The Impact of Specific Gut Microbiota Metabolites on Chronic Kidney Disease Progression: Novel Diagnostic Biomarkers and Therapeutic Targets
DOI:
https://doi.org/10.12775/JEHS.2025.77.57110Keywords
chronic kidney disease, gut microbiota, modulation of bacterial metabolites, fecal microbiota transplantationAbstract
Introduction: Chronic kidney disease is characterized by an irreversible and gradually progressive process. Recent research has highlighted the role of metabolites derived from the intestinal microbiota as important factors in the progression of this disease. Consequently, numerous studies have focused on the impact of the microbiota, its diagnostic potential, and its therapeutic applications.
Aim of the study: This study highlights the role of specific gut microbiota in chronic kidney disease and its potential applications in diagnosis and therapy.
Material and methods: An English-language literature review was conducted, analyzing studies from the PubMed database up to December 2024 regarding the correlation between specific gut microbiota and chronic kidney disease. The review was performed using the PubMed database, with 57 works used.
Conclusion: Chronic kidney disease is characterized by a slow, progressive, and irreversible decline in kidney function. Recent studies have highlighted the significant role of metabolites produced by the intestinal microbiota in the progression of this disease. Consequently, extensive research has been conducted on the impact of these metabolites for diagnostic purposes as well as their potential therapeutic applications. These metabolites can aid in both diagnosing the condition and predicting its progression. Emerging therapies that manipulate the microbiota—through approaches such as dietary changes, probiotics, modulation of bacterial metabolites, fecal microbiota transplantation, or the use of genetically modified bacteria—have shown promising results. However, further research is essential to fully develop and refine these therapeutic strategies.
References
1. Ammirati AL. Chronic Kidney Disease. Rev Assoc Med Bras. 2020;66Suppl 1(Suppl 1):s03–9. https://doi.org/10.1590/1806-9282.66.S1.3
2. Yan M-T, Chao C-T, Lin S-H. Chronic kidney disease: strategies to retard progression. Int J Mol Sci. 2021;22(18). https://doi.org/10.3390/ijms221810084
3. Luyckx VA, Tonelli M, Stanifer JW. The global burden of kidney disease and the sustainable development goals. Bull World Health Organ. 2018;96(6):414-422D. https://doi.org/10.2471/BLT.17.206441
4. Yin L, Li X, Ghosh S, Xie C, Chen J, Huang H. Role of gut microbiota-derived metabolites on vascular calcification in CKD. J Cell Mol Med. 2021;25(3):1332–41. https://doi.org/10.1111/jcmm.16230
5. Voroneanu L, Burlacu A, Brinza C, Covic A, Balan GG, Nistor I, Popa C, Hogas S, Covic A. Gut Microbiota in Chronic Kidney Disease: From Composition to Modulation towards Better Outcomes-A Systematic Review. J Clin Med. 2023;12(5). https://doi.org/10.3390/jcm12051948
6. He M, Wei W, Zhang Y, Xiang Z, Peng D, Kasimumali A, Rong S. Gut microbial metabolites SCFAs and chronic kidney disease. J Transl Med. 2024;22(1):172. https://doi.org/10.1186/s12967-024-04974-6
7. Mafune A, Iwamoto T, Tsutsumi Y, Nakashima A, Yamamoto I, Yokoyama K, Yokoo T, Urashima M. Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: a cross-sectional study. Clin Exp Nephrol. 2016;20(5):731–9. https://doi.org/10.1007/s10157-015-1207-y
8. Zhen J, Zhou Z, He M, Han H-X, Lv E-H, Wen P-B, Liu X, Wang Y-T, Cai X-C, Tian J-Q, Zhang M-Y, Xiao L, Kang X-X. The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases. Front Endocrinol (Lausanne). 2023;14:1085041. https://doi.org/10.3389/fendo.2023.1085041
9. Rysz J, Franczyk B, Ławiński J, Olszewski R, Ciałkowska-Rysz A, Gluba-Brzózka A. The impact of CKD on uremic toxins and gut microbiota. Toxins (Basel). 2021;13(4). https://doi.org/10.3390/toxins13040252
