The role of the intestinal microbiota in uremic solute accumulation: a focus on sulfur compounds

  • Alessandra F. PernaEmail author
  • Griet Glorieux
  • Miriam Zacchia
  • Francesco Trepiccione
  • Giovanna Capolongo
  • Carmela Vigorito
  • Evgeniya Anishchenko
  • Diego Ingrosso


The gut microbiota is considered to be a novel important factor to take into account in the pathogenesis of chronic kidney disease and uremia. Much attention has been paid to specific uremic retention solutes of microbial origin, such as indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide. However, other novel less well studied compounds, such as hydrogen sulfide and related sulfur metabolites (sulfane sulfur, lanthionine, etc.), should be included in a more comprehensive appraisal of this topic, in light of the potential therapeutic opportunities for the future.


Microbiota Homocysteine Hydrogen sulfide Sulfane sulfur Lanthionine Chronic kidney disease Uremia Uremic toxins Dialysis 



We thank the European Uremic Toxin (EUTox) Work Group for supporting our research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest, except for AFP, who received research fundings from Gnosis S.p.A and EUTox.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.


  1. 1.
    Vanholder R, De Smet R, Glorieux G, Argilés A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jörres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W, European Uremic Toxin Work Group (EUTox) (2003) Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 63(5):1934–1943Google Scholar
  2. 2.
    Meijers B, Glorieux G, Poesen R, Bakker SJ (2014) Nonextracorporeal methods for decreasing uremic solute concentration: a future way to go? Semin Nephrol 34(2):228–243Google Scholar
  3. 3.
    Einheber A, Carter D (1966) The role of the microbial flora in uremia. I. Survival times of germfree, limited-flora, and conventionalized rats after bilateral nephrectomy and fasting. J Exp Med 123(2):239–250Google Scholar
  4. 4.
    Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI (2012) Human gut microbiome viewed across age and geography. Nature 486(7402):222–227Google Scholar
  5. 5.
    Ottman N, Smidt H, de Vos WM, Belzer C (2012) The function of our microbiota: who is out there and what do they do? Front Cell Infect Microbiol 2:104. Google Scholar
  6. 6.
    Aronov PA, Luo FJ, Plummer NS, Quan Z, Holmes S, Hostetter TH, Meyer TW (2011) Colonic contribution to uremic solutes. J Am Soc Nephrol 22(9):1769–1776Google Scholar
  7. 7.
    Mair RD, Sirich TL, Plummer NS, Meyer TW (2018) Characteristics of colon-derived uremic solutes. Clin J Am Soc Nephrol 13(9):1398–1404Google Scholar
  8. 8.
    Vanholder R, Glorieux G (2018) Gut-derived metabolites and chronic kidney disease. The forest (f) or the trees? Clin J Am Soc Nephrol 13:1311–1313Google Scholar
  9. 9.
    Cosola C, Rocchetti MT, Cupisti A, Gesualdo L (2018) Microbiota metabolites: pivotal players of cardiovascular damage in chronic kidney disease. Pharmacol Res 130:132–142Google Scholar
  10. 10.
    Li DY, Tang WHW (2018) Contributory role of gut microbiota and their metabolites toward cardiovascular complications in chronic kidney disease. Semin Nephrol 38(2):193–205Google Scholar
  11. 11.
    Lau WL, Savoj J, Nakata MB, Vaziri ND (2018) Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins. Clin Sci (Lond) 132(5):509–522Google Scholar
  12. 12.
    Noel S, Martina-Lingua MN, Bandapalle S, Pluznick J, Hamad AR, Peterson DA, Rabb H (2014) Intestinal microbiota-kidney cross talk in acute kidney injury and chronic kidney disease. Nephron Clin Pract 127(1–4):139–143Google Scholar
  13. 13.
    Fernandez-Prado R, Esteras R, Perez-Gomez MV, Gracia-Iguacel C, Gonzalez-Parra E, Sanz AB, Ortiz A, Sanchez-Niño MD (2017) Nutrients turned into toxins: microbiota modulation of nutrient properties in chronic kidney disease. Nutrients 9(5):489Google Scholar
  14. 14.
    Kikuchi M, Ueno M, Itoh Y, Suda W, Hattori M (2017) Uremic toxin-producing gut microbiota in rats with chronic kidney disease. Nephron 135(1):51–60Google Scholar
  15. 15.
    Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D (2014) Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol 9(3):399–410Google Scholar
  16. 16.
    Chaves LD, McSkimming DI, Bryniarski MA, Honan AM, Abyad S, Thomas SA, Wells S, Buck M, Sun Y, Genco RJ, Quigg RJ, Yacoub R (2018) Chronic kidney disease, uremic milieu, and its effects on gut bacterial microbiota dysbiosis. Am J Physiol Renal Physiol 315(3):F487–F502Google Scholar
  17. 17.
    Koppe L, Fouque D, Soulage CO (2018) The role of gut microbiota and diet on uremic retention solutes production in the context of chronic kidney disease. Toxins (Basel) 10(4):155Google Scholar
  18. 18.
    Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj DS (2016) Role of the gut microbiome in uremia: a potential therapeutic target. Am J Kidney Dis 67(3):483–498Google Scholar
  19. 19.
    Jankowski J, Westhof T, Vaziri ND, Ingrosso D, Perna AF (2014) Gases as uremic toxins: is there something in the air? Semin Nephrol 34(2):135–150Google Scholar
  20. 20.
    Devlin AS, Marcobal A, Dodd D, Nayfach S, Plummer N, Meyer T, Pollard KS, Sonnenburg JL, Fischbach MA (2016) Modulation of a circulating uremic solute via rational genetic manipulation of the gut microbiota. Cell Host Microbe 20(6):709–715Google Scholar
  21. 21.
    Yacoub R, Wyatt CM (2017) Manipulating the gut microbiome to decrease uremic toxins. Kidney Int 91(3):521–523Google Scholar
  22. 22.
    Kieffer DA, Piccolo BD, Vaziri ND, Liu S, Lau WL, Khazaeli M, Nazertehrani S, Moore ME, Marco ML, Martin RJ, Adams SH (2016) Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats. Am J Physiol Renal Physiol 310(9):F857–F871Google Scholar
  23. 23.
    Cupisti A, Brunori G, Di Iorio BR, D’Alessandro C, Pasticci F, Cosola C, Bellizzi V, Bolasco P, Capitanini A, Fantuzzi AL, Gennari A, Piccoli GB, Quintaliani G, Salomone M, Sandrini M, Santoro D, Babini P, Fiaccadori E, Gambaro G, Garibotto G, Gregorini M, Mandreoli M, Minutolo R, C (2018) Nutritional treatment of advanced CKD: twenty consensus statements. J Nephrol 31(4):457–473Google Scholar
  24. 24.
    Bellizzi V, Conte G, Borrelli S, Cupisti A, De Nicola L, Di Iorio BR, Cabiddu G, Mandreoli M, Paoletti E, Piccoli GB, Quintaliani G, Ravera M, Santoro D, Torraca S, Minutolo R, “Conservative Treatment of CKD” Study Group of the Italian Society of Nephrology (2017) Controversial issues in CKD clinical practice: position statement of the CKD-treatment working group of the Italian Society of Nephrology. J Nephrol 30(2):159–170Google Scholar
  25. 25.
    Di Iorio BR, Cupisti A, D’Alessandro C, Bellasi A, Barbera V, Di Lullo L (2018) Nutritional therapy in autosomal dominant polycystic kidney disease. J Nephrol 31(5):635–643Google Scholar
  26. 26.
    Cosola C, Rocchetti MT, Sabatino A, Fiaccadori E, Di Iorio BR, Gesualdo L (2018) Microbiota issue in CKD: how promising are gut-targeted approaches ? J Nephrol. Google Scholar
  27. 27.
    Rollino C, Vischini G, Coppo R (2016) IgA nephropathy and infections. J Nephrol 29(4):463–468Google Scholar
  28. 28.
    Black AP, Anjos JS, Cardozo L, Carmo FL, Dolenga CJ, Nakao LS, de Carvalho Ferreira D, Rosado A, Carraro Eduardo JC, Mafra D (2018) Does low-protein diet influence the uremic toxin serum levels from the gut microbiota in nondialysis chronic kidney disease patients? J Ren Nutr 28(3):208–214Google Scholar
  29. 29.
    Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, Choukroun G, Vanholder R, Massy ZA, European Uremic Toxin Work Group (EUTox) (2009) Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 4(10):1551–1558Google Scholar
  30. 30.
    Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y (2006) Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int 69(6):1081–1087Google Scholar
  31. 31.
    Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, Schepers E, Temmar M, Choukroun G, Vanholder R, Massy ZA, European Uraemic Toxin Work Group (EUTox) (2010) Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transpl 25(4):1183–1191Google Scholar
  32. 32.
    Liabeuf S, Glorieux G, Lenglet A, Diouf M, Schepers E, Desjardins L, Choukroun G, Vanholder R, Massy ZA, European Uremic Toxin (EUTox) Work Group (2013) Does p-cresylglucuronide have the same impact on mortality as other protein-bound uremic toxins? PLoS One 8(6):e67168Google Scholar
