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Intestinal microbiome and fitness in kidney disease

Nature Reviews Nephrology volume 15, pages 531–545 (2019)Cite this article

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Abstract

Environmental changes can induce diversity shifts within ecosystems that affect interactions between species. Similarly, the development of kidney disease induces shifts within the ecosystem of the intestinal microbiome, affecting host physiology and fitness. Renal failure itself, together with related changes in diet and medication, alters the microbiota and its secretome of micronutrients, nutrients and regulatory metabolites towards a phenotype characterized by the production of uraemic toxins, hence contributing to the clinical syndrome of uraemia and its complications. These alterations are associated with structural changes in the intestinal wall that impair barrier function and cause leakage of bacterial metabolites, bacterial wall products and live bacteria into the circulation. Thus, the intestinal microbiota represents a new therapeutic target to improve outcomes of chronic kidney disease (CKD), including symptoms of uraemia, metabolic changes, cardiovascular complications, aberrant immunity and disease progression. Initial interventional studies have shown promising effects of unselective probiotic preparations on kidney inflammation and uraemia in patients with CKD but longer-term studies are needed. Here, we take an ecological approach to understand the role of the intestinal microbiota in determining survival fitness in kidney disease.

Key points

  • The intestinal microbiota is a highly versatile ecosystem that contributes to host physiological processes, including intestinal barrier integrity, immunological fitness and metabolic fitness, and responds dynamically to intrinsic and extrinsic challenges.

  • Crosstalk between the gut microbial ecosystem and human physiological systems is context-dependent; nutrient intake and drug therapy are the most important exogenous modifiers of this crosstalk.

  • CKD can induce changes in both the composition and metabolic activity of gut microbiota (dysbiosis), with consequences for various physiological processes.

  • CKD and related changes in the microbiota impair intestinal barrier fitness and promote translocation of bacterial components into the circulation, which impairs immunological fitness by driving persistent systemic inflammation and immune paralysis.

  • CKD and related changes in the microbiota also impair metabolic and cardiovascular fitness by secreting metabolites that favour insulin resistance, obesity, endothelial dysfunction and cardiovascular ageing.

  • Faecal transplantation, specific microorganism-targeted interventions or the use of prebiotics, probiotics or dietary interventions are potential strategies to correct or manipulate CKD-related changes in the intestinal microbiota that contribute to uraemia, as well as the progression of CKD and CKD complications.

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Fig. 1: Mutual benefits between the host and intestinal microbiota.
Fig. 2: The adaptive landscape of the gut microbial ecosystem.
Fig. 3: The symbiosis between a host and its microbiota.
Fig. 4: The intestinal barrier at the intersection between microbiome and human physiology.
Fig. 5: Effects of CKD-associated changes in intestinal flora on intestinal barrier integrity and immunological fitness.
Fig. 6: Therapeutic targeting of the intestinal microbiota.

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References

  1. Kahrstrom, C. T., Pariente, N. & Weiss, U. Intestinal microbiota in health and disease. Nature 535, 47 (2016).

    CAS  PubMed  Google Scholar 

  2. Lloyd-Price, J. et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature 550, 61–66 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Thevaranjan, N. et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21, 455–466 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Thaiss, C. A. et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 540, 544–551 (2016).

    CAS  PubMed  Google Scholar 

  6. Vatanen, T. et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 562, 589–594 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rune, I. et al. Modulating the gut microbiota improves glucose tolerance, lipoprotein profile and atherosclerotic plaque development in ApoE-deficient mice. PLOS ONE 11, e0146439 (2016).

    PubMed  PubMed Central  Google Scholar 

  10. Skagen, K. et al. The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis. Atherosclerosis 247, 64–69 (2016).

    CAS  PubMed  Google Scholar 

  11. Yoshida, N. et al. Bacteroides vulgatus and Bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation 138, 2486–2498 (2018).

    CAS  PubMed  Google Scholar 

  12. Zhernakova, D. V. et al. Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome. Nat. Genet. 50, 1524–1532 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Anders, H. J., Andersen, K. & Stecher, B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 83, 1010–1016 (2013).

    CAS  PubMed  Google Scholar 

  14. Andersen, K. et al. Intestinal dysbiosis, barrier dysfunction, and bacterial translocation account for CKD-related systemic inflammation. J. Am. Soc. Nephrol. 28, 76–83 (2017).

    CAS  PubMed  Google Scholar 

  15. Joossens, M. et al. Gut microbiota dynamics and uraemic toxins: one size does not fit all. Gut https://doi.org/10.1136/gutjnl-2018-317561 (2018).

    Article  PubMed  Google Scholar 

  16. Poesen, R. et al. The influence of CKD on colonic microbial metabolism. J. Am. Soc. Nephrol. 27, 1389–1399 (2016).

    CAS  PubMed  Google Scholar 

  17. Vaziri, N. D. et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 83, 308–315 (2013).

    PubMed  Google Scholar 

  18. Costello, E. K., Stagaman, K., Dethlefsen, L., Bohannan, B. J. & Relman, D. A. The application of ecological theory toward an understanding of the human microbiome. Science 336, 1255–1262 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Dethlefsen, L., McFall-Ngai, M. & Relman, D. A. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449, 811–818 (2007).