10. Mutalub YB, Abdulwahab M, Mohammed A, Yahkub AM, Al-Mhanna SB, Yusof W, Tang SP, Rasool AHG, Mokhtar SS. Gut microbiota modulation as a novel therapeutic strategy in cardiometabolic diseases. Foods. 2022;11(17). https://doi.org/10.3390/toxins13040252
11. Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021;70(6):1174–82. https://doi.org/10.1136/gutjnl-2020-323071
12. Coker OO, Liu C, Wu WKK, Wong SH, Jia W, Sung JJY, Yu J. Altered gut metabolites and microbiota interactions are implicated in colorectal carcinogenesis and can be non-invasive diagnostic biomarkers. Microbiome. 2022;10(1):35. https://doi.org/10.1186/s40168-021-01208-5
13. Hajjo R, Sabbah DA, Al Bawab AQ. Unlocking the potential of the human microbiome for identifying disease diagnostic biomarkers. Diagnostics (Basel). 2022;12(7). https://doi.org/10.3390/diagnostics12071742
14. Joshi S, Hashmi S, Shah S, Kalantar-Zadeh K. Plant-based diets for prevention and management of chronic kidney disease. Curr Opin Nephrol Hypertens. 2020;29(1):16–21. https://doi.org/10.1097/MNH.0000000000000574
15. Huang Y, Xin W, Xiong J, Yao M, Zhang B, Zhao J. The Intestinal Microbiota and Metabolites in the Gut-Kidney-Heart Axis of Chronic Kidney Disease. Front Pharmacol. 2022;13:837500. https://doi.org/10.3389/fphar.2022.837500
16. Kalantar-Zadeh K, Joshi S, Schlueter R, Cooke J, Brown-Tortorici A, Donnelly M, Schulman S, Lau W-L, Rhee CM, Streja E, Tantisattamo E, Ferrey AJ, Hanna R, Chen JLT, Malik S, Nguyen DV, Crowley ST, Kovesdy CP. Plant-Dominant Low-Protein Diet for Conservative Management of Chronic Kidney Disease. Nutrients. 2020;12(7). https://doi.org/10.3390/nu12071931
17. Lobel L, Cao YG, Fenn K, Glickman JN, Garrett WS. Diet posttranslationally modifies the mouse gut microbial proteome to modulate renal function. Science. 2020;369(6510):1518–24. https://doi.org/10.1126/science.abb3763
18. Ikizler TA, Burrowes JD, Byham-Gray LD, Campbell KL, Carrero J-J, Chan W, Fouque D, Friedman AN, Ghaddar S, Goldstein-Fuchs DJ, Kaysen GA, Kopple JD, Teta D, Yee-Moon Wang A, Cuppari L. KDOQI clinical practice guideline for nutrition in CKD: 2020 update. Am J Kidney Dis. 2020;76(3 Suppl 1):S1–107. https://doi.org/10.1053/j.ajkd.2020.05.006
19. Guida B, Germanò R, Trio R, Russo D, Memoli B, Grumetto L, Barbato F, Cataldi M. Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: a randomized clinical trial. Nutr Metab Cardiovasc Dis. 2014;24(9):1043–9. https://doi.org/10.1016/j.numecd.2014.04.007
20. Riccio E, Sabbatini M, Bruzzese D, Grumetto L, Marchetiello C, Amicone M, Andreucci M, Guida B, Passaretti D, Russo G, Pisani A. Plasma p-cresol lowering effect of sevelamer in non-dialysis CKD patients: evidence from a randomized controlled trial. Clin Exp Nephrol. 2018;22(3):529–38. https://doi.org/10.1007/s10157-017-1504-8
21. Lin C-J, Wu V, Wu P-C, Wu C-J. Meta-Analysis of the Associations of p-Cresyl Sulfate (PCS) and Indoxyl Sulfate (IS) with Cardiovascular Events and All-Cause Mortality in Patients with Chronic Renal Failure. PLoS ONE. 2015;10(7):e0132589. https://doi.org/10.1371/journal.pone.0132589
22. McFarlane C, Ramos CI, Johnson DW, Campbell KL. Prebiotic, Probiotic, and Synbiotic Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-analysis. J Ren Nutr. 2019;29(3):209–20. https://doi.org/10.1053/j.jrn.2018.08.008
23. Palmquist R. A Preliminary Clincial Evaluation of Kibow Biotics , ® a Probiotic Agent , on Feline Azotemia. 2006;
24. Vaziri ND, Liu S-M, Lau WL, Khazaeli M, Nazertehrani S, Farzaneh SH, Kieffer DA, Adams SH, Martin RJ. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease. PLoS ONE. 2014;9(12):e114881. https://doi.org/10.1371/journal.pone.0114881
25. Kieffer DA, Piccolo BD, Vaziri ND, Liu S, Lau WL, Khazaeli M, Nazertehrani S, Moore ME, Marco ML, Martin RJ, Adams SH. Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats. Am J Physiol Renal Physiol. 2016;310(9):F857-71. https://doi.org/10.1152/ajprenal.00513.2015
