Advertisement
American Journal of Kidney Diseases

Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target

Published:November 15, 2015DOI:https://doi.org/10.1053/j.ajkd.2015.09.027
      Also known as the “second human genome,” the gut microbiome plays important roles in both the maintenance of health and the pathogenesis of disease. The symbiotic relationship between host and microbiome is disturbed due to the proliferation of dysbiotic bacteria in patients with chronic kidney disease (CKD). Fermentation of protein and amino acids by gut bacteria generates excess amounts of potentially toxic compounds such as ammonia, amines, thiols, phenols, and indoles, but the generation of short-chain fatty acids is reduced. Impaired intestinal barrier function in patients with CKD permits translocation of gut-derived uremic toxins into the systemic circulation, contributing to the progression of CKD, cardiovascular disease, insulin resistance, and protein-energy wasting. The field of microbiome research is still nascent, but is evolving rapidly. Establishing symbiosis to treat uremic syndrome is a novel concept, but if proved effective, it will have a significant impact on the management of patients with CKD.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Qin J.
        • Li R.
        • Raes J.
        • et al.
        A human gut microbial gene catalogue established by metagenomic sequencing.
        Nature. 2010; 464: 59-65
        • Gevers D.
        • Knight R.
        • Petrosino J.F.
        • et al.
        The Human Microbiome Project: a community resource for the healthy human microbiome.
        PLoS Biol. 2012; 10: e1001377
        • Backhed F.
        • Ley R.E.
        • Sonnenburg J.L.
        • Peterson D.A.
        • Gordon J.I.
        Host-bacterial mutualism in the human intestine.
        Science. 2005; 307: 1915-1920
        • Lederberg J.
        Infectious history.
        Science. 2000; 288: 287-293
        • Hawrelak J.A.
        • Myers S.P.
        The causes of intestinal dysbiosis: a review.
        Altern Med Rev. 2004; 9: 180-197
        • Backhed F.
        • Ding H.
        • Wang T.
        • et al.
        The gut microbiota as an environmental factor that regulates fat storage.
        Proc Natl Acad Sci U S A. 2004; 101: 15718-15723
        • Turnbaugh P.J.
        • Ley R.E.
        • Mahowald M.A.
        • Magrini V.
        • Mardis E.R.
        • Gordon J.I.
        An obesity-associated gut microbiome with increased capacity for energy harvest.
        Nature. 2006; 444: 1027-1031
        • Tang W.H.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
        N Engl J Med. 2013; 368: 1575-1584
        • Hooper L.V.
        • Midtvedt T.
        • Gordon J.I.
        How host-microbial interactions shape the nutrient environment of the mammalian intestine.
        Annu Rev Nutr. 2002; 22: 283-307
        • Hill M.J.
        Intestinal flora and endogenous vitamin synthesis.
        Eur J Cancer Prev. 1997; 6: S43-S45
        • Hylemon P.B.
        • Harder J.
        Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems.
        FEMS Microbiol Rev. 1998; 22: 475-488
        • Duncan S.H.
        • Richardson A.J.
        • Kaul P.
        • Holmes R.P.
        • Allison M.J.
        • Stewart C.S.
        Oxalobacter formigenes and its potential role in human health.
        Appl Environ Microbiol. 2002; 68: 3841-3847
        • Braun-Fahrlander C.
        • Riedler J.
        • Herz U.
        • et al.
        Environmental exposure to endotoxin and its relation to asthma in school-age children.
        N Engl J Med. 2002; 347: 869-877
        • Xu J.
        • Gordon J.I.
        Honor thy symbionts.
        Proc Natl Acad Sci U S A. 2003; 100: 10452-10459
        • The Human Microbiome Project consortium
        A framework for human microbiome research.
        Nature. 2012; 486: 215-221
        • The Human Microbiome Project consortium
        Structure, function and diversity of the healthy human microbiome.
        Nature. 2012; 486: 207-214
        • Eckburg P.B.
        • Bik E.M.
        • Bernstein C.N.
        • et al.
        Diversity of the human intestinal microbial flora.
        Science. 2005; 308: 1635-1638
        • Tremaroli V.
        • Backhed F.
        Functional interactions between the gut microbiota and host metabolism.
