Uremic solutes from colon microbes
2012; Elsevier BV; Volume: 81; Issue: 10 Linguagem: Inglês
10.1038/ki.2011.504
ISSN1523-1755
AutoresTimothy W. Meyer, Thomas H. Hostetter,
Tópico(s)Renal function and acid-base balance
ResumoThere is renewed interest in identifying organic waste solutes that are normally excreted by the kidneys and must be removed by renal replacement therapy when the kidneys fail. A large number of these waste solutes are produced by colon microbes. Mass spectrometry is expanding our knowledge of their chemical identity, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. There is evidence that the most extensively studied of the colon-derived solutes, indoxyl sulfate and p-cresol sulfate, are toxic. Much more study is required to establish the toxicity of other solutes in this class. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other waste solutes. To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis. There is renewed interest in identifying organic waste solutes that are normally excreted by the kidneys and must be removed by renal replacement therapy when the kidneys fail. A large number of these waste solutes are produced by colon microbes. Mass spectrometry is expanding our knowledge of their chemical identity, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. There is evidence that the most extensively studied of the colon-derived solutes, indoxyl sulfate and p-cresol sulfate, are toxic. Much more study is required to establish the toxicity of other solutes in this class. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other waste solutes. To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis. The kidney excretes a large number of organic waste solutes whose origins are diverse. Better knowledge of these solutes could lead to improved treatment for patients with kidney failure. Many waste solutes are produced by colon microbes. There is reason to suppose that some of these compounds, which are foreign to mammalian metabolism, have toxic effects. Because they are made in an isolated body compartment by microbes, their production may prove simpler to suppress than the production of other uremic waste solutes. Our human bodies are heavily colonized by microbes.1.Dethlefsen L. McFall-Ngai M. Relman D.A. An ecological and evolutionary perspective on human-microbe mutualism and disease.Nature. 2007; 449: 811-818Crossref PubMed Scopus (1035) Google Scholar The largest collection of these microbes, with a density of 1010 to 1012cell/ml, inhabits the colon.1.Dethlefsen L. McFall-Ngai M. Relman D.A. An ecological and evolutionary perspective on human-microbe mutualism and disease.Nature. 2007; 449: 811-818Crossref PubMed Scopus (1035) Google Scholar, 2.Goodman A.L. Gordon J.I. Our unindicted coconspirators: human metabolism from a microbial perspective.Cell Metab. 2010; 12: 111-116Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 3.Walter J. Britton R.A. Roos S. Host-microbial symbiosis in the vertebrate gastrointestinal tract and the Lactobacillus reuteri paradigm.Proc Natl Acad Sci USA. 2011; 108: 4645-4652Crossref PubMed Scopus (181) Google Scholar In cell number and even more in gene number, the colon microbial population or colon ‘microbiome’ dwarfs its human host. DNA sequencing technology has greatly increased our knowledge of the diversity and function of the colon microbes. In mammalian evolution, their chief value has been to extract energy from plant polysaccharides that cannot be digested by host enzymes. Microbial fermentation of these polysaccharides yields short chain fatty acids. While this process provides only a small portion of the energy used daily in humans consuming an ‘industrialized’ diet, it can be a crucial source of energy when the diet contains more unprocessed plant food.4.Nordgaard I. Mortensen P.B. Digestive processes in the human colon.Nutrition. 1995; 11: 37-45PubMed Google Scholar Colon microbes also provide micronutrients including vitamins and produce hormones that promote fat storage. Through co-evolution with their mammalian hosts, they have developed the capacity to limit colonization of the gut by pathogens and to stimulate the host immune system in useful ways. The action of colon microbes on foodstuffs and intestinal secretions, however, generates numerous organic compounds in addition to those that are useful to their host.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar The burden of excreting some of these compounds in the urine represents a biological price paid by the host for harboring the microbes. Colon-derived solutes that are normally excreted in the urine accumulate in the plasma when the kidneys fail and may contribute to uremic toxicity.6.Evenepoel P. Meijers B.K. Bammens B.R. et al.Uremic toxins originating from colonic microbial metabolism.Kidney Int Suppl. 