  33. 33.
    Mishima E, Fukuda S, Mukawa C, Yuri A, Kanemitsu Y, Matsumoto Y, Akiyama Y, Fukuda NN, Tsukamoto H, Asaji K, Shima H, Kikuchi K, Suzuki C, Suzuki T, Tomioka Y, Soga T, Ito S, Abe T (2017) Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach. Kidney Int 92(3):634–645Google Scholar
  34. 34.
    Vanholder R, Glorieux G (2015) The intestine and the kidneys: a bad marriage can be hazardous. Clin Kidney J 8(2):168–179Google Scholar
  35. 35.
    Streeter E, Ng HH, Hart JL (2013) Hydrogen sulfide as a vasculoprotective factor. Med Gas Res 3(1):9Google Scholar
  36. 36.
    Weber GJ, Pushpakumar S, Tyagi SC, Sen U (2016) Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension. Pharmacol Res 113:300–312Google Scholar
  37. 37.
    Flannigan KL, McCoy KD, Wallace JL (2011) Eukaryotic and prokaryotic contributions to colonic hydrogen sulfide synthesis. Am J Physiol Gastrointest Liver Physiol 301(1):G188–G193Google Scholar
  38. 38.
    Barton LL, Ritz NL, Fauque GD, Lin HC (2017) Sulfur cycling and the intestinal microbiome. Dig Dis Sci 62(9):2241–2257Google Scholar
  39. 39.
    Perna AF, Luciano MG, Ingrosso D, Pulzella P, Sepe I, Lanza D, Violetti E, Capasso R, Lombardi C, De Santo NG (2009) Hydrogen sulphide-generating pathways in haemodialysis patients: a study on relevant metabolites and transcriptional regulation of genes encoding for key enzymes. Nephrol Dial Transpl 24(12):3756–3763Google Scholar
  40. 40.
    Aminzadeh MA, Vaziri ND (2012) Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease. Nephrol Dial Transpl 27(2):498–504Google Scholar
  41. 41.
    Kuang Q, Xue N, Chen J, Shen Z, Cui X, Fang Y, Ding X (2018) Low plasma hydrogen sulfide is associated with impaired renal function and cardiac dysfunction. Am J Nephrol 47(5):361–371Google Scholar
  42. 42.
    Zacchia M, Capasso G (2015) The importance of uromodulin as regulator of salt reabsorption along the thick ascending limb. Nephrol Dial Transpl 30(2):158–160Google Scholar
  43. 43.
    Perna AF, Ingrosso D (2012) Low hydrogen sulphide and chronic kidney disease: a dangerous liaison. Nephrol Dial Transpl 27(2):486–493Google Scholar
  44. 44.
    Shen X, Carlström M, Borniquel S, Jädert C, Kevil CG, Lundberg JO (2013) Microbial regulation of host hydrogen sulfide bioavailability and metabolism. Free Radic Biol Med 60:195–200Google Scholar
  45. 45.
    Perna AF, Di Nunzio A, Amoresano A, Pane F, Fontanarosa C, Pucci P, Vigorito C, Cirillo G, Zacchia M, Trepiccione F, Ingrosso D (2016) Divergent behavior of hydrogen sulfide pools and of the sulfur metabolite lanthionine, a novel uremic toxin, in dialysis patients. Biochimie 126:97–107Google Scholar
  46. 46.
    Patrick J. Knerr, Wilfred A, van der Donk (2012) Discovery, biosynthesis, and engineering of lantipeptides. Annu Rev Biochem 81:479–505Google Scholar
  47. 47.
    Perna AF, Zacchia M, Trepiccione F, Ingrosso D (2017) The sulfur metabolite lanthionine: evidence for a role as a novel uremic toxin. Toxins (Basel) 9(1):26Google Scholar
  48. 48.
    Perna AF, Anishchenko E, Vigorito C, Zacchia M, Trepiccione F, D’Aniello S, Ingrosso D (2018) Zebrafish, a novel model system to study uremic toxins: the case for the sulfur amino acid lanthionine. Int J Mol Sci 19(5):E1323. Google Scholar
  49. 49.
    Perna AF, Ingrosso D, Satta E, Lombardi C, Acanfora F, De Santo NG (2004) Homocysteine metabolism in renal failure. Curr Opin Clin Nutr Metab Care 7(1):53–57Google Scholar
  50. 50.
    Perna AF, Ingrosso D, Satta E, Romano M, Cimmino A, Galletti P, Zappia V, De Santo NG (2001) Metabolic consequences of hyperhomocysteinemia in uremia. Am J Kidney Dis 38(4 Suppl 1):S85–S90Google Scholar
  51. 51.
    Perna AF, Acanfora F, Luciano MG, Pulzella P, Capasso R, Satta E, Cinzia L, Pollastro RM, Iannelli S, Ingrosso D, De Santo NG (2007) Plasma protein homocysteinylation in uremia. Clin Chem Lab Med 45(12):1678–1682Google Scholar
  52. 52.