        Nature. 2012; 489: 242-249
        • Yatsunenko T.
        • Rey F.E.
        • Manary M.J.
        • et al.
        Human gut microbiome viewed across age and geography.
        Nature. 2012; 486: 222-227
        • Muegge B.D.
        • Kuczynski J.
        • Knights D.
        • et al.
        Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans.
        Science. 2011; 332: 970-974
        • Metchnikoff E.
        Essais optimistes.
        in: Chalmers Mitchell P, transl, ed. Paris. The Prolongation of Life: Optimistic Studies. Heinemann, London1907: 73-83
        • Ramezani A.
        • Raj D.S.
        The gut microbiome, kidney disease, and targeted interventions.
        J Am Soc Nephrol. 2014; 25: 657-670
        • Vaziri N.D.
        • Wong J.
        • Pahl M.
        • et al.
        Chronic kidney disease alters intestinal microbial flora.
        Kidney Int. 2013; 83: 308-315
        • Hida M.
        • Aiba Y.
        • Sawamura S.
        • Suzuki N.
        • Satoh T.
        • Koga Y.
        Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis.
        Nephron. 1996; 74: 349-355
        • Wu M.J.
        • Chang C.S.
        • Cheng C.H.
        • et al.
        Colonic transit time in long-term dialysis patients.
        Am J Kidney Dis. 2004; 44: 322-327
        • Bammens B.
        • Verbeke K.
        • Vanrenterghem Y.
        • Evenepoel P.
        Evidence for impaired assimilation of protein in chronic renal failure.
        Kidney Int. 2003; 64: 2196-2203
        • Krishnamurthy V.M.
        • Wei G.
        • Baird B.C.
        • et al.
        High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease.
        Kidney Int. 2012; 81: 300-306
        • Wandersman C.
        • Delepelaire P.
        Bacterial iron sources: from siderophores to hemophores.
        Annu Rev Microbiol. 2004; 58: 611-647
        • Jernberg C.
        • Lofmark S.
        • Edlund C.
        • Jansson J.K.
        Long-term impacts of antibiotic exposure on the human intestinal microbiota.
        Microbiology. 2010; 156: 3216-3223
        • Dethlefsen L.
        • Relman D.A.
        Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation.
        Proc Natl Acad Sci U S A. 2011; 108: 4554-4561
        • Dethlefsen L.
        • Huse S.
        • Sogin M.L.
        • Relman D.A.
        The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing.
        PLoS Biol. 2008; 6: e280
        • 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. 1966; 123: 239-250
        • Aronov P.A.
        • Luo F.J.
        • Plummer N.S.
        • et al.
        Colonic contribution to uremic solutes.
        J Am Soc Nephrol. 2011; 22: 1769-1776
        • Wikoff W.R.
        • Anfora A.T.
        • Liu J.
        • et al.
        Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.
        Proc Natl Acad Sci U S A. 2009; 106: 3698-3703
        • Sorensen L.B.
        Role of the intestinal tract in the elimination of uric acid.
        Arthritis Rheum. 1965; 8: 694-706
        • Gibson S.A.
        • McFarlan C.
        • Hay S.
        • Macfarlane G.T.
        Significance of microflora in proteolysis in the colon.
        Appl Environ Microbiol. 1989; 55: 679-683
        • Walser M.
        • Bodenlos L.J.
        Urea metabolism in man.
        J Clin Invest. 1959; 38: 1617-1626
        • Stewart G.S.
        • Smith C.P.
        Urea nitrogen salvage mechanisms and their relevance to ruminants, non-ruminants and man.
        Nutr Res Rev. 2005; 18: 49-62
        • Vaziri N.D.
        • Yuan J.
        • Rahimi A.
        • Ni Z.
        • Said H.
        • Subramanian V.S.
        Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation.
        Nephrol Dial Transplant. 2012; 27: 2686-2693
        • Vaziri N.D.
        • Goshtasbi N.
        • Yuan J.
        • et al.
        Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium.
        Am J Nephrol. 2012; 36: 438-443
        • 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. 2013; 37: 1-6
        • Jones J.D.
        • Burnett P.C.
        Creatinine metabolism in humans with decreased renal function: creatinine deficit.