    CAS  PubMed  Google Scholar 

  20. Crespo-Salgado, J. et al. Intestinal microbiota in pediatric patients with end stage renal disease: a Midwest Pediatric Nephrology Consortium study. Microbiome 4, 50 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. Rakoff-Nahoum, S., Foster, K. R. & Comstock, L. E. The evolution of cooperation within the gut microbiota. Nature 533, 255–259 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).

    CAS  PubMed  Google Scholar 

  23. Deschasaux, M. et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat. Med. 24, 1526–1531 (2018).

    CAS  PubMed  Google Scholar 

  24. Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).

    CAS  PubMed  Google Scholar 

  25. Viaene, L. et al. Heritability and clinical determinants of serum indoxyl sulfate and p-cresyl sulfate, candidate biomarkers of the human microbiome enterotype. PLOS ONE 9, e79682 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Sonnenburg, J. L. & Backhed, F. Diet-microbiota interactions as moderators of human metabolism. Nature 535, 56–64 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zierer, J. et al. The fecal metabolome as a functional readout of the gut microbiome. Nat. Genet. 50, 790–795 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. France, M. M. & Turner, J. R. The mucosal barrier at a glance. J. Cell Sci. 130, 307–314 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565, 600–605 (2019).

    CAS  PubMed  Google Scholar 

  31. Meijers, B., Farre, R., Dejongh, S., Vicario, M. & Evenepoel, P. Intestinal barrier function in chronic kidney disease. Toxins 10, E298 (2018).

    PubMed  Google Scholar 

  32. Pelaseyed, T. et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8–20 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Johansson, M. E., Larsson, J. M. & Hansson, G. C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4659–4665 (2011).

    CAS  PubMed  Google Scholar 

  34. Zarepour, M. et al. The mucin Muc2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar Typhimurium colitis. Infect. Immun. 81, 3672–3683 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

    CAS  PubMed  Google Scholar 

  36. Fritz, J. H. et al. Acquisition of a multifunctional IgA+plasma cell phenotype in the gut. Nature 481, 199–203 (2011).

    PubMed  PubMed Central  Google Scholar 

  37. Nakashima, K. et al. Chitin-based barrier immunity and its loss predated mucus-colonization by indigenous gut microbiota. Nat. Commun. 9, 3402 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. Joossens, M. et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 60, 631–637 (2011).

    PubMed  Google Scholar 

  39. Leon-Coria, A., Kumar, M., Moreau, F. & Chadee, K. Defining cooperative roles for colonic microbiota and Muc2 mucin in mediating innate host defense against Entamoeba histolytica. PLOS Pathog. 14, e1007466 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. Martinez-Medina, M. et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut 63, 116–124 (2014).

    PubMed  Google Scholar 

  41. Hendrickx, A. P. et al. Antibiotic-driven dysbiosis mediates intraluminal agglutination and alternative segregation of Enterococcus faecium from the intestinal epithelium. mBio 6, e01346–15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).

    CAS  PubMed  Google Scholar 

  43. Thaiss, C. A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016).

    CAS  PubMed  Google Scholar 

  44. Gensollen, T., Iyer, S. S., Kasper, D. L. & Blumberg, R. S. How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390 (2007).

    CAS  PubMed  Google Scholar 

  46. Rosshart, S. P. et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 171, 1015–1028 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bach, J. F. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat. Rev. Immunol. 18, 105–120 (2018).

    CAS  PubMed  Google Scholar 

  48. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Nakajima, A. et al. IgA regulates the composition and metabolic function of gut microbiota by promoting symbiosis between bacteria. J. Exp. Med. 215, 2019–2034 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Aronov, P. A. et al. Colonic contribution to uremic solutes. J. Am. Soc. Nephrol. 22, 1769–1776 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dodd, D. et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Nature 551, 648–652 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Cleophas, M. C. P. et al. Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males. Sci. Rep. 9, 775 (2019).

    PubMed  PubMed Central  Google Scholar 

  55. Marinelli, L. et al. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci. Rep. 9, 643 (2019).

    PubMed  PubMed Central  Google Scholar 

  56. Martin-Gallausiaux, C. et al. Butyrate produced by commensal bacteria down-regulates indolamine 2,3-dioxygenase 1 (IDO-1) expression via a dual mechanism in human intestinal epithelial cells. Front. Immunol. 9, 2838 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Masereeuw, R. et al. The kidney and uremic toxin removal: glomerulus or tubule? Semin. Nephrol. 34, 191–208 (2014).

    CAS  PubMed  Google Scholar 

  58. Poesen, R. et al. Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD. Clin. J. Am. Soc. Nephrol. 8, 1508–1514 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sirich, T. L., Aronov, P. A., Plummer, N. S., Hostetter, T. H. & Meyer, T. W. Numerous protein-bound solutes are cleared by the kidney with high efficiency. Kidney Int. 84, 585–590 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Rabbers, I. et al. Metabolism at evolutionary optimal States. Metabolites 5, 311–343 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Crittenden, A. N. & Schnorr, S. L. Current views on hunter-gatherer nutrition and the evolution of the human diet. Am. J. Phys. Anthropol. 162 (Suppl. 63), 84–109 (2017).

