Can curcumin supplementation reduce plasma levels of gut-derived uremic toxins in hemodialysis patients? A pilot randomized, double-blind, controlled study

International Urology and Nephrology (2021)Cite this article

Abstract

Background

Gut dysbiosis is common in patients with chronic kidney disease (CKD) and is closely related to inflammatory processes. Some nutritional strategies, such as bioactive compounds present in curcumin, have been proposed as an option to modulate the gut microbiota and decrease the production of uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS) and indole-3 acetic acid (IAA).

Objective

To evaluate the effects of curcumin supplementation on uremic toxins plasma levels produced by gut microbiota in patients with CKD on hemodialysis (HD).

Methods

Randomized, double-blind trial in 28 patients [53.6 ± 13.4 years, fourteen men, BMI 26.7 ± 3.7 kg/m2, dialysis vintage 37.5 (12–193) months]. Fourteen patients were randomly allocated to the curcumin group and received 100 mL of orange juice with 12 g carrot and 2.5 g of turmeric and 14 patients to the control group who received the same juice but without turmeric three times per week after HD sessions for three months. IS, pCS, IAA plasma levels were measured by reverse-phase high-performance liquid chromatography

Results

After three months of supplementation, the curcumin group showed a significant decrease in pCS plasma levels [from 32.4 (22.1–45.9) to 25.2 (17.9–37.9) mg/L, p = 0.009], which did not occur in the control group. No statistical difference was observed in IS and IAA levels in both groups.

Conclusion

The oral supplementation of curcumin for three months seems to reduce p-CS plasma levels in HD patients, suggesting a gut microbiota modulation.

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References

  1. 1.

    Koppe L, Mafra D, Fouque D (2015) Probiotics and chronic kidney disease. Kidney Int 88(5):958–966. https://doi.org/10.1038/ki.2015.255

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R (2012) Diversity, stability and resilience of the human gut microbiota. Nature 489(7415):220–230. https://doi.org/10.1038/nature11550

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Vaziri ND, Liu S, Farzaneh SH, Nazertehrani S, Khazaeli M, Zhao YY (2015) Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease. Free Radic Biol Med 86:374–381. https://doi.org/10.1016/j.freeradbiomed.2015.04.022

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E (2017) Dysbiosis and the immune system. Nat Rev Immunol 17(4):219–232. https://doi.org/10.1038/nri.2017.7

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Meijers BK, Evenepoel P (2011) The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrol Dial Transplant 26(3):759–761. https://doi.org/10.1093/ndt/gfq818

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Musso G, Gambino R, Cassader M (2011) Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med 62:361–380. https://doi.org/10.1146/annurev-med-012510-175505

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    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):399–410. https://doi.org/10.2217/fmb.13.165

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Barros AF, Borges NA, Ferreira DC et al (2015) Is there interaction between gut microbial profile and cardiovascular risk in chronic kidney disease patients? Future Microbiol 10(4):517–526. https://doi.org/10.2217/fmb.14.140

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Basile C, Libutti P, Di Turo AL et al (2011) Removal of uraemic retention solutes in standard bicarbonate haemodialysis and long-hour slow-flow bicarbonate haemodialysis. Nephrol Dial Transplant 26(4):1296–1303. https://doi.org/10.1093/ndt/gfq543

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Meyer TW, Hostetter TH (2012) Uremic solutes from colon microbes. Kidney Int 81(10):949–954. https://doi.org/10.1038/ki.2011.504

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Borges NA, Barros AF, Nakao LS, Dolenga CJ, Fouque D, Mafra D (2016) Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease. J Ren Nutr 26(6):396–400. https://doi.org/10.1053/j.jrn.2016.07.005

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Borges NA, Carmo FL, Stockler-Pinto MB et al (2018) Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled Trial. J Ren Nutr 28(1):28–36. https://doi.org/10.1053/j.jrn.2017.06.010

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Liakopoulos V, Roumeliotis S, Zarogiannis S, Eleftheriadis T, Mertens PR (2019) Oxidative stress in hemodialysis: causative mechanisms, clinical implications, and possible therapeutic interventions. Semin Dial 32(1):58–71. https://doi.org/10.1111/sdi.12745

    Article  PubMed  Google Scholar 

  14. 14.

