TL, et al. Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction. Am J Physiol Endocrinol Metab. 2018;314:E468–77.

    CAS  PubMed  Google Scholar 

  198. 198.

    Mastrocola R, Ferrocino I, Liberto E, Chiazza F, Cento AS, Collotta D, et al. Fructose liquid and solid formulations differently affect gut integrity, microbiota composition and related liver toxicity: a comparative in vivo study. J Nutr Biochem. 2018;55:185–99.

    CAS  PubMed  Google Scholar 

  199. 199.

    Qu W, Yuan X, Zhao J, Zhang Y, Hu J, Wang J, et al. Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats. Mol Nutr Food Res. 2017. https://doi.org/10.1002/mnfr.201700118.

  200. 200.

    Clementi A, Virzi GM, Goh CY, Cruz DN, Granata A, Vescovo G, et al. Cardiorenal syndrome type 4: a review. Cardiorenal Med. 2013;3:63–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Preeti J, Alexandre M, Pupalan I, Merlin TC, Claudio R. Chronic heart failure and comorbid renal dysfunction - a focus on type 2 cardiorenal syndrome. Curr Cardiol Rev. 2016;12:186–94.

    PubMed  PubMed Central  Google Scholar 

  202. 202.

    Lekawanvijit S. Role of gut-derived protein-bound uremic toxins in cardiorenal syndrome and potential treatment modalities. Circ J. Society. 2015;79:2088–97.

    CAS  Google Scholar 

  203. 203.

    Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 2013;83:1010–6.

    CAS  PubMed  Google Scholar 

  204. 204.

    Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008;3:1526–33.

    PubMed  PubMed Central  Google Scholar 

  205. 205.

    Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336:1268–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol. 2011;23:473–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353:1838–42.

    CAS  PubMed  Google Scholar 

  208. 208.

    Wang F, Zhang P, Jiang H, Cheng S. Gut bacterial translocation contributes to microinflammation in experimental uremia. Dig Dis Sci. 2012;57:2856–62.

    CAS  PubMed  Google Scholar 

  209. 209.

    Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002;347:185–92.

    CAS  PubMed  Google Scholar 

  210. 210.

    Niwa T. Role of indoxyl sulfate in the progression of chronic kidney disease and cardiovascular disease: experimental and clinical effects of oral sorbent AST-120. Ther Apher Dial. 2011;15:120–4.

    CAS  PubMed  Google Scholar 

  211. 211.

    Li T, Gua C, Wu B, Chen Y. Increased circulating trimethylamine N-oxide contributes to endothelial dysfunction in a rat model of chronic kidney disease. Biochem Biophys Res Commun. 2018;495:2071–7.

    CAS  PubMed  Google Scholar 

  212. 212.

    Borges NA, Barros AF, Nakao LS, Dolenga CJ, Fouque D, Mafra D. Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease. J Ren Nutr. 2016;26:396–400.

    CAS  PubMed  Google Scholar 

  213. 213.

    Mafra D, Fouque D. Gut microbiota and inflammation in chronic kidney disease patients. Clin Kidney J. 2015;8:332–4.

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Chan Q, Loo RL, Ebbels TM, Van Horn L, Daviglus ML, Stamler J, et al. Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview. Hypertens Res. 2017;40:336–45.

    PubMed  Google Scholar 

  215. 215.

    van Baarlen P, Troost FJ, van Hemert S, van der Meer C, de Vos WM, de Groot PJ, et al. Differential NF-kappaB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance. Proc Natl Acad Sci USA. 2009;106:2371–6.

    PubMed  Google Scholar 

  216. 216.

    Rastall RA, Gibson GR, Gill HS, Guarner F, Klaenhammer TR, Pot B, et al. Modulation of the microbial ecology of the human colon by probiotics, prebiotics and synbiotics to enhance human health: an overview of enabling science and potential applications. FEMS Microbiol Ecol. 2005;52:145–52.

    CAS  PubMed  Google Scholar 

  217. 217.

    Chen L, Liu W, Li Y, Luo S, Liu Q, Zhong Y, et al. Lactobacillus acidophilus ATCC 4356 attenuates the atherosclerotic progression through modulation of oxidative stress and inflammatory process. Int Immunopharmacol. 2013;17:108–15.

    PubMed  Google Scholar 

  218. 218.

    Wang IK, Wu YY, Yang YF, Ting IW, Lin CC, Yen TH, et al. The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial. Benef Microbes. 2015;6:423–30.