2009; 76 (Suppl 114): S12-S19Abstract Full Text Full Text PDF Scopus (270) Google Scholar,7.Schepers E. Glorieux G. Vanholder R. The gut: the forgotten organ in uremia?.Blood Purif. 2010; 29: 130-136Crossref PubMed Scopus (102) Google Scholar While knowledge of the colon's microbial diversity is new, the hypothesis that colon microbes produce toxic solutes is old. In his original description of hemodialysis, Kolff8.Kolff W.J. The Artificial Kidney. J. H. Kok, Kampen1946Google Scholar noted that“Besides indoxyl still other various putrefaction products of the intestine may be increased in the blood in renal insufficienty [sic]. They are phenoles, cresoles, aromatic oxyacids, and other aromatic substances.” Putrefaction—the breakdown of proteins by bacteria—excited both scientific and popular interest in the late nineteenth and early twentieth centuries.9.Chen T.S. Chen P.S. Intestinal autointoxication: a medical leitmotif.J Clin Gastroenterol. 1989; 11: 434-441Crossref PubMed Scopus (31) Google Scholar The Russian Nobel Laureate Metchnikoff believed that in modern humans the colon was not only useless but harmful, and that ‘autointoxication’ caused by colonic putrefaction accelerated aging and caused disease. He advocated the consumption of milk soured by lactic acid–producing bacteria to inhibit proteolysis in the colon. The British surgeon W. Arbuthnot Lane went further and bypassed the colon to treat diseases ranging from tuberculosis to rheumatoid arthritis.9.Chen T.S. Chen P.S. Intestinal autointoxication: a medical leitmotif.J Clin Gastroenterol. 1989; 11: 434-441Crossref PubMed Scopus (31) Google Scholar The autointoxication theory had been largely discredited by Kolff's time, but it had left behind a legacy of solid biochemical research. Gut bacteria had been shown to degrade tryptophan into a variety of indoles and phenylalanine and tyrosine into a variety of phenyl compounds. Some of these compounds were found first in the urine of normal humans and then in the plasma of patients with kidney failure.10.Ludwig G.D. Senesky D. Bluemle Jr, L.W. et al.Indoles in ureamia: identification by countercurrent distribution and paper chromatography.Am J Clin Nutr. 1968; 21: 436-450Crossref PubMed Scopus (25) Google Scholar The colon-derived uremic solutes that have been most extensively investigated are indoxyl sulfate and p-cresol sulfate, which are formed as depicted in Figure 1.11.Niwa T. Indoxyl sulfate is a nephro-vascular toxin.J Ren Nutr. 2010; 20: S2-S6Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar,12.Vanholder R. Bammens B. de Loor H. et al.Warning: the unfortunate end of p-cresol as a uraemic toxin.Nephrol Dial Transplant. 2011; 26: 1464-1467Crossref PubMed Scopus (70) Google Scholar These compounds have received the most attention because they are formed in relatively large quantities and therefore proved easiest to measure. As reviewed below, there is considerable, though not conclusive, evidence that they are toxic. Indoxyl sulfate and p-cresol sulfate are only two, however, of a very large number of colon-derived uremic solutes. Other compounds in this class may be more toxic, although they are present in lower concentration. Between 1940 and 1990, numerous indoles and phenols were identified in uremic plasma first by paper and then gas chromatography.10.Ludwig G.D. Senesky D. Bluemle Jr, L.W. et al.Indoles in ureamia: identification by countercurrent distribution and paper chromatography.Am J Clin Nutr. 1968; 21: 436-450Crossref PubMed Scopus (25) Google Scholar, 13.Niwa T. Maeda K. Ohki T. et al.A gas chromatographic-mass spectrometric analysis for phenols in uremic serum.Clin Chim Acta. 1981; 110: 51-57Crossref PubMed Scopus (58) Google Scholar, 14Van Haard P. Pavel S. Chromatography of urinary indole derivatives.J Chromatogr. 1988; 429: 59-94Crossref PubMed Scopus (42) Google Scholar Researchers hypothesized that many of them were made by colon microbes. In most cases, however, their origin was not confirmed and there has been very little evaluation of their toxicity. The application of mass spectrometry has the power to greatly enlarge our knowledge of uremic solutes in general and of colon-derived uremic solutes in particular.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar, 15.Niwa T. Recent progress in the analysis of uremic toxins by mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877: 2600-2606Crossref PubMed Scopus (27) Google Scholar, 16.Rhee E.P. Souza A. Farrell L. et al.Metabolite profiling identifies markers of uremia.J Am Soc Nephrol. 2010; 21: 1041-1051Crossref PubMed Scopus (133) Google Scholar High-resolution detectors that resolve the mass to charge (m/z) ratios of ions to within a few parts per million may prove particularly valuable in uremia research. These instruments make it possible to perform ‘nontargeted’ metabolomic studies in which numerous unnamed chemical features characterized only by their m/z ratios are detected along with known compounds. Kikuchi et al.17.