    PubMed  Google Scholar 

  62. Lazaridis, I. et al. Ancient human genomes suggest three ancestral populations for present-day Europeans. Nature 513, 409–413 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    PubMed Central  Google Scholar 

  64. Fragiadakis, G. K. et al. Links between environment, diet, and the hunter-gatherer microbiome. Gut Microbes 10, 216–227 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Schnorr, S. L. et al. Gut microbiome of the Hadza hunter-gatherers. Nat. Commun. 5, 3654 (2014).

    CAS  PubMed  Google Scholar 

  66. Obregon-Tito, A. J. et al. Subsistence strategies in traditional societies distinguish gut microbiomes. Nat. Commun. 6, 6505 (2015).

    CAS  PubMed  Google Scholar 

  67. Urla, C. et al. Surgical treatment of children with total colonic aganglionosis: functional and metabolic long-term outcome. BMC Surg. 18, 58 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Perry, R. J. et al. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Pedersen, H. K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).

    CAS  PubMed  Google Scholar 

  70. Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of prevotella. Cell Metab. 22, 971–982 (2015).

    CAS  PubMed  Google Scholar 

  71. Baez, S. & Gordon, H. A. Tone and reactivity of vascular smooth muscle in germfree rat mesentery. J. Exp. Med. 134, 846–856 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017).

    CAS  PubMed  Google Scholar 

  73. Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).

    PubMed  PubMed Central  Google Scholar 

  74. Marques, F. Z. et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 135, 964–977 (2017).

    CAS  PubMed  Google Scholar 

  75. Yang, T. et al. Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340 (2015).

    CAS  PubMed  Google Scholar 

  76. Hu, J. et al. Enteric dysbiosis-linked gut barrier disruption triggers early renal injury induced by chronic high salt feeding in mice. Exp. Mol. Med. 49, e370 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Richards, E. M., Pepine, C. J., Raizada, M. K. & Kim, S. The gut, its microbiome, and hypertension. Curr. Hypertens. Rep. 19, 36 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Jose, P. A. & Raj, D. Gut microbiota in hypertension. Curr. Opin. Nephrol. Hypertens. 24, 403–409 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Haghikia, A. et al. Gut microbiota-dependent trimethylamine N-oxide predicts risk of cardiovascular events in patients with stroke and is related to proinflammatory monocytes. Arterioscler. Thromb. Vasc. Biol. 38, 2225–2235 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Meijers, B., Jouret, F. & Evenepoel, P. Linking gut microbiota to cardiovascular disease and hypertension: lessons from chronic kidney disease. Pharmacol. Res. 133, 101–107 (2018).

    CAS  PubMed  Google Scholar 

  82. Sun, C. Y., Chang, S. C. & Wu, M. S. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int. 81, 640–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Woo, V. & Alenghat, T. Host-microbiota interactions: epigenomic regulation. Curr. Opin. Immunol. 44, 52–60 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Pluznick, J. L. Renal and cardiovascular sensory receptors and blood pressure regulation. Am. J. Physiol. Renal Physiol. 305, F439–F444 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, X. S. et al. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur. Heart J. 38, 814–824 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tang, W. H. et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116, 448–455 (2015).

    CAS  PubMed  Google Scholar 

  87. Tomlinson, J. A. P. & Wheeler, D. C. The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease. Kidney Int. 92, 809–815 (2017).

    CAS  PubMed  Google Scholar 

  88. Vanholder, R., Schepers, E., Pletinck, A., Nagler, E. V. & Glorieux, G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J. Am. Soc. Nephrol. 25, 1897–1907 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Brown, J. M. & Hazen, S. L. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu. Rev. Med. 66, 343–359 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015).

    CAS  PubMed  Google Scholar 

  91. Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Shafi, T. et al. Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. J. Am. Soc. Nephrol. 28, 321–331 (2017).

    CAS  PubMed  Google Scholar 

  93. Afsar, B., Vaziri, N. D., Aslan, G., Tarim, K. & Kanbay, M. Gut hormones and gut microbiota: implications for kidney function and hypertension. J. Am. Soc. Hypertens. 10, 954–961 (2016).

    CAS  PubMed  Google Scholar 

  94. Bammens, B., Verbeke, K., Vanrenterghem, Y. & Evenepoel, P. Evidence for impaired assimilation of protein in chronic renal failure. Kidney Int. 64, 2196–2203 (2003).

    CAS  PubMed  Google Scholar 

  95. Evenepoel, P., Meijers, B. K., Bammens, B. R. & Verbeke, K. Uremic toxins originating from colonic microbial metabolism. Kidney Int. Suppl. 76 (Suppl. 114), S12–S19 (2009).

    Google Scholar 

  96. Hoibian, E., Florens, N., Koppe, L., Vidal, H. & Soulage, C. O. Distal colon motor dysfunction in mice with chronic kidney disease: putative role of uremic toxins. Toxins 10, E204 (2018).