        Clin Chem. 1974; 20: 1204-1212
        • Van Eyk H.G.
        • Vermaat R.J.
        • Leijnse-Ybema H.J.
        • Leijnse B.
        The conversion of creatinine by creatiniase of bacterial origin.
        Enzymologia. 1986; 34: 198-202
        • Olsen N.S.
        • Bassett J.W.
        Blood levels of urea nitrogen, phenol, guanidine and creatinine in uremia.
        Am J Med. 1951; 10: 52-59
        • Yokozawa T.
        • Mo Z.L.
        • Oura H.
        Comparison of toxic effects of methylguanidine, guanidinosuccinic acid and creatinine in rats with adenine-induced chronic renal failure.
        Nephron. 1989; 51: 388-392
        • Alderman M.H.
        • Cohen H.
        • Madhavan S.
        • Kivlighn S.
        Serum uric acid and cardiovascular events in successfully treated hypertensive patients.
        Hypertension. 1999; 34: 144-150
        • Gibson T.
        • Highton J.
        • Potter C.
        • Simmonds H.A.
        Renal impairment and gout.
        Ann Rheum Dis. 1980; 39: 417-423
        • Hatch M.
        • Vaziri N.D.
        Enhanced enteric excretion of urate in rats with chronic renal failure.
        Clin Sci (Lond). 1994; 86: 511-516
        • Wong J.
        • Piceno Y.M.
        • Desantis T.Z.
        • Pahl M.
        • Andersen G.L.
        • Vaziri N.D.
        Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD.
        Am J Nephrol. 2014; 39: 230-237
        • van Haard P.M.
        Chromatography of urinary indole derivatives.
        J Chromatogr. 1988; 429: 59-94
        • Lin C.J.
        • Chen H.H.
        • Pan C.F.
        • et al.
        p-Cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease.
        J Clin Lab Anal. 2011; 25: 191-197
        • Wu I.W.
        • Hsu K.H.
        • Lee C.C.
        • et al.
        p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease.
        Nephrol Dial Transplant. 2011; 26: 938-947
        • Motojima M.
        • Hosokawa A.
        • Yamato H.
        • Muraki T.
        • Yoshioka T.
        Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake.
        Br J Pharmacol. 2002; 135: 555-563
        • Motojima M.
        • Hosokawa A.
        • Yamato H.
        • Muraki T.
        • Yoshioka T.
        Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells.
        Kidney Int. 2003; 63: 1671-1680
        • Lysaght M.J.
        • Vonesh E.F.
        • Gotch F.
        • et al.
        The influence of dialysis treatment modality on the decline of remaining renal function.
        ASAIO Trans. 1991; 37: 598-604
        • Miyazaki T.
        • Ise M.
        • Seo H.
        • Niwa T.
        Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys.
        Kidney Int Suppl. 1997; 62: S15-S22
        • Adijiang A.
        • Higuchi Y.
        • Nishijima F.
        • Shimizu H.
        • Niwa T.
        Indoxyl sulfate, a uremic toxin, promotes cell senescence in aorta of hypertensive rats.
        Biochem Biophys Res Commun. 2010; 399: 637-641
        • Barreto F.C.
        • Barreto D.V.
        • Liabeuf S.
        • et al.
        Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients.
        Clin J Am Soc Nephrol. 2009; 4: 1551-1558
        • Yamamoto H.
        • Tsuruoka S.
        • Ioka T.
        • et al.
        Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells.
        Kidney Int. 2006; 69: 1780-1785
        • Dou L.
        • Jourde-Chiche N.
        • Faure V.
        • et al.
        The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells.
        J Thromb Haemost. 2007; 5: 1302-1308
        • Amabile N.
        • Guerin A.P.
        • Leroyer A.
        • et al.
        Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure.
        J Am Soc Nephrol. 2005; 16: 3381-3388
        • Dou L.
        • Bertrand E.
        • Cerini C.
        • et al.
        The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair.
        Kidney Int. 2004; 65: 442-451
        • Chiang C.K.
        • Tanaka T.
        • Inagi R.
        • Fujita T.
        • Nangaku M.
        Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner.
        Lab Invest. 2011; 91: 1564-1571
        • Nii-Kono T.