26. Rossi M, Johnson DW, Morrison M, Pascoe EM, Coombes JS, Forbes JM, Szeto C-C, McWhinney BC, Ungerer JPJ, Campbell KL. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): A randomized trial. Clin J Am Soc Nephrol. 2016;11(2):223–31. https://doi.org/10.2215/CJN.05240515
27. Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol. 2014;25(4):657–70. https://doi.org/10.1681/ASN.2013080905
28. Ueda H, Shibahara N, Takagi S, Inoue T, Katsuoka Y. AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases. Ther Apher Dial. 2007;11(3):189–95. https://doi.org/10.1111/j.1744-9987.2007.00430.x
29. Hsu C-N, Tain Y-L. Chronic kidney disease and gut microbiota: what is their connection in early life? Int J Mol Sci. 2022;23(7). https://doi.org/10.3390/ijms23073954
30. 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. https://doi.org/10.1016/j.trsl.2016.04.007
31. Feng Y-L, Cao G, Chen D-Q, Vaziri ND, Chen L, Zhang J, Wang M, Guo Y, Zhao Y-Y. Microbiome-metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease. Cell Mol Life Sci. 2019;76(24):4961–78. https://doi.org/10.1007/s00018-019-03155-9
32. Koppe L, Fouque D. Microbiota and prebiotics modulation of uremic toxin generation. Panminerva Med. 2017;59(2):173–87. https://doi.org/10.23736/S0031-0808.16.03282-1
33. Sumida K, Pierre JF, Yuzefpolskaya M, Colombo PC, Demmer RT, Kovesdy CP. Gut Microbiota-Targeted Interventions in the Management of Chronic Kidney Disease. Semin Nephrol. 2023;43(2):151408. https://doi.org/10.1016/j.semnephrol.2023.151408
34. Zhao J, Bai M, Yang X, Wang Y, Li R, Sun S. Alleviation of refractory IgA nephropathy by intensive fecal microbiota transplantation: the first case reports. Ren Fail. 2021;43(1):928–33. https://doi.org/10.1080/0886022X.2021.1936038
35. Zhou G, Zeng J, Peng L, Wang L, Zheng W, Di Wu, Yang Y. Fecal microbiota transplantation for membranous nephropathy. CEN Case Rep. 2021;10(2):261–4. https://doi.org/10.1007/s13730-020-00560-z
36. Devlin AS, Marcobal A, Dodd D, Nayfach S, Plummer N, Meyer T, Pollard KS, Sonnenburg JL, Fischbach MA. Modulation of a circulating uremic solute via rational genetic manipulation of the gut microbiota. Cell Host Microbe. 2016;20(6):709–15. https://doi.org/10.1016/j.chom.2016.10.021
37. Mafra D, Borges NA, Lindholm B, Shiels PG, Evenepoel P, Stenvinkel P. Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nat Rev Nephrol. 2021;17(3):153–71. https://doi.org/10.1038/s41581-020-00345-8
38. Huang Y, Zhou J, Wang S, Xiong J, Chen Y, Liu Y, Xiao T, Li Y, He T, Li Y, Bi X, Yang K, Han W, Qiao Y, Yu Y, Zhao J. Indoxyl sulfate induces intestinal barrier injury through IRF1-DRP1 axis-mediated mitophagy impairment. Theranostics. 2020;10(16):7384–400. https://doi.org/10.7150/thno.45455
39. Popkov VA, Zharikova AA, Demchenko EA, Andrianova NV, Zorov DB, Plotnikov EY. Gut microbiota as a source of uremic toxins. Int J Mol Sci. 2022;23(1),483. https://doi.org/10.3390/ijms23010483
40. Caggiano G, Cosola C, Di Leo V, Gesualdo M, Gesualdo L. Microbiome modulation to correct uremic toxins and to preserve kidney functions. Curr Opin Nephrol Hypertens. 2020;29(1):49–56. https://doi.org/10.1097/MNH.0000000000000565
41. Zhao J, Ning X, Liu B, Dong R, Bai M, Sun S. Specific alterations in gut microbiota in patients with chronic kidney disease: an updated systematic review. Ren Fail. 2021;43(1):102–12. https://doi.org/10.1080/0886022X.2020.1864404
42. Vaziri ND, Yuan J, Norris K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am J Nephrol. 2013;37(1):1–6. https://doi.org/10.1159/000345969
43. Inagi R, Ishimoto Y, Nangaku M. Proteostasis in endoplasmic reticulum--new mechanisms in kidney disease. Nat Rev Nephrol. 2014;10(7):369–78 https://doi.org/10.1038/nrneph.2014.67.