    PubMed  Google Scholar 

  97. Wong, J. et al. 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. 39, 230–237 (2014).

    CAS  PubMed  Google Scholar 

  98. Chiu, Y. W. et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin. J. Am. Soc. Nephrol. 4, 1089–1096 (2009).

    PubMed  PubMed Central  Google Scholar 

  99. Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Jiang, S. et al. Alteration of the gut microbiota in Chinese population with chronic kidney disease. Sci. Rep. 7, 2870 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  102. Liu, Y. et al. Disorder of gut amino acids metabolism during CKD progression is related with gut microbiota dysbiosis and metagenome change. J. Pharm. Biomed. Anal. 149, 425–435 (2018).

    CAS  PubMed  Google Scholar 

  103. Nishiyama, K. et al. Chronic kidney disease after 5/6 nephrectomy disturbs the intestinal microbiota and alters intestinal motility. J. Cell. Physiol. 234, 6667–6678 (2018).

    PubMed  Google Scholar 

  104. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451–455 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Mishima, E. et al. Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach. Kidney Int. 92, 634–645 (2017).

    CAS  PubMed  Google Scholar 

  106. Jiang, S. et al. A reduction in the butyrate producing species Roseburia spp. and Faecalibacterium prausnitzii is associated with chronic kidney disease progression. Antonie Van Leeuwenhoek 109, 1389–1396 (2016).

    CAS  PubMed  Google Scholar 

  107. Ho, W. C. & Zhang, J. Evolutionary adaptations to new environments generally reverse plastic phenotypic changes. Nat. Commun. 9, 350 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. McIntyre, C. W. et al. Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 133–141 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Poesen, R. et al. Associations of soluble CD14 and endotoxin with mortality, cardiovascular disease, and progression of kidney disease among patients with CKD. Clin. J. Am. Soc. Nephrol. 10, 1525–1533 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wei, M. et al. Probiotic Bifidobacterium animalis subsp. lactis Bi-07 alleviates bacterial translocation and ameliorates microinflammation in experimental uraemia. Nephrology 19, 500–506 (2014).

    CAS  PubMed  Google Scholar 

  111. Sun, L. et al. Macrophages are involved in gut bacterial translocation and reversed by Lactobacillus in experimental uremia. Dig. Dis. Sci. 61, 1534–1544 (2016).

    CAS  PubMed  Google Scholar 

  112. Magnusson, M., Magnusson, K. E., Sundqvist, T. & Denneberg, T. Increased intestinal permeability to differently sized polyethylene glycols in uremic rats: effects of low- and high-protein diets. Nephron 56, 306–311 (1990).

    CAS  PubMed  Google Scholar 

  113. Magnusson, M., Magnusson, K. E., Sundqvist, T. & Denneberg, T. Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure. Gut 32, 754–759 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Vaziri, N. D., Yuan, J., Nazertehrani, S., Ni, Z. & Liu, S. Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction. Am. J. Nephrol. 38, 99–103 (2013).

    CAS  PubMed  Google Scholar 

  115. Vaziri, N. D., Dure-Smith, B., Miller, R. & Mirahmadi, M. K. Pathology of gastrointestinal tract in chronic hemodialysis patients: an autopsy study of 78 cases. Am. J. Gastroenterol. 80, 608–611 (1985).

    CAS  PubMed  Google Scholar 

  116. Vaziri, N. D. et al. Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium. Am. J. Nephrol. 36, 438–443 (2012).

    CAS  PubMed  Google Scholar 

  117. Vaziri, N. D., Yuan, J. & Norris, K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am. J. Nephrol. 37, 1–6 (2013).

    CAS  PubMed  Google Scholar 

  118. Vaziri, N. D. et al. Oral activated charcoal adsorbent (AST-120) ameliorates chronic kidney disease-induced intestinal epithelial barrier disruption. Am. J. Nephrol. 37, 518–525 (2013).

    CAS  PubMed  Google Scholar 

  119. Converse, R. L. Jr et al. Sympathetic overactivity in patients with chronic renal failure. N. Engl. J. Med. 327, 1912–1918 (1992).

    PubMed  Google Scholar 

  120. Peschel, T. et al. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur. J. Heart Fail. 5, 609–614 (2003).

    CAS  PubMed  Google Scholar 

  121. Vaziri, N. D., Zhao, Y. Y. & Pahl, M. V. Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment. Nephrol. Dial. Transplant. 31, 737–746 (2016).

    CAS  PubMed  Google Scholar 

  122. Seong, E. Y., Zheng, Y., Winkelmayer, W. C., Montez-Rath, M. E. & Chang, T. I. The relationship between intradialytic hypotension and hospitalized mesenteric ischemia: a case-control study. Clin. J. Am. Soc. Nephrol. 13, 1517–1525 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. Shi, K. et al. Gut bacterial translocation may aggravate microinflammation in hemodialysis patients. Dig. Dis. Sci. 59, 2109–2117 (2014).

    CAS  PubMed  Google Scholar 

  124. Lau, W. L., Kalantar-Zadeh, K. & Vaziri, N. D. The gut as a source of inflammation in chronic kidney disease. Nephron 130, 92–98 (2015).