    Liakopoulos V, Roumeliotis S, Gorny X, Dounousi E, Mertens PR (2017) Oxidative stress in hemodialysis patients: a review of the literature. Oxid Med Cell Longev 2017:3081856. https://doi.org/10.1155/2017/3081856

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Sonnenburg JL, Bäckhed F (2016) Diet–microbiota interactions as moderators of human metabolism. Nature 535(7610):56–64. https://doi.org/10.1038/nature18846

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Singh R, Chandrashekharappa S, Bodduluri SR et al (2019) Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 10(1):89. https://doi.org/10.1038/s41467-018-07859-7 (Published 2019 Jan 9)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Meijers BK, Bammens B, De Moor B, Verbeke K, Vanrenterghem Y, Evenepoel P (2008) Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int 73(10):1174–1180. https://doi.org/10.1038/ki.2008.31

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Shao W, Yu Z, Chiang Y et al (2012) Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. PLoS ONE 7(1):e28784. https://doi.org/10.1371/journal.pone.0028784

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Weisberg SP, Leibel R, Tortoriello DV (2008) Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology 149(7):3549–3558. https://doi.org/10.1210/en.2008-0262

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Pakfetrat M, Akmali M, Malekmakan L, Dabaghimanesh M, Khorsand M (2015) Role of turmeric in oxidative modulation in end-stage renal disease patients. Hemodial Int 19(1):124–131. https://doi.org/10.1111/hdi.12204

    Article  PubMed  Google Scholar 

  21. 21.

    Mafra D, Borges N, Alvarenga L et al (2019) Dietary components that may influence the disturbed gut microbiota in chronic kidney disease. Nutrients 11(3):496. https://doi.org/10.3390/nu11030496

    CAS  Article  PubMed Central  Google Scholar 

  22. 22.

    Wang Y, Lu Z, Wu H, Lv F (2009) Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens. Int J Food Microbiol 136(1):71–74. https://doi.org/10.1016/j.ijfoodmicro.2009.09.001

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ghosh SS, Gehr TW, Ghosh S (2014) Curcumin and chronic kidney disease (CKD): major mode of action through stimulating endogenous intestinal alkaline phosphatase. Molecules 19(12):20139–20156. https://doi.org/10.3390/molecules191220139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Feng W, Wang H, Zhang P et al (2017) Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats. Biochim Biophys Acta Gen Subj 1861(7):1801–1812. https://doi.org/10.1016/j.bbagen.2017.03.017

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Wang J, Ghosh SS, Ghosh S (2017) Curcumin improves intestinal barrier function: modulation of intracellular signaling, and organization of tight junctions. Am J Physiol Cell Physiol 312(4):C438–C445. https://doi.org/10.1152/ajpcell.00235.2016

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Alvarenga LA, Leal VO, Borges NA, Aguiar AS, Faxen-Irving G, Stenvinkel P et al (2018) Curcumin—a promising nutritional strategy for chronic kidney disease patients. J Funct Foods 40:715. https://doi.org/10.1016/j.jff.2017.12.015

    CAS  Article  Google Scholar 

  27. 27.

    Khajehdehi P (2012) Turmeric: reemerging of a neglected Asian traditional remedy. J Nephropathol 1(1):17–22. https://doi.org/10.5812/jnp.5

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Roumeliotis S, Roumeliotis A, Gorny X, Mertens P (2020) Could antioxidant supplementation delay progression of cardiovascular disease in end-stage renal disease patients? Curr Vasc Pharmacol. https://doi.org/10.2174/1570161118666200317151553

    Article  Google Scholar 

  29. 29.

    Liakopoulos V, Roumeliotis S, Bozikas A, Eleftheriadis T, Dounousi E (2019) Antioxidant supplementation in renal replacement therapy patients: is there evidence? Oxid Med Cell Longev 2019:9109473. https://doi.org/10.1155/2019/9109473

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Alvarenga L, Salarolli R, Cardozo LFMF et al (2020) Impact of curcumin supplementation on expression of inflammatory transcription factors in hemodialysis patients: a pilot randomized, double-blind, controlled study. Clin Nutr S0261–5614(20):30110–30112. https://doi.org/10.1016/j.clnu.2020.03.007

    CAS  Article  Google Scholar 

  31. 31.

    Meert N, Schepers E, Glorieux G et al (2012) Novel method for simultaneous determination of p-cresylsulphate and p-cresylglucuronide: clinical data and pathophysiological implications. Nephrol Dial Transplant 27(6):2388–2396. https://doi.org/10.1093/ndt/gfr672

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Espi M, Koppe L, Fouque D, Thaunat O (2020) Chronic kidney disease-associated immune dysfunctions: impact of protein-bound uremic retention solutes on immune cells. Toxins (Basel) 12(5):300. https://doi.org/10.3390/toxins12050300

    CAS  Article  Google Scholar 

  33. 33.