    Capasso R, Sambri I, Cimmino A, Salemme S, Lombardi C, Acanfora F, Satta E, Puppione DL, Perna AF, Ingrosso D (2012) Homocysteinylated albumin promotes increased monocyte-endothelial cell adhesion and up-regulation of MCP1, Hsp60 and ADAM17. PLoS One 7(2):e31388Google Scholar
  53. 53.
    Perna AF, Ingrosso D, Satta E, Lombardi C, Galletti P, D’Aniello A, De Santo NG (2004) Plasma protein aspartyl damage is increased in hemodialysis patients: studies on causes and consequences. J Am Soc Nephrol 15(10):2747–2754Google Scholar
  54. 54.
    Perna AF, Castaldo P, De Santo NG, di Carlo E, Cimmino A, Galletti P, Zappia V, Ingrosso D (2001) Plasma proteins containing damaged L-isoaspartyl residues are increased in uremia: implications for mechanism. Kidney Int 59(6):2299–2308Google Scholar
  55. 55.
    Perna AF, D’Aniello A, Lowenson JD, Clarke S, De Santo NG, Ingrosso D (1997) D-aspartate content of erythrocyte membrane proteins is decreased in uremia: implications for the repair of damaged proteins. J Am Soc Nephrol 8(1):95–104Google Scholar
  56. 56.
    Hill MJ (1997) Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev 6(Suppl 1):S43–S45Google Scholar
  57. 57.
    Rossi M, Amaretti A, Raimondi S (2011) Folate production by probiotic bacteria. Nutrients 3(1):118–134Google Scholar
  58. 58.
    Gerhauser C (2018) Impact of dietary gut microbial metabolites on the epigenome. Philos Trans R Soc B 373(1748):20170359Google Scholar
  59. 59.
    Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, De Bonis ML, Vacca M, D’Esposito M, D’Urso M, Galletti P, Zappia V (2003) Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361(9370):1693–1699Google Scholar
  60. 60.
    Perna AF, Lanza D, Sepe I, Conzo G, Altucci L, Ingrosso D (2013) Altered folate receptor 2 expression in uraemic patients on haemodialysis: implications for folate resistance. Nephrol Dial Transpl 28:1214–1224Google Scholar
  61. 61.
    Xu X, Qin X, Li Y, Sun D, Wang J, Liang M, Wang B, Huo Y, Hou FF, investigators of the Renal Substudy of the China Stroke Primary Prevention Trial (CSPPT) (2016) Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal substudy of the china stroke primary prevention trial. JAMA Intern Med 176(10):1443–1450Google Scholar
  62. 62.
    Wyatt CM, Spence JD (2016) Folic acid supplemetation and chronic kidney disease progression. Kidney Int 90:1142–1145Google Scholar
  63. 63.
    Feng SJ, Li H, Wang SX (2015) Lower hydrogen sulfide is associated with cardiovascular mortality, which involves cPKCβII/Akt pathway in chronic hemodialysis patients. Blood Purif 240(3):260–269. Google Scholar
  64. 64.
    Wu D, Luo N, Wang L, Zhao Z, Bu H, Xu G, Yan Y, Che X, Jiao Z, Zhao T, Chen J, Ji A, Li Y, Lee GD (2017) Hydrogen sulfide ameliorates chronic renal failure in rats by inhibiting apoptosis and inflammation through ROS/MAPK and NF-κB signaling pathways. Sci Rep 7(1):455Google Scholar
  65. 65.
    Zhang L, Wang Y, Li Y, Li L, Xu S, Feng X, Liu S (2018) Hydrogen sulfide (H2S)-releasing compounds: therapeutic potential in cardiovascular diseases. Front Pharmacol 9:1066Google Scholar
  66. 66.
    Giustarini D, Tazzari V, Bassanini I, Rossi R, Sparatore A (2018) The new H2S-releasing compound ACS94 exerts protective effects through the modulation of thiol homoeostasis. J Enzyme Inhib Med Chem 33(1):1392–1404Google Scholar
  67. 67.
    Hsu C, Tain Y (2019) Hydrogen sulfide in hypertension and kidney disease of developmental origins. J Mol Sci 19:1438. Google Scholar
  68. 68.
    Vicente JB, Malagrinò F, Arese M, Forte E, Sarti P, Giuffrè A (2016) Bioenergetic relevance of hydrogen sulfide and the interplay between gasotransmitters at human cystathionine β-synthase. Biochim Biophys Acta 1857(8):1127–1138Google Scholar

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© Italian Society of Nephrology 2019

Authors and Affiliations

  1. 1.First Division of Nephrology, Department of Translational Medical Sciences, School of MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly
  2. 2.Nephrology Section, Department of Internal Medicine and PediatricsGhent University HospitalGhentBelgium
  3. 3.Department of Precision Medicine, School of MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly

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