    CAS  PubMed  Google Scholar 

  125. Li, L., Ma, L. & Fu, P. Gut microbiota-derived short-chain fatty acids and kidney diseases. Drug Des. Devel. Ther. 11, 3531–3542 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Pluznick, J. L. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 90, 1191–1198 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Carlsson, A. C. et al. Soluble TNF receptors and kidney dysfunction in the elderly. J. Am. Soc. Nephrol. 25, 1313–1320 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Lai, X. et al. Outcomes of stage 1–5 chronic kidney disease in Mainland China. Ren. Fail. 36, 520–525 (2014).

    PubMed  Google Scholar 

  129. Saran, R. et al. US Renal Data System 2017 annual data report: epidemiology of kidney disease in the United States. Am. J. Kidney Dis. 71, A7 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. Biswas, S. K. & Lopez-Collazo, E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 30, 475–487 (2009).

    CAS  PubMed  Google Scholar 

  131. Hotchkiss, R. S., Coopersmith, C. M., McDunn, J. E. & Ferguson, T. A. The sepsis seesaw: tilting toward immunosuppression. Nat. Med. 15, 496–497 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Stearns-Kurosawa, D. J., Osuchowski, M. F., Valentine, C., Kurosawa, S. & Remick, D. G. The pathogenesis of sepsis. Annu. Rev. Pathol. 6, 19–48 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Einheber, A. & Carter, D. 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, 239–250 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Duranton, F. et al. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 23, 1258–1270 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Barreto, F. C. et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 1551–1558 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Hu, J. R. et al. Serum metabolites are associated with all-cause mortality in chronic kidney disease. Kidney Int. 94, 381–389 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Meijers, B. K. et al. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin. J. Am. Soc. Nephrol. 5, 1182–1189 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Shafi, T. et al. Serum asymmetric and symmetric dimethylarginine and morbidity and mortality in hemodialysis patients. Am. J. Kidney Dis. 70, 48–58 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zoccali, C. et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358, 2113–2117 (2001).

    CAS  PubMed  Google Scholar 

  140. Meijers, B. K., Bammens, B., Verbeke, K. & Evenepoel, P. A review of albumin binding in CKD. Am. J. Kidney Dis. 51, 839–850 (2008).

    PubMed  Google Scholar 

  141. Klammt, S. et al. Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins. Nephrol. Dial. Transplant. 27, 2377–2383 (2012).

    CAS  PubMed  Google Scholar 

  142. Deltombe, O. et al. Exploring binding characteristics and the related competition of different protein-bound uremic toxins. Biochimie 139, 20–26 (2017).

    CAS  PubMed  Google Scholar 

  143. Meijers, B. K. et al. p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 4, 1932–1938 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Kasanen, A. Serum indican and endogenous indican clearance in renal insufficiency. Ann. Med. Intern. Fenn. Suppl. 46, 1–71 (1957).

    CAS  PubMed  Google Scholar 

  145. Pasternack, A., Kuhlbaeck, B. & Tallgren, L. G. Serum indican in haemodialysis. Acta. Med. Scand. 175 (Suppl. 412), 93–96 (1964).

    Google Scholar 

  146. Niwa, T. et al. Urinary indoxyl sulfate is a clinical factor that affects the progression of renal failure. Miner. Electrolyte Metab. 25, 118–122 (1999).

    CAS  PubMed  Google Scholar 

  147. Niwa, T. & Ise, M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J. Lab. Clin. Med. 124, 96–104 (1994).

    CAS  PubMed  Google Scholar 

  148. Niwa, T., Ise, M. & Miyazaki, T. Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am. J. Nephrol. 14, 207–212 (1994).

    CAS  PubMed  Google Scholar 

  149. Miyazaki, T. et al. Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta 1 and progression of renal failure. Kidney Int. Suppl. 63, S211–S214 (1997).

    CAS  PubMed  Google Scholar 

  150. Dou, L. et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 65, 442–451 (2004).

    CAS  PubMed  Google Scholar 

  151. Muteliefu, G., Enomoto, A., Jiang, P., Takahashi, M. & Niwa, T. Indoxyl sulphate induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. Nephrol. Dial. Transplant. 24, 2051–2058 (2009).

    CAS  PubMed  Google Scholar 

  152. Masai, N., Tatebe, J., Yoshino, G. & Morita, T. Indoxyl sulfate stimulates monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells by inducing oxidative stress through activation of the NADPH oxidase-nuclear factor-kappaB pathway. Circ. J. 74, 2216–2224 (2010).

    CAS  PubMed  Google Scholar 

  153. Fujii, H. et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol. Dial. Transplant. 24, 2089–2095 (2009).

    CAS  PubMed  Google Scholar 

  154. Chiu, C. A. et al. Increased levels of total P-Cresylsulphate and indoxyl sulphate are associated with coronary artery disease in patients with diabetic nephropathy. Rev. Diabet. Stud. 7, 275–284 (2010).

    PubMed  Google Scholar 

  155. Nii-Kono, T. et al. Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells. Kidney Int. 71, 738–743 (2007).

    CAS  PubMed  Google Scholar 

  156. Watanabe, K. et al. Indoxyl sulfate, a uremic toxin in chronic kidney disease, suppresses both bone formation and bone resorption. FEBS Open Bio 7, 1178–1185 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Hirata, J. et al. Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats. Bone 79, 252–258 (2015).