        • Iwasaki Y.
        • Uchida M.
        • et al.
        Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells.
        Kidney Int. 2007; 71: 738-743
        • Mozar A.
        • Louvet L.
        • Godin C.
        • et al.
        Indoxyl sulphate inhibits osteoclast differentiation and function.
        Nephrol Dial Transplant. 2012; 27: 2176-2181
        • Barreto F.C.
        • Barreto D.V.
        • Canziani M.E.
        • et al.
        Association between indoxyl sulfate and bone histomorphometry in pre-dialysis chronic kidney disease patients.
        J Bras Nefrol. 2014; 36: 289-296
        • Ichii O.
        • Otsuka-Kanazawa S.
        • Nakamura T.
        • et al.
        Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand.
        PLoS One. 2014; 9: e108448
        • Niwa T.
        • Takeda N.
        • Tatematsu A.
        • Maeda K.
        Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography.
        Clin Chem. 1988; 34: 2264-2267
        • Martinez A.W.
        • Recht N.S.
        • Hostetter T.H.
        • Meyer T.W.
        Removal of p-cresol sulfate by hemodialysis.
        J Am Soc Nephrol. 2005; 16: 3430-3436
        • De Smet R.
        • Dhondt A.
        • Eloot S.
        • Galli F.
        • Waterloos M.A.
        • Vanholder R.
        Effect of the super-flux cellulose triacetate dialyser membrane on the removal of non-protein-bound and protein-bound uraemic solutes.
        Nephrol Dial Transplant. 2007; 22: 2006-2012
        • Satoh M.
        • Hayashi H.
        • Watanabe M.
        • et al.
        Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure.
        Nephron Exp Nephrol. 2003; 95: e111-e118
        • Dou L.
        • Sallee M.
        • Cerini C.
        • et al.
        The cardiovascular effect of the uremic solute indole-3 acetic acid.
        J Am Soc Nephrol. 2015; 26: 876-887
        • Cummings J.H.
        Fermentation in the human large intestine: evidence and implications for health.
        Lancet. 1983; 1: 1206-1209
        • de Loor H.
        • Bammens B.
        • Evenepoel P.
        • De Preter V.
        • Verbeke K.
        Gas chromatographic-mass spectrometric analysis for measurement of p-cresol and its conjugated metabolites in uremic and normal serum.
        Clin Chem. 2005; 51: 1535-1538
        • Meijers B.K.
        • Evenepoel P.
        The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression.
        Nephrol Dial Transplant. 2011; 26: 759-761
        • Mutsaers H.A.
        • Wilmer M.J.
        • van den Heuvel L.P.
        • Hoenderop J.G.
        • Masereeuw R.
        Basolateral transport of the uraemic toxin p-cresyl sulfate: role for organic anion transporters?.
        Nephrol Dial Transplant. 2011; 26: 4149
        • Poesen R.
        • Viaene L.
        • Verbeke K.
        • et al.
        Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD.
        Clin J Am Soc Nephrol. 2013; 8: 1508-1514
        • Sun C.Y.
        • Chang S.C.
        • Wu M.S.
        Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition.
        PLoS One. 2012; 7: e34026
        • Watanabe H.
        • Miyamoto Y.
        • Honda D.
        • et al.
        p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase.
        Kidney Int. 2013; 83: 582-592
        • Bammens B.
        • Evenepoel P.
        • Keuleers H.
        • Verbeke K.
        • Vanrenterghem Y.
        Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients.
        Kidney Int. 2006; 69: 1081-1087
        • Liabeuf S.
        • Barreto D.V.
        • Barreto F.C.
        • et al.
        Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease.
        Nephrol Dial Transplant. 2010; 25: 1183-1191
        • Meijers B.K.
        • Claes K.
        • Bammens B.
        • et al.
        p-Cresol and cardiovascular risk in mild-to-moderate kidney disease.
        Clin J Am Soc Nephrol. 2010; 5: 1182-1189
        • Koppe L.
        • Pillon N.J.
        • Vella R.E.
        • et al.
        p-Cresyl sulfate promotes insulin resistance associated with CKD.
        J Am Soc Nephrol. 2013; 24: 88-99
        • Zimmerman L.