44. Sabatino A, Regolisti G, Brusasco I, Cabassi A, Morabito S, Fiaccadori E. Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrol Dial Transplant. 2015;30(6):924–33. https://doi.org/10.1093/ndt/gfu287
45. Zhu H, Cao C, Wu Z, Zhang H, Sun Z, Wang M, Xu H, Zhao Z, Wang Y, Pei G, Yang Q, Zhu F, Yang J, Deng X, Hong Y, Li Y, Sun J, Zhu F, Shi M, Qian K, Zeng R. The probiotic L. casei Zhang slows the progression of acute and chronic kidney disease. Cell Metab. 2021;33(10):1926-1942.e8. https://doi.org/10.1016/j.cmet.2021.06.014
46. Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj DS. Role of the gut microbiome in uremia: A potential therapeutic target. Am J Kidney Dis. 2016;67(3):483–98. https://doi.org/10.1053/j.ajkd.2015.09.027
47. Mamic P, Chaikijurajai T, Tang WHW. Gut microbiome - A potential mediator of pathogenesis in heart failure and its comorbidities: State-of-the-art review. J Mol Cell Cardiol. 2021;152:105–17. https://doi.org/10.1016/j.yjmcc.2020.12.001
48. Kootte RS, Levin E, Salojärvi J, Smits LP, Hartstra AV, Udayappan SD, Hermes G, Bouter KE, Koopen AM, Holst JJ, Knop FK, Blaak EE, Zhao J, Smidt H, Harms AC, Hankemeijer T, Bergman JJGHM, Romijn HA, Schaap FG, Olde Damink SWM, Nieuwdorp M. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell Metab. 2017;26(4):611-619.e6. https://doi.org/10.1016/j.cmet.2017.09.008
49. Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell. 2015;163(7):1585–95. https://doi.org/10.1016/j.cell.2015.11.055
50. Liu M, Tang F, Liu Q, Xiao J, Cao H, Chen X. Inhibition of resveratrol glucosides (REs) on advanced glycation endproducts (AGEs) formation: inhibitory mechanism and structure-activity relationship. Nat Prod Res. 2020;34(17):2490–4. https://doi.org/10.1080/14786419.2018.1538224
51. Hudson BI, Lippman ME. Targeting RAGE signaling in inflammatory disease. Annu Rev Med. 2018;69:349–64. https://doi.org/10.1146/annurev-med-041316-085215
52. Nazzal L, Roberts J, Singh P, Jhawar S, Matalon A, Gao Z, Holzman R, Liebes L, Blaser MJ, Lowenstein J. Microbiome perturbation by oral vancomycin reduces plasma concentration of two gut-derived uremic solutes, indoxyl sulfate and p-cresyl sulfate, in end-stage renal disease. Nephrol Dial Transplant. 2017;32(11):1809–17. https://doi.org/10.1093/ndt/gfx029
53. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446–50. https://doi.org/10.1038/nature12721
54. Mishima E, Fukuda S, Shima H, Hirayama A, Akiyama Y, Takeuchi Y, Fukuda NN, Suzuki T, Suzuki C, Yuri A, Kikuchi K, Tomioka Y, Ito S, Soga T, Abe T. Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD. J Am Soc Nephrol. 2015;26(8):1787–94. https://doi.org/10.1681/ASN.2014060530
55. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, Escobar JS. Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care. 2017;40(1):54–62. https://doi.org/10.2337/dc16-1324
56. Zheng L, Chen S, Wang F, Huang S, Liu X, Yang X, Zhou H, Zhao G-P, Luo M, Li S, Chen J. Distinct Responses of Gut Microbiota to Jian-Pi-Yi-Shen Decoction Are Associated With Improved Clinical Outcomes in 5/6 Nephrectomized Rats. Front Pharmacol. 2020;11:604. https://doi.org/10.3389/fphar.2020.00604
57. Ticinesi A, Milani C, Guerra A, Allegri F, Lauretani F, Nouvenne A, Mancabelli L, Lugli GA, Turroni F, Duranti S, Mangifesta M, Viappiani A, Ferrario C, Dodi R, Dall’Asta M, Del Rio D, Ventura M, Meschi T. Understanding the gut-kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers. Gut. 2018;67(12):2097–106. https://doi.org/10.1136/gutjnl-2017-315734
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Daria Dąbkowska, Agnieszka Mioskowska, Joanna Szydziak, Aleksandra Hrapkowicz, Kinga Janowska, Olga Szeidl, Dominika Rehan, Julia Wołoszczak
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 163
Number of citations: 0