    CAS  PubMed  Google Scholar 

  158. Opdebeeck, B. et al. Indoxyl sulfate and p-Cresyl sulfate promote vascular calcification and associate with glucose intolerance. J. Am. Soc. Nephrol. 30, 751–766 (2019).

    PubMed  PubMed Central  Google Scholar 

  159. Niwa, T. et al. The protein metabolite hypothesis, a model for the progression of renal failure: an oral adsorbent lowers indoxyl sulfate levels in undialyzed uremic patients. Kidney Int. Suppl. 62, S23–S28 (1997).

    CAS  PubMed  Google Scholar 

  160. Konishi, K. et al. AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects. Diabetes Res. Clin. Pract. 81, 310–315 (2008).

    CAS  PubMed  Google Scholar 

  161. Schulman, G. et al. Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J. Am. Soc. Nephrol. 26, 1732–1746 (2015).

    CAS  PubMed  Google Scholar 

  162. Sato, E. et al. Impact of the oral adsorbent AST-120 on organ-specific accumulation of uremic toxins: LC-MS/MS and MS imaging techniques. Toxins 10, 19 (2018).

    Google Scholar 

  163. Koppe, L. et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J. Am. Soc. Nephrol. 24, 88–99 (2013).

    CAS  PubMed  Google Scholar 

  164. Buchanan, C. et al. Intradialytic cardiac magnetic resonance imaging to assess cardiovascular responses in a short-term trial of hemodiafiltration and hemodialysis. J. Am. Soc. Nephrol. 28, 1269–1277 (2017).

    PubMed  Google Scholar 

  165. Velasquez, M. T., Centron, P., Barrows, I., Dwivedi, R. & Raj, D. S. Gut microbiota and cardiovascular uremic toxicities. Toxins 10, E287 (2018).

    PubMed  Google Scholar 

  166. Kolachalama, V. B. et al. Uremic solute-aryl hydrocarbon receptor-tissue factor axis associates with thrombosis after vascular injury in humans. J. Am. Soc. Nephrol. 29, 1063–1072 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Shafi, T. et al. Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes. Kidney Int. 92, 1484–1492 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Bogiatzi, C. et al. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis 273, 91–97 (2018).

    CAS  PubMed  Google Scholar 

  169. Evenepoel, P., Glorieux, G. & Meijers, B. p-Cresol sulfate and indoxyl sulfate: some clouds are gathering in the uremic toxin sky. Kidney Int. 92, 1323–1324 (2017).

    CAS  PubMed  Google Scholar 

  170. Vanholder, R. & Glorieux, G. The intestine and the kidneys: a bad marriage can be hazardous. Clin. Kidney J. 8, 168–179 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Noel, S. et al. Intestinal microbiota-kidney cross talk in acute kidney injury and chronic kidney disease. Nephron Clin. Pract. 127, 139–143 (2014).

    CAS  PubMed  Google Scholar 

  172. Levey, A. S. & James, M. T. Acute kidney injury. Ann. Intern. Med. 167, ITC66–ITC80 (2017).

    PubMed  Google Scholar 

  173. Emal, D. et al. Depletion of gut microbiota protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 28, 1450–1461 (2017).

    CAS  PubMed  Google Scholar 

  174. Andrade-Oliveira, V. et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Kieffer, D. A. et al. Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats. Am. J. Physiol. Renal Physiol. 310, F857–F871 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Vaziri, N. D. et al. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease. PLOS ONE 9, e114881 (2014).

    PubMed  PubMed Central  Google Scholar 

  177. 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. 495, 2071–2077 (2018).

    CAS  PubMed  Google Scholar 

  178. Sun, G. et al. Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity. Biochem. Biophys. Res. Commun. 493, 964–970 (2017).

    CAS  PubMed  Google Scholar 

  179. Castillo-Rodriguez, E. et al. Impact of altered intestinal microbiota on chronic kidney disease progression. Toxins 10, 300 (2018).

    PubMed Central  Google Scholar 

  180. Koppe, L. & Fouque, D. Microbiota and prebiotics modulation of uremic toxin generation. Panminerva Med. 59, 173–187 (2017).

    PubMed  Google Scholar 

  181. Mishima, E. et al. Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD. J. Am. Soc. Nephrol. 26, 1787–1794 (2015).

    CAS  PubMed  Google Scholar 

  182. Spaulding, C. N. et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 546, 528–532 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Yacoub, R. & Wyatt, C. M. Manipulating the gut microbiome to decrease uremic toxins. Kidney Int. 91, 521–523 (2017).

    CAS  PubMed  Google Scholar 

  185. Rossi, M. et al. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): a randomized trial. Clin. J. Am. Soc. Nephrol. 11, 223–231 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Tayebi Khosroshahi, H. et al. Effect of high amylose resistant starch (HAM-RS2) supplementation on biomarkers of inflammation and oxidative stress in hemodialysis patients: a randomized clinical trial. Hemodial. Int. 22, 492–500 (2018).

    PubMed  Google Scholar 

  187. Mishima, E. et al. Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model. Am. J. Physiol. Renal Physiol. 315, F824–F833 (2018).