        • Egestad B.
        • Jornvall H.
        • Bergstrom J.
        Identification and determination of phenylacetylglutamine, a major nitrogenous metabolite in plasma of uremic patients.
        Clin Nephrol. 1989; 32: 124-128
        • Smith E.A.
        • Macfarlane G.T.
        Formation of phenolic and indolic compounds by anaerobic bacteria in the human large intestine.
        Microb Ecol. 1997; 33: 180-188
        • Seakins J.W.
        The determination of urinary phenylacetylglutamine as phenylacetic acid. Studies on its origin in normal subjects and children with cystic fibrosis.
        Clin Chim Acta. 1971; 35: 121-131
        • Yang D.
        • Beylot M.
        • Agarwal K.C.
        • Soloviev M.V.
        • Brunengraber H.
        Assay of the human liver citric acid cycle probe phenylacetylglutamine and of phenylacetate in plasma by gas chromatography-mass spectrometry.
        Anal Biochem. 1993; 212: 277-282
        • Sherwin C.P.
        • Kennard S.
        Toxicity of phenylacetic acid.
        J Biol Chem. 1919; 12: 259-264
        • Schmidt S.
        • Westhoff T.H.
        • Krauser P.
        • et al.
        The uraemic toxin phenylacetic acid impairs macrophage function.
        Nephrol Dial Transplant. 2008; 23: 3485-3493
        • Schmidt S.
        • Westhoff T.H.
        • Krauser P.
        • Zidek W.
        • van der Giet M.
        The uraemic toxin phenylacetic acid increases the formation of reactive oxygen species in vascular smooth muscle cells.
        Nephrol Dial Transplant. 2008; 23: 65-71
        • Yano S.
        • Yamaguchi T.
        • Kanazawa I.
        • et al.
        The uraemic toxin phenylacetic acid inhibits osteoblastic proliferation and differentiation: an implication for the pathogenesis of low turnover bone in chronic renal failure.
        Nephrol Dial Transplant. 2007; 22: 3160-3165
        • Remer T.
        • Manz F.
        Paleolithic diet, sweet potato eaters, and potential renal acid load.
        Am J Clin Nutr. 2003; 78: 802-803
        • Li M.
        • Wang B.
        • Zhang M.
        • et al.
        Symbiotic gut microbes modulate human metabolic phenotypes.
        Proc Natl Acad Sci U S A. 2008; 105: 2117-2122
        • Cathcart-Rake W.
        • Porter R.
        • Whittier F.
        • Stein P.
        • Carey M.
        • Grantham J.
        Effect of diet on serum accumulation and renal excretion of aryl acids and secretory activity in normal and uremic man.
        Am J Clin Nutr. 1975; 28: 1110-1115
        • Mitch W.E.
        • Brusilow S.
        Benzoate-induced changes in glycine and urea metabolism in patients with chronic renal failure.
        J Pharmacol Exp Ther. 1982; 222: 572-575
        • Ringoir S.
        • Vanholder R.
        • Massy Z.
        Proceedings of the Ghent Symposium on Uremic Toxins.
        Adv Exp Med Biol. 1986; 223: 59-67
        • Igarashi K.
        • Ueda S.
        • Yoshida K.
        • Kashiwagi K.
        Polyamines in renal failure.
        Amino Acids. 2006; 31: 477-483
        • Campbell R.A.
        • Grettie D.P.
        • Bartos F.
        • Bartos D.
        • Marton L.J.
        Uremic polyamine dysmetabolism.
        Proc Clin Dial Transplant Forum. 1978; 8: 194-198
        • Kushner D.
        • Beckman B.
        • Nguyen L.
        • et al.
        Polyamines in the anemia of end-stage renal disease.
        Kidney Int. 1991; 39: 725-732
        • Bruckner H.
        • Hausch M.
        Gas chromatographic characterization of free d-amino acids in the blood serum of patients with renal disorders and of healthy volunteers.
        J Chromatogr. 1993; 614: 7-17
        • Oh M.S.
        • Phelps K.R.
        • Traube M.
        • Barbosa-Saldivar J.L.
        • Boxhill C.
        • Carroll H.J.
        d-Lactic acidosis in a man with the short-bowel syndrome.