    PubMed  Google Scholar 

  219. 219.

    Brugere JF, Borrel G, Gaci N, Tottey W, O’Toole PW, Malpuech-Brugere C. Archaebiotics: proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease. Gut Microbes. 2014;5:5–10.

    PubMed  Google Scholar 

  220. 220.

    Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    Klinder A, Shen Q, Heppel S, Lovegrove JA, Rowland I, Tuohy KM. Impact of increasing fruit and vegetables and flavonoid intake on the human gut microbiota. Food Funct. 2016;7:1788–96.

    CAS  PubMed  Google Scholar 

  222. 222.

    Richter CK, Skulas-Ray AC, Champagne CM, Kris-Etherton PM. Plant protein and animal proteins: do they differentially affect cardiovascular disease risk? Adv Nutr. 2015;6:712–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Silk DB, Davis A, Vulevic J, Tzortzis G, Gibson GR. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. 2009;29:508–18.

    CAS  PubMed  Google Scholar 

  224. 224.

    Krishnamurthy VM, Wei G, Baird BC, Murtaugh M, Chonchol MB, Raphael KL, et al. High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease. Kidney Int. 2012;81:300–6.

    CAS  PubMed  Google Scholar 

  225. 225.

    Vaziri ND, Liu SM, Lau WL, Khazaeli M, Nazertehrani S, Farzaneh SH, et al. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease. PLoS ONE. 2014;9:e114881.

    PubMed  PubMed Central  Google Scholar 

  226. 226.

    Tome-Carneiro J, Visioli F. Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: review of human evidence. Phytomedicine. 2016;23:1145–74.

    CAS  PubMed  Google Scholar 

  227. 227.

    Cantarel BL, Waubant E, Chehoud C, Kuczynski J, DeSantis TZ, Warrington J, et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Invest Med. 2015;63:729–34.

    CAS  Google Scholar 

  228. 228.

    Shao Y, Lei Z, Yuan J, Yang Y, Guo Y, Zhang B. Effect of zinc on growth performance, gut morphometry, and cecal microbial community in broilers challenged with Salmonella enterica serovar typhimurium. J Microbiol. 2014;52:1002–11.

    CAS  PubMed  Google Scholar 

  229. 229.

    Dostal A, Lacroix C, Bircher L, Pham VT, Follador R, Zimmermann MB, et al. Iron modulates butyrate production by a child gut microbiota in vitro. mBio. 2015;6:e01453–01415.

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Hawrelak JA, Cattley T, Myers SP. Essential oils in the treatment of intestinal dysbiosis: a preliminary in vitro study. Altern Med Rev: a J Clin Ther. 2009;14:380–4.

    Google Scholar 

  231. 231.

    Yu HN, Zhu J, Pan WS, Shen SR, Shan WG, Das UN. Effects of fish oil with a high content of n-3 polyunsaturated fatty acids on mouse gut microbiota. Arch Med Res. 2014;45:195–202.

    CAS  PubMed  Google Scholar 

  232. 232.

    Zhu HL, Liu YL, Xie XL, Huang JJ, Hou YQ. Effect of L-arginine on intestinal mucosal immune barrier function in weaned pigs after Escherichia coli LPS challenge. Innate Immun. 2013;19:242–52.

    CAS  PubMed  Google Scholar 

  233. 233.

    McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59:426–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234.

    Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE. 2014;9:e100778.

    PubMed  PubMed Central  Google Scholar 

  235. 235.

    Wang L, Li P, Tang Z, Yan X, Feng B. Structural modulation of the gut microbiota and the relationship with body weight: compared evaluation of liraglutide and saxagliptin treatment. Sci Rep. 2016;6:33251.

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236.

    Mishima E, Fukuda S, Shima H, Hirayama A, Akiyama Y, Takeuchi Y, et al. Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD. J Am Soc Nephrol. 2015;26:1787–94.

    CAS  PubMed  Google Scholar 

  237. 237.

    Zeng YQ, Dai Z, Lu F, Lu Z, Liu X, Chen C, et al. Emodin via colonic irrigation modulates gut microbiota and reduces uremic toxins in rats with chronic kidney disease. Oncotarget. 2016;7:17468–78.

    PubMed  PubMed Central  Google Scholar 

  238. 238.