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic analysis of uremic toxins by liquid chromatography/electrospray ionization-tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 1662-1668Crossref PubMed Scopus (67) Google Scholar first used nontargeted mass spectrometry to detect solutes that accumulate in the plasma of rats with renal insufficiency, and Sato et al.18.Sato E. Kohno M. Yamamoto M. et al.Metabolomic analysis of human plasma from haemodialysis patients.Eur J Clin Invest. 2011; 41: 241-255Crossref PubMed Scopus (49) Google Scholar have recently demonstrated the capacity of nontargeted mass spectrometry to detect both known and unknown compounds in a study evaluating the effect of hemodialysis on plasma solute concentrations. Solutes produced by colon microbes can be identified by combining mass spectrometry with maneuvers that suppress microbial solute production. A pioneering study by Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar used high-resolution mass spectrometry to identify plasma solutes produced by gut microbes in rats. Of several thousand features detected in plasma, ∼10 percent was considered to vary in concentration between conventional and germ-free rats. The majority of these features was less prevalent in the germ-free animals, and thus considered to be of microbial origin. Of note, some features considered to be of microbial origin were later found to accumulate in the plasma of mice lacking the renal anion transporter OAT1, suggesting that they are largely removed from the body by renal tubular secretion.19.Wikoff W.R. Nagle M.A. Kouznetsova V.L. et al.Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1).J Proteome Res. 2011; 10: 2842-2851Crossref PubMed Scopus (113) Google Scholar Kikuchi et al.20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar subsequently used mass spectrometry to identify solutes in whose plasma levels were reduced by the administration of the oral sorbent AST-120 in rats with renal insufficiency. We recently used an approach similar to that used by Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar to compare plasma solute profiles in dialysis patients with and without colons.21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar The difference between patients with and without colons was readily apparent on superficial examination of mass spectra, as illustrated in Figure 2. Statistical analysis identified more than 20 mass spectrometric features that were colon-derived. Of note, the great majority of these was more prominent in dialysis patients than normal subjects and so could be considered to represent uremic solutes. A weakness of nontargeted mass spectrometry is that it provides mass values but not chemical identities for the numerous features detected. Chemical identification requires further analysis of samples containing reagent standards and/or ‘MS/MS’ measurements of the ion masses produced by fragmentation of the original ions.22.Roux A. Lison D. Junot C. et al.Applications of liquid chromatography coupled to mass spectrometry-based metabolomics in clinical chemistry and toxicology: a review.Clin Biochem. 2011; 44: 119-135Crossref PubMed Scopus (157) Google Scholar Only a small number of the colon-derived solutes recently detected by mass spectrometry have been chemically identified. Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar identified only 16 of several hundred features that were more prominent in the plasma of conventional than germ-free rats. These included three indole and six phenyl compounds. We identified three indole and two phenyl compounds that were present at higher concentration in dialysis patients with colons than in dialysis patients without colons and normal subjects.21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar Part of the problem is that organic waste compounds are often conjugated to form sulfates, glucuronides, or other complex ions. Conjugation, as illustrated for p-cresol and indoxyl in Figure 1, can at once reduce the toxicity of waste compounds and facilitate their excretion by tubular secretion. But conjugation makes it harder to determine the chemical identity of features for which mass spectrometry provides only the m/z ratio. Standard databases usually do not contain mass values for conjugates of microbial metabolites and reagent standards for such compounds are rarely available. Colon-derived uremic solutes that have been identified to date are listed in Table 1. The list will get longer as more mass spectrometric studies are performed. We will thus face an increasingly large task in determining the extent to which any of these solutes are toxic. Indoxyl sulfate has been shown to be toxic in vitro, and levels of p-cresol sulfate have been correlated with poor outcomes in dialysis patients.6.Evenepoel P. Meijers B.K. Bammens B.R. et al.Uremic toxins originating from colonic microbial metabolism.Kidney Int Suppl. 