        N Engl J Med. 1979; 301: 249-252
        • Wang Z.
        • Klipfell E.
        • Bennett B.J.
        • et al.
        Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
        Nature. 2011; 472: 57-63
        • Koeth R.A.
        • Wang Z.
        • Levison B.S.
        • et al.
        Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis.
        Nat Med. 2013; 19: 576-585
        • Tang W.H.
        • Wang Z.
        • Fan Y.
        • et al.
        Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis.
        J Am Coll Cardiol. 2014; 64: 1908-1914
        • Tang W.H.
        • Wang Z.
        • Kennedy D.J.
        • 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. 2015; 116: 448-455
        • Reiffenstein R.J.
        • Hulbert W.C.
        • Roth S.H.
        Toxicology of hydrogen sulfide.
        Annu Rev Pharmacol Toxicol. 1992; 32: 109-134
        • Aminzadeh M.A.
        • Vaziri N.D.
        Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease.
        Nephrol Dial Transplant. 2012; 27: 498-504
        • Perna A.F.
        • Lanza D.
        • Sepe I.
        • et al.
        Hydrogen sulfide, a toxic gas with cardiovascular properties in uremia: how harmful is it?.
        Blood Purif. 2011; 31: 102-106
        • Perna A.F.
        • Luciano M.G.
        • Ingrosso D.
        • et al.
        Hydrogen sulphide-generating pathways in haemodialysis patients: a study on relevant metabolites and transcriptional regulation of genes encoding for key enzymes.
        Nephrol Dial Transplant. 2009; 24: 3756-3763
        • Song K.
        • Wang F.
        • Li Q.
        • et al.
        Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy.
        Kidney Int. 2014; 85: 1318-1329
        • Pugin J.
        • Heumann I.D.
        • Tomasz A.
        • et al.
        CD14 is a pattern recognition receptor.
        Immunity. 1994; 1: 509-516
        • Freudenberg M.A.
        • Tchaptchet S.
        • Keck S.
        • et al.
        Lipopolysaccharide sensing an important factor in the innate immune response to gram-negative bacterial infections: benefits and hazards of LPS hypersensitivity.
        Immunobiology. 2008; 213: 193-203
        • Eggesbo J.B.
        • Hjermann I.
        • Ovstebo R.
        • Joo G.B.
        • Kierulf P.
        LPS induced procoagulant activity and plasminogen activator activity in mononuclear cells from persons with high or low levels of HDL lipoprotein.
        Thromb Res. 1995; 77: 441-452
        • Reidy M.A.
        • Bowyer D.E.
        Distortion of endothelial repair. The effect of hypercholesterolaemia on regeneration of aortic endothelium following injury by endotoxin. A scanning electron microscope study.
        Atherosclerosis. 1978; 29: 459-466
        • Poesen R.
        • Ramezani A.
        • Claes K.
        • 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. 2015; 10: 1525-1533
        • Raj D.S.
        • Carrero J.J.
        • Shah V.O.
        • et al.
        Soluble CD14 levels, interleukin 6, and mortality among prevalent hemodialysis patients.
        Am J Kidney Dis. 2009; 54: 1072-1080
        • Raj D.S.
        • Shah V.O.
        • Rambod M.
        • Kovesdy C.P.
        • Kalantar-Zadeh K.
        Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis.
        Am J Kidney Dis. 2009; 54: 1062-1071
        • Cani P.D.
        • Amar J.
        • Iglesias M.A.
        • et al.
        Metabolic endotoxemia initiates obesity and insulin resistance.
        Diabetes. 2007; 56: 1761-1772
        • Macpherson A.J.
        • Harris N.L.
        Interactions between commensal intestinal bacteria and the immune system.
        Nat Rev Immunol. 2004; 4: 478-485
        • Round J.L.
        • Mazmanian S.K.
        Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota.
        Proc Natl Acad Sci U S A. 2010; 107: 12204-12209
        • Clarke T.B.
        • Davis K.M.
        • Lysenko E.S.
        • Zhou A.Y.
        • Yu Y.
        • Weiser J.N.
        Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity.
        Nat Med. 2010; 16: 228-231
        • Layden B.T.