    CAS  PubMed  Google Scholar 

  188. Jing, W. et al. Phosphate binder, ferric citrate, attenuates anemia, renal dysfunction, oxidative stress, inflammation, and fibrosis in 5/6 nephrectomized CKD rats. J. Pharmacol. Exp. Ther. 367, 129–137 (2018).

    CAS  PubMed  Google Scholar 

  189. Lau, W. L. et al. The phosphate binder ferric citrate alters the gut microbiome in rats with chronic kidney disease. J. Pharmacol. Exp. Ther. 367, 452–460 (2018).

    CAS  PubMed  Google Scholar 

  190. Ramezani, A. & Raj, D. S. The gut microbiome, kidney disease, and targeted interventions. J. Am. Soc. Nephrol. 25, 657–670 (2014).

    CAS  PubMed  Google Scholar 

  191. Cavalcanti Neto, M. P. et al. Gut microbiota and probiotics intervention: a potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol. Res. 130, 152–163 (2018).

    CAS  PubMed  Google Scholar 

  192. Soleimani, A. et al. Probiotic supplementation in diabetic hemodialysis patients has beneficial metabolic effects. Kidney Int. 91, 435–442 (2017).

    CAS  PubMed  Google Scholar 

  193. Kelly, J. T. et al. Healthy dietary patterns and risk of mortality and ESRD in CKD: a meta-analysis of cohort studies. Clin. J. Am. Soc. Nephrol. 12, 272–279 (2017).

    PubMed  Google Scholar 

  194. Saglimbene, V. M. et al. The association of Mediterranean and DASH diets with mortality in adults on hemodialysis: the DIET-HD multinational cohort study. J. Am. Soc. Nephrol. 29, 1741–1751 (2018).

    PubMed  PubMed Central  Google Scholar 

  195. Poesen, R. et al. The influence of prebiotic arabinoxylan oligosaccharides on microbiota derived uremic retention solutes in patients with chronic kidney disease: a randomized controlled trial. PLOS ONE 11, e0153893 (2016).

    PubMed  PubMed Central  Google Scholar 

  196. So, D. et al. Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. Am. J. Clin. Nutr. 107, 965–983 (2018).

    PubMed  Google Scholar 

  197. Evenepoel, P., Bammens, B., Verbeke, K. & Vanrenterghem, Y. Acarbose treatment lowers generation and serum concentrations of the protein-bound solute p-cresol: a pilot study. Kidney Int. 70, 192–198 (2006).

    CAS  PubMed  Google Scholar 

  198. Lee, D. M. et al. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc. Diabetol. 17, 62 (2018).

  199. Devlin, A. S. et al. Modulation of a circulating uremic solute via rational genetic manipulation of the gut microbiota. Cell Host Microbe 20, 709–715 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Roberts, A. B. et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24, 1407–1417 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Ooijevaar, R. E., Terveer, E. M., Verspaget, H. W., Kuijper, E. J. & Keller, J. J. Clinical application and potential of fecal microbiota transplantation. Annu. Rev. Med. 70, 335–351 (2019).

    CAS  PubMed  Google Scholar 

  202. Mu, Q. et al. Control of lupus nephritis by changes of gut microbiota. Microbiome 5, 73 (2017).

    PubMed  PubMed Central  Google Scholar 

  203. Laue, C. et al. Effect of a yoghurt drink containing Lactobacillus strains on bacterial vaginosis in women - a double-blind, randomised, controlled clinical pilot trial. Benef. Microbes 9, 35–50 (2018).

    CAS  PubMed  Google Scholar 

  204. Derwa, Y., Gracie, D. J., Hamlin, P. J. & Ford, A. C. Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease. Aliment. Pharmacol. Ther. 46, 389–400 (2017).

    CAS  PubMed  Google Scholar 

  205. Nadelman, P., Magno, M. B., Masterson, D., da Cruz, A. G. & Maia, L. C. Are dairy products containing probiotics beneficial for oral health? A systematic review and meta-analysis. Clin. Oral Investig. 22, 2763–2785 (2018).

    PubMed  Google Scholar 

  206. Degnan, F. H. The US Food and Drug Administration and probiotics: regulatory categorization. Clin. Infect. Dis. 46, S133–S136 (2008). Suppl. 2.

    PubMed  Google Scholar 

  207. Enache-Angoulvant, A. & Hennequin, C. Invasive Saccharomyces infection: a comprehensive review. Clin. Infect. Dis. 41, 1559–1568 (2005).

    PubMed  Google Scholar 

  208. Rescigno, M. & Di Sabatino, A. Dendritic cells in intestinal homeostasis and disease. J. Clin. Invest. 119, 2441–2450 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

H.-J.A. is supported by the Heisenberg programme of the Deutsche Forschungsgemeinschaft (AN372/24-1).

Peer review information

Nature Reviews Nephrology thanks J. Spence, N. Vaziri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. KU Leuven, Department of Nephrology and Department of Immunology and Microbiology, Laboratory of Nephrology, Leuven, Belgium

    Björn Meijers & Pieter Evenepoel

  2. Division of Nephrology, Medizinische Klinik and Poliklinik IV, Klinikum der LMU München–Innenstadt, München, Germany

    Hans-Joachim Anders

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Glossary

Microbiome

Ecological community of commensal, symbiotic or pathogenic microorganisms that reside inside and outside all multicellular organisms. A microbiome includes bacteria, archaea, meiofauna, fungi and viruses.