    Deltombe O, Van Biesen W, Glorieux G, Massy Z, Dhondt A, Eloot S (2015) Exploring protein binding of uremic toxins in patients with different stages of chronic kidney disease and during hemodialysis. Toxins (Basel) 7(10):3933–3946. https://doi.org/10.3390/toxins7103933

    CAS  Article  Google Scholar 

  34. 34.

    Nigam SK, Bush KT (2019) Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling. Nat Rev Nephrol 15(5):301–316. https://doi.org/10.1038/s41581-019-0111-1

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    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):509–522. https://doi.org/10.1042/CS20171107

    CAS  Article  Google Scholar 

  36. 36.

    Plata C, Cruz C, Cervantes LG, Ramírez V (2019) The gut microbiota and its relationship with chronic kidney disease. Int Urol Nephrol 51(12):2209–2226. https://doi.org/10.1007/s11255-019-02291-2

    Article  PubMed  Google Scholar 

  37. 37.

    Briskey D, Tucker P, Johnson DW, Coombes JS (2017) The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development. Clin Exp Nephrol 21(1):7–15. https://doi.org/10.1007/s10157-016-1255-y

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Rodrigues SD, Santos SS, Meireles T et al (2020) Uremic toxins promote accumulation of oxidized protein and increased sensitivity to hydrogen peroxide in endothelial cells by impairing the autophagic flux. Biochem Biophys Res Commun 523(1):123–129. https://doi.org/10.1016/j.bbrc.2019.12.022

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Sumida K, Kovesdy CP (2019) The gut–kidney–heart axis in chronic kidney disease. Physiol Int 106(3):195–206. https://doi.org/10.1556/2060.106.2019.19

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Glorieux G, Gryp T, Perna A (2020) Gut-derived metabolites and their role in immune dysfunction in chronic kidney disease. Toxins (Basel) 12(4):245. https://doi.org/10.3390/toxins12040245

    CAS  Article  Google Scholar 

  41. 41.

    Pieniazek A, Gwozdzinski L, Hikisz P, Gwozdzinski K (2018) Indoxyl sulfate generates free radicals, decreases antioxidant defense, and leads to damage to mononuclear blood cells. Chem Res Toxicol 31(9):869–875. https://doi.org/10.1021/acs.chemrestox.8b00065

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D (2017) Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res 179:24–37. https://doi.org/10.1016/j.trsl.2016.04.007

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Mafra D, Fouque D (2015) Gut microbiota and inflammation in chronic kidney disease patients. Clin Kidney J 8(3):332–334. https://doi.org/10.1093/ckj/sfv026

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Stockler-Pinto MB, Soulage CO, Borges NA et al (2018) From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF-κB/Nrf2 expression. Int Urol Nephrol 50(2):347–354. https://doi.org/10.1007/s11255-017-1748-y

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Gouroju S, Rao PVLNS, Bitla AR, Vinapamula KS, Manohar SM, Vishnubhotla S (2017) Role of gut-derived uremic toxins on oxidative stress and inflammation in patients with chronic kidney disease. Indian J Nephrol. 27(5):359–364. https://doi.org/10.4103/ijn.IJN_71_17

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Castillo-Rodriguez E, Fernandez-Prado R, Esteras R et al (2018) Impact of altered intestinal microbiota on chronic kidney disease progression. Toxins (Basel) 10(7):300. https://doi.org/10.3390/toxins10070300

    CAS  Article  Google Scholar 

  47. 47.

    Cases A, Cigarrán-Guldrís S, Mas S, Gonzalez-Parra E (2019) Vegetable-based diets for chronic kidney disease? It is time to reconsider. Nutrients 11(6):1263. https://doi.org/10.3390/nu11061263 (Published 2019 Jun 4)

    CAS  Article  PubMed Central  Google Scholar 

  48. 48.

    Bao N, Chen F, Dai D (2020) The regulation of host intestinal microbiota by polyphenols in the development and prevention of chronic kidney disease. Front Immunol 10:2981. https://doi.org/10.3389/fimmu.2019.02981

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Zhang Z, Chen Y, Xiang L, Wang Z, Xiao GG, Hu J (2017) Effect of curcumin on the diversity of gut microbiota in ovariectomized rats. Nutrients 9(10):1146. https://doi.org/10.3390/nu9101146

    CAS  Article  PubMed Central  Google Scholar 

  50. 50.