        • Angueira A.R.
        • Brodsky M.
        • Durai V.
        • Lowe Jr., W.L.
        Short chain fatty acids and their receptors: new metabolic targets.
        Transl Res. 2013; 161: 131-140
        • Andrade-Oliveira V.
        • Amano M.T.
        • Correa-Costa M.
        • et al.
        Gut bacteria products prevent AKI induced by ischemia-reperfusion.
        J Am Soc Nephrol. 2015; 26: 1877-1888
        • Barrows I.R.
        • Ramezani A.
        • Raj D.S.
        Gut feeling in AKI: the long arm of short-chain fatty acids.
        J Am Soc Nephrol. 2015; 26: 1755-1757
        • Pluznick J.L.
        • Protzko R.J.
        • Gevorgyan H.
        • et al.
        Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation.
        Proc Natl Acad Sci U S A. 2013; 110: 4410-4415
        • Vanholder R.
        • Argiles A.
        • Baurmeister U.
        • et al.
        Uremic toxicity: present state of the art.
        Int J Artif Organs. 2001; 24: 695-725
        • Duranton F.
        • Cohen G.
        • De Smit R.
        • et al.
        Normal and pathologic concentrations of uremic toxins.
        J Am Soc Nephrol. 2012; 23: 1258-1270
        • Vanholder R.
        • Boelaert J.
        • Glorieux G.
        • Eloot S.
        New methods and technologies for measuring uremic toxins and quantifying dialysis adequacy.
        Semin Dial. 2015; 28: 114-124
        • Tringe S.G.
        • Rubin E.M.
        Metagenomics: DNA sequencing of environmental samples.
        Nat Rev Genet. 2005; 6: 805-814
        • Rhee E.P.
        • Clish C.B.
        • Ghorbani A.
        • et al.
        A combined epidemiologic and metabolomic approach improves CKD prediction.
        J Am Soc Nephrol. 2013; 24: 1330-1338
        • Mutsaers H.A.
        • Engelke U.F.
        • Wilmer M.J.
        • et al.
        Optimized metabolomic approach to identify uremic solutes in plasma of stage 3-4 chronic kidney disease patients.
        PLoS One. 2013; 8: e71199
        • Qin J.
        • Li Y.
        • Cai Z.
        • et al.
        A metagenome-wide association study of gut microbiota in type 2 diabetes.
        Nature. 2012; 490: 55-60
        • Hevia A.
        • Milani C.
        • Lopez P.
        • et al.
        Intestinal dysbiosis associated with systemic lupus erythematosus.
        MBio. 2014; 5 (e01548-14)
        • De Angelis M.
        • Montemurno E.
        • Piccolo M.
        • et al.
        Microbiota and metabolome associated with immunoglobulin A nephropathy (IgAN).
        PLoS One. 2014; 9: e99006
        • Miyamoto Y.
        • Watanabe H.
        • Noguchi T.
        • et al.
        Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney.
        Nephrol Dial Transplant. 2011; 26: 2498-2502
        • Ando Y.
        • Miyata Y.
        • Tanba K.
        • et al.
        [Effect of oral intake of an enteric capsule preparation containing Bifidobacterium longum on the progression of chronic renal failure].
        Nihon Jinzo Gakkai Shi. 2003; 45: 759-764
        • Natarajan R.
        • Pechenyak B.
        • Vyas U.
        • et al.
        Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients.
        Biomed Res Int. 2014; 2014: 568571
        • Wang I.K.
        • Wu Y.Y.
        • Yang Y.F.
        • et al.
        The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial.
        Benef Microbes. 2015; 6: 423-430
        • Guida B.
        • Germano R.
        • Trio R.
        • et al.
        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: 1043-1049
        • Meijers B.K.
        • De Preter V.
        • Verbeke K.
        • Vanrenterghem Y.
        • Evenepoel P.
        p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin.
        Nephrol Dial Transplant. 2010; 25: 219-224
        • Sirich T.L.
        • Plummer N.S.
        • Gardner C.D.
        • Hostetter T.H.
        • Meyer T.W.
        Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients.
        Clin J Am Soc Nephrol. 2014; 9: 1603-1610
        • Vaziri N.D.
        • Liu S.M.