    Zhang X, Fang Z, Zhang C, Xia H, Jie Z, Han X, et al. Effects of acarbose on the gut microbiota of prediabetic patients: a randomized, double-blind, controlled crossover trial. Diabetes Ther. 2017;8:293–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239.

    Montandon SA, Jornayvaz FR. Effects of antidiabetic drugs on gut microbiota composition. Genes (Basel) 2017;8:E250.

  240. 240.

    Khan TJ, Ahmed YM, Zamzami MA, Siddiqui AM, Khan I, Baothman OAS, et al. Atorvastatin treatment modulates the gut microbiota of the hypercholesterolemic patients. OMICS. 2018;22:154–63.

    CAS  PubMed  Google Scholar 

  241. 241.

    Catry E, Pachikian BD, Salazar N, Neyrinck AM, Cani PD, Delzenne NM. Ezetimibe and simvastatin modulate gut microbiota and expression of genes related to cholesterol metabolism. Life Sci. 2015;132:77–84.

    CAS  PubMed  Google Scholar 

  242. 242.

    Costabile A, Buttarazzi I, Kolida S, Quercia S, Baldini J, Swann JR, et al. An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults. PLoS ONE. 2017;12:e0187964.

    PubMed  PubMed Central  Google Scholar 

  243. 243.

    Robles-Vera I, Toral M, Romero M, Jimenez R, Sanchez M, Perez-Vizcaino F, et al. Antihypertensive effects of probiotics. Curr Hypertens Rep. 2017;19:26.

    PubMed  Google Scholar 

  244. 244.

    Monda V, Villano I, Messina A, Valenzano A, Esposito T, Moscatelli F. et al. Exercise modifies the gut microbiota with positive health effects. Oxid Med Cell Longev. 2017;2017:3831972

    PubMed  PubMed Central  Google Scholar 

  245. 245.

    Delbes AS, Castel J, Denis RGP, Morel C, Quinones M, Everard A, et al. Prebiotics supplementation impact on the reinforcing and motivational aspect of feeding. Front Endocrinol (Lausanne). 2018;9:273.

    Google Scholar 

  246. 246.

    Bauer PV, Hamr SC, Duca FA. Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota. Cell Mol Life Sci. 2016;73:737–55.

    CAS  PubMed  Google Scholar 

  247. 247.

    Lyte M. Microbial endocrinology: host-microbiota neuroendocrine interactions influencing brain and behavior. Gut Microbes. 2014;5:381–9.

    PubMed  PubMed Central  Google Scholar 

  248. 248.

    Cani PD, Joly E, Horsmans Y, Delzenne NM. Oligofructose promotes satiety in healthy human: a pilot study. Eur J Clin Nutr. 2006;60:567–72.

    CAS  PubMed  Google Scholar 

  249. 249.

    Mack I, Cuntz U, Gramer C, Niedermaier S, Pohl C, Schwiertz A, et al. Weight gain in anorexia nervosa does not ameliorate the faecal microbiota, branched chain fatty acid profiles, and gastrointestinal complaints. Sci Rep. 2016;6:26752.

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250.

    Dinan TG, Cryan JF. Melancholic microbes: a link between gut microbiota and depression?. Neurogastroenterol Motil. 2013;25:713–9.

    CAS  PubMed  Google Scholar 

  251. 251.

    Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol. 2014;25:657–70.

    CAS  PubMed  Google Scholar 

  252. 252.

    Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D. Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res. 2017;179:24–37.

    CAS  PubMed  Google Scholar 

  253. 253.

    Ellis RJ, Small DM, Vesey DA, Johnson DW, Francis R, Vitetta L, et al. Indoxyl sulphate and kidney disease: causes, consequences and interventions. Nephrology (Carlton). 2016;21:170–7.

    CAS  Google Scholar 

  254. 254.

    Abratt VR, Reid SJ. Oxalate-degrading bacteria of the human gut as probiotics in the management of kidney stone disease. Adv Appl Microbiol. 2010;72:63–87.

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Mehmet Kanbay.

Ethics declarations

Funding

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Onal, E.M., Afsar, B., Covic, A. et al. Gut microbiota and inflammation in chronic kidney disease and their roles in the development of cardiovascular disease. Hypertens Res 42, 123–140 (2019). https://doi.org/10.1038/s41440-018-0144-z

Download citation

Keywords

  • Gut microbiota
  • Chronic kidney disease
  • Uremic toxins
  • Cardiovascular disease

Further reading

Search

Quick links