    Peterson CT, Vaughn AR, Sharma V et al (2018) Effects of turmeric and curcumin dietary supplementation on human gut microbiota: a double-blind, randomized, placebo-controlled pilot study. J Evid Based Integr Med. https://doi.org/10.1177/2515690X18790725

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zam W (2018) Gut microbiota as a prospective therapeutic target for curcumin: a review of mutual influence. J Nutr Metab 2018:1367984. https://doi.org/10.1155/2018/1367984

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Shen L, Liu L, Ji HF (2017) Regulative effects of curcumin spice administration on gut microbiota and its pharmacological implications. Food Nutr Res 61(1):1361780. https://doi.org/10.1080/16546628.2017.1361780

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Chen YM, Chiu WC, Chiu YS, Li T, Sung HC, Hsiao CY (2020) Supplementation of nano-bubble curcumin extract improves gut microbiota composition and exercise performance in mice. Food Funct 11(4):3574–3584. https://doi.org/10.1039/c9fo02487e

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Shen L, Ji HF (2019) Bidirectional interactions between dietary curcumin and gut microbiota. Crit Rev Food Sci Nutr 59(18):2896–2902. https://doi.org/10.1080/10408398.2018.1478388

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Pluta R, Januszewski S, Ułamek-Kozioł M (2020) Mutual two-way interactions of curcumin and gut microbiota. Int J Mol Sci 21(3):1055. https://doi.org/10.3390/ijms21031055 (Published 2020 Feb 5)

    CAS  Article  PubMed Central  Google Scholar 

  56. 56.

    Burge K, Gunasekaran A, Eckert J, Chaaban H (2019) Curcumin and intestinal inflammatory diseases: molecular mechanisms of protection. Int J Mol Sci 20(8):1912. https://doi.org/10.3390/ijms20081912 (Published 2019 Apr 18)

    CAS  Article  PubMed Central  Google Scholar 

  57. 57.

    Ali BH, Karaca T, Al Suleimani Y et al (2017) The effect of swimming exercise on adenine-induced kidney disease in rats, and the influence of curcumin or lisinopril thereon. PLoS ONE 12(4):e0176316. https://doi.org/10.1371/journal.pone.0176316

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ohno M, Nishida A, Sugitani Y et al (2017) Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells. PLoS ONE 12(10):e0185999. https://doi.org/10.1371/journal.pone.0185999

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Ali BH, Al-Salam S, Al Suleimani Y et al (2018) Curcumin ameliorates kidney function and oxidative stress in experimental chronic kidney disease. Basic Clin Pharmacol Toxicol 122(1):65–73. https://doi.org/10.1111/bcpt.12817

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Vamanu E, Gatea F, Sârbu I, Pelinescu D (2019) An in vitro study of the influence of curcuma longa extracts on the microbiota modulation process, in patients with hypertension. Pharmaceutics 11(4):191. https://doi.org/10.3390/pharmaceutics11040191

    CAS  Article  PubMed Central  Google Scholar 

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Acknowledgements

Conselho Nacional de Pesquisa (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) support Denise Mafra research. CAPES-COFECUB (Comité Français d´Evaluation de la Coopération Universitaire avec le Brésil) support Denis Fouque and Denise Mafra.

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Affiliations

  1. Graduate Program in Nutrition Sciences, Federal Fluminense University (UFF), Niterói, RJ, Brazil

    Roberta T. Salarolli & Denise Mafra

  2. Graduate Program in Medical Sciences, Federal Fluminense University (UFF), Niterói, RJ, Brazil

    Livia Alvarenga, Karla T. R. Teixeira, Laís de S. G. Moreira & Denise Mafra

  3. Graduate Program in Cardiovascular Sciences, Federal Fluminense University (UFF), Niterói, RJ, Brazil

    Ludmila F. M. F. Cardozo & Denise Mafra

  4. Department of Basic Pathology, Federal University of Parana (UFPR), Curitiba, Brazil

    Jordana D. Lima, Silvia D. Rodrigues & Lia S. Nakao

  5. Department of Nephrology, Hospital Lyon Sud, INSERM 1060, Université Claude Bernard, 69495, Lyon, France

    Denis Fouque

  6. Unidade de Pesquisa Clínica, Rua Marques do Paraná, 303, Niterói, RJ, 24033-900, Brazil

    Denise Mafra

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Salarolli, R.T., Alvarenga, L., Cardozo, L.F.M.F. et al. Can curcumin supplementation reduce plasma levels of gut-derived uremic toxins in hemodialysis patients? A pilot randomized, double-blind, controlled study. Int Urol Nephrol (2021). https://doi.org/10.1007/s11255-020-02760-z

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Keywords

  • Chronic kidney disease
  • Hemodialysis
  • Uremic toxins
  • Curcumin
  • Gut microbiota