Archaeal microbiome

Archaea are single-cell microorganisms with metabolic and biochemical properties that distinguish them from bacteria. The archaeal microbiome is the community of archaea residing within a host.

Virome

The collection of nucleic acids (RNA and DNA) that define the viral community inside or on multicellular organisms.

Mycobiome

Fungal communities inside or on multicellular organisms.

Meiofauna

Small invertebrates including unicellular protozoa and helminthic worms (for example, Entamoeba, Trichomonas or Schistosoma).

Vertical transmission

Transmission from mother to child.

16S ribosomal RNA (rRNA) pyrosequencing

A method of DNA sequencing in which the sequencing is performed by detecting the nucleotide incorporated by a DNA polymerase, which releases pyrophosphate. This method is frequently used in microbiome genotyping.

Intestinal congestion

Oedema of the intestinal wall due to volume overload and/or vascular barrier dysfunction.

Symbiosis

A close and long-term biological interaction between two different biological organisms, the symbionts; the interaction can be mutualistic, commensalistic or parasitic.

Symbionts

Organisms that live in a symbiotic relationship with their host, for example, Escherichia coli in the human intestinal tract.

α-Diversity

Mean species diversity in a single environment (that is, within a single location).

β-Diversity

The number and variability of local niches in larger environments (for example, the diversity of species between samples taken from different locations within a single host or the diversity of species between different hosts), which contribute to species diversity at a larger scale.

Transcellular transport

Transport across cellular barriers through cells.

Paracellular transport

Transport across cellular barriers between cells.

Secretory IgA

IgA secreted by plasma cells of the gut-associated lymphoid tissue into the lumen of the intestinal tract. Secretory IgA is one of several intrinsic regulators of the intestinal microbiome.

Chordates

A large group of bilateral symmetric animals sharing the anatomical structure of a stiff rod of cartilage that extends along the inside of the body. All vertebrates are chordates, but chordates also include also non-vertebrate species such as sea squirts and lancelets.

Chitin

A long-chain polymer made of N-acetylglucosamine that is the primary component of cell walls in fungi, the exoskeleton of crustaceans and insects and the scales of fish.

Dysbiosis

Microbial imbalance or maladaptation on or inside the body, turning a previous mutual, commensal or neutral symbiosis into a harmful of dysfunctional form of symbiosis.

Pathobionts

Any potentially disease-causing organisms that, under normal circumstances, live as symbionts.

Peyer’s patches

Organized lymph follicles that are part of the gut-associated lymphoid tissue. In humans, Peyer’s patches are mainly found in the small intestine.

Metagenomic studies

Microbiome characterization by DNA sequencing.

Culturomics

High-throughput culture-based approaches to enable extensive assessment of the microbial composition.

Phase II metabolism

The metabolism of xenobiotics aims to detoxify molecules that are foreign to mammalian metabolism, for example, microbial metabolites. Phase I reactions are chemical reactions that modify the molecular structure (including oxidation, reduction and hydrolysis) and often increase the reactivity of the metabolite. Phase II reactions involve conjugation of the xenobiotic to sulfate, glucuronide or glycine, which typically reduces the reactivity of the xenobiotic.

Microbial–host co-metabolites

The transformation of microbial metabolites by phase I and II metabolism results in a wide array of derivatives. These metabolites require the combined action of both microbial and mammalian metabolism.

Hirschsprung disease

A congenital disorder characterized by the absence of nerves from parts of the intestinal tract, causing intestinal symptoms and growth retardation.

Short-chain fatty acids

(SCFAs). The end products of carbohydrate fermentation. A group of gut-flora-derived lipid metabolites with important regulatory roles in energy metabolism, hormone secretion, systemic inflammation, hypertension and cancer.

Saccharolytic fermentation

The digestion of carbohydrates under anaerobic conditions, resulting in short-chain fatty acids.

Proteolytic fermentation

The digestion of peptides and amino acids under anaerobic conditions.

Pentraxins

A conserved family of protein complexes made of five identical proteins. Pentraxins are acute phase proteins secreted from tissue cells or cells of the innate immune system that bind to and opsonize foreign particles or dead cell structures conceptually similar to antibodies.

Immune paralysis

Acquired immunodeficiency due to the long-lasting deactivation of immune cells, which can occur following a short-lasting phase of activation, for example, as described for ‘endotoxin tolerance’ that occurs upon rechallenge with bacterial endotoxin.

Type II errors

An error by which an analytical test gives a negative result although the effect is indeed present (false negative).

Myocardial stunning

Persistent dysfunction of the cardiac muscle upon a transient episode of ischaemia.

Probiotics

Live microorganisms that are intended to provide health benefits when consumed, typically by restoring the intestinal microflora.

Prebiotics

Products that are intended to restore the intestinal microflora through ingestion of nutrients that endorse the growth or activity of beneficial microorganisms.

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Meijers, B., Evenepoel, P. & Anders, HJ. Intestinal microbiome and fitness in kidney disease. Nat Rev Nephrol 15, 531–545 (2019). https://doi.org/10.1038/s41581-019-0172-1

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