        • Lau W.L.
        • et al.
        High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease.
        PLoS One. 2014; 9: e114881
        • Nakabayashi I.
        • Nakamura M.
        • Kawakami K.
        • et al.
        Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study.
        Nephrol Dial Transplant. 2011; 26: 1094-1098
        • Prakash S.
        • Chang T.M.
        Genetically engineered E. coli cells containing K. aerogenes gene, microencapsulated in artificial cells for urea and ammonia removal.
        Biomater Artif Cells Immobilization Biotechnol. 1993; 21: 629-636
        • Prakash S.
        • Chang T.M.
        Microencapsulated genetically engineered live E. coli DH5 cells administered orally to maintain normal plasma urea level in uremic rats.
        Nat Med. 1996; 2: 883-887
        • Schulman G.
        • Agarwal R.
        • Acharya M.
        • Berl T.
        • Blumenthal S.
        • Kopyt N.
        A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD.
        Am J Kidney Dis. 2006; 47: 565-577
        • Vaziri N.D.
        • Yuan J.
        • Khazaeli M.
        • Masuda Y.
        • Ichii H.
        • Liu S.
        Oral activated charcoal adsorbent (AST-120) ameliorates chronic kidney disease-induced intestinal epithelial barrier disruption.
        Am J Nephrol. 2013; 37: 518-525
        • Schulman G.
        • Berl T.
        • Beck G.J.
        • et al.
        Randomized placebo-controlled EPPIC trials of AST-120 in CKD.
        J Am Soc Nephrol. 2015; 26: 1732-1746
        • Rossi M.
        • Johnson D.W.
        • Morrison M.
        • et al.
        SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial.
        BMC Nephrol. 2014; 15: 106
        • Andriamihaja M.
        • Lan A.
        • Beaumont M.
        • et al.
        The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells.
        Free Radic Biol Med. 2015; 85: 219-227
        • Strid H.
        • Simren M.
        • Stotzer P.O.
        • Ringstrom G.
        • Abrahamsson H.
        • Bjornsson E.S.
        Patients with chronic renal failure have abnormal small intestinal motility and a high prevalence of small intestinal bacterial overgrowth.
        Digestion. 2003; 67: 129-137
        • Simenhoff M.L.
        • Dunn S.R.
        • Zollner G.P.
        • et al.
        Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus.
        Miner Electrolyte Metab. 1996; 22: 92-96
        • Shi K.
        • Wang F.
        • Jiang H.
        • et al.
        Gut bacterial translocation may aggravate microinflammation in hemodialysis patients.
        Dig Dis Sci. 2014; 59: 2109-2117
        • de Almeida Duarte J.B.
        • de Aguilar-Nascimento J.E.
        • Nascimento M.
        • Nochi Jr., R.J.
        Bacterial translocation in experimental uremia.
        Urol Res. 2004; 32: 266-270
        • 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. 1985; 80: 608-611
        • Richardson A.J.
        • McKain N.
        • Wallace R.J.
        Ammonia production by human faecal bacteria, and the enumeration, isolation and characterization of bacteria capable of growth on peptides and amino acids.
        BMC Microbiol. 2013; 13: 6
        • Perna A.F.
        • Ingrosso D.
        • Lombardi C.
        • et al.
        Homocysteine in uremia.
        Am J Kidney Dis. 2003; 41: S123-S126
        • Turkmen K.
        • Erdur F.M.
        The relationship between colonization of Oxalobacter formigenes serum oxalic acid and endothelial dysfunction in hemodialysis patients: from impaired colon to impaired endothelium.
        Med Hypotheses. 2015; 84: 273-275
        • Cerini C.
        • Dou L.
        • Anfosso F.
        • et al.
        p-Cresol, a uremic retention solute, alters the endothelial barrier function in vitro.
        Thromb Haemost. 2004; 92: 140-150
        • 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. 2006; 70: 192-198
      1. The effect of arabinoxylan-oligosaccharides (AXOS) on intestinal generation of microbial metabolites in chronic kidney disease. https://clinicaltrials.gov/ct2/show/study/NCT02141815?term=Bj%C3%B6rn+Meijers&rank=4 2015. Accessed August 17, 2015.