2009; 76 (Suppl 114): S12-S19Abstract Full Text Full Text PDF Scopus (270) Google Scholar, 7.Schepers E. Glorieux G. Vanholder R. The gut: the forgotten organ in uremia?.Blood Purif. 2010; 29: 130-136Crossref PubMed Scopus (102) Google Scholar, 23.De Smet R. Van Kaer J. Van Vlem B. et al.Toxicity of free p-cresol: a prospective and cross-sectional analysis.Clin Chem. 2003; 49: 470-478Crossref PubMed Scopus (103) Google Scholar, 24.Bammens B. Evenepoel P. Keuleers H. et al.Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients.Kidney Int. 2006; 69: 1081-1087Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar Recent studies have concentrated on the possibility that these compounds cause vascular injury.11.Niwa T. Indoxyl sulfate is a nephro-vascular toxin.J Ren Nutr. 2010; 20: S2-S6Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 25.Faure V. Dou L. Sabatier F. et al.Elevation of circulating endothelial microparticles in patients with chronic renal failure.J Thromb Haemost. 2006; 4: 566-573Crossref PubMed Scopus (247) Google Scholar, 26.Meijers B.K. Van Kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar The structural relation of the uremic indoles and phenols to neurotransmitters previously encouraged speculation that they impair cognitive function, and it has recently been noted that they could do this by interfering with cleansing of the brain interstitium by the blood–brain barrier.27.Hosoya K.I. Tachikawa M. Roles of organic anion/cation transporters at the blood-brain and blood-cerebrospinal fluid barriers involving uremic toxins.Clin Exp Nephrol. 2011; 15: 478-485Crossref PubMed Scopus (52) Google Scholar A separate body of work suggests that indoxyl sulfate injures renal tubular cells and may thereby contribute to the progression of renal insufficiency.11.Niwa T. Indoxyl sulfate is a nephro-vascular toxin.J Ren Nutr. 2010; 20: S2-S6Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar While indoxyl sulfate and p-cresol sulfate are the only colon-derived solutes that have been studied extensively to date, recent metabolomic studies suggest that other solutes derived from gut bacteria are also risk factors for cardiovascular disease in humans and appear to have causative roles as judged by animal studies.28.Wang Z. Klipfell E. Bennett B.J. et al.Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature. 2011; 472: 57-63Crossref PubMed Scopus (2796) Google ScholarTable 1Colon-derived uremic solutesReferencesIndole compounds Indoxyl sulfate5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar, 20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar, 21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar, and Indoxyl glucuronide21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar and 45.Niwa T. Miyazaki T. Tsukushi S. et al.Accumulation of indoxyl-beta-D-glucuronide in uremic serum: suppression of its production by oral sorbent and efficient removal by hemodialysis.Nephron. 1996; 74: 72-78Crossref PubMed Scopus (45) Google Scholar 5-Hydroxyindole21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar Indole-3-propionic acid5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google ScholarPhenyl compounds p-Cresol sulfate5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar, 20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar, 21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar, and p-Cresol glucuronide46.Lesaffer G. De Smet R. Belpaire F.M. et al.Urinary excretion of the uraemic toxin p-cresol in the rat: contribution of glucuronidation to its metabolization.Nephrol Dial Transplant. 2003; 18: 1299-1306Crossref PubMed Scopus (30) Google Scholar Phenyl sulfate5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar and 20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar Phenyl glucuronide21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar α-N-phenylacetyl-L-glutamine5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar and 21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar Phenylpropionylglycine5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar Cinnamoylglycine5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar and 21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar 4-Ethylphenyl sulfate20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar Hippuric acid5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar and 20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google ScholarThis list, based heavily on references 5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar, 19.Wikoff W.R. Nagle M.A. Kouznetsova V.L. et al.Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1).J Proteome Res. 2011; 10: 2842-2851Crossref PubMed Scopus (113) Google Scholar, 20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar, and , is certainly incomplete. Indole-3-propionic acid and phenylpropionylglycine were identified by Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar as microbial products in rat plasma and other studies have demonstrated their excretion in the urine. The results of Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar suggest that hippuric acid is largely of microbial origin in rats, but those of Aronov et al.21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar suggest important nonmicrobial production of hippuric acid in humans. Open table in a new tab This list, based heavily on references 5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar, 19.Wikoff W.R. Nagle M.A. Kouznetsova V.L. et al.Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1).J Proteome Res. 2011; 10: 2842-2851Crossref PubMed Scopus (113) Google Scholar, 20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar, and , is certainly incomplete. Indole-3-propionic acid and phenylpropionylglycine were identified by Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar as microbial products in rat plasma and other studies have demonstrated their excretion in the urine. The results of Wikoff et al.5.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 USA. 2009; 106: 3698-3703Crossref PubMed Scopus (1477) Google Scholar suggest that hippuric acid is largely of microbial origin in rats, but those of Aronov et al.21.Aronov P. Luo F.Y. Plummer N.S. et al.Colonic contribution to uremic solutes.J Am Soc Nephrol. 2011; 22: 1769-1776Crossref PubMed Scopus (237) Google Scholar suggest important nonmicrobial production of hippuric acid in humans. Most efforts to lower uremic solute levels have focused on increasing solute removal and ignored the alternate strategy of suppressing solute production. Maneuvers to suppress production, however, could prove particularly effective for solutes that are made in an isolated body compartment by microbes. In addition, maneuvers that suppress the production of multiple colon-derived solutes could be tested without first establishing which of these solutes are most toxic. One potential means to limit the production of colon-derived solutes is to alter the food supplied to colon microbes. The known colon-derived solutes are derived from amino acids, as is illustrated for indoxyl sulfate and p-cresol sulfate in Figure 1. On an ‘industrialized’ diet, the colon microbes are supplied with ∼10g of amino acids in the form of incompletely digested proteins, sloughed intestinal cells, and secretions.4.Nordgaard I. Mortensen P.B. Digestive processes in the human colon.Nutrition. 1995; 11: 37-45PubMed Google Scholar,29.Chacko A. Cummings J.H. Nitrogen losses from the human small bowel: obligatory losses and the effect of physical form of food.Gut. 1988; 29: 809-815Crossref PubMed Scopus (118) Google Scholar There is evidence that intestinal protein absorption is impaired in renal failure, so that the portion of ingested protein delivered to the colon microbes is increased.30.Bammens B. Verbeke K. Vanrenterghem Y. et al.Evidence for impaired assimilation of protein in chronic renal failure.Kidney Int. 2003; 64: 2196-2203Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar One means to limit this supply is to restrict protein intake. Before dialysis became available, uremic symptoms were relieved by dietary protein restriction and reduced production of colon-derived solutes may have contributed to the effectiveness of this treatment. Protein restriction, however, is unpalatable and can cause negative nitrogen balance. Increasing dietary fiber intake could provide a simpler and safer means to reduce the production of colon-derived uremic solutes.31.Meijers B.K. De Preter V. Verbeke K. et al.p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin.Nephrol Dial Transplant. 2009; 25: 219-224Crossref PubMed Scopus (184) Google Scholar The term fiber includes both nonstarch polysaccharides and resistant starches that escape digestion in the small intestine.31.Meijers B.K. De Preter V. Verbeke K. et al.p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin.Nephrol Dial Transplant. 2009; 25: 219-224Crossref PubMed Scopus (184) Google Scholar,32.De Preter V. Hamer H.M. Windey K. et al.The impact of pre- and/or probiotics on human colonic metabolism: does it affect human health?.Mol Nutr Food Res. 2011; 55: 46-57Crossref PubMed Scopus (102) Google Scholar Industrialized diets contain less fiber than primitive diets, and dialysis patients consume even less fiber than their healthy neighbors.33Kalantar-Zadeh K. Kopple J.D. Deepak S. et al.Food intake characteristics of hemodialysis patients as obtained by food frequency questionnaire.J Ren Nutr. 2002; 12: 17-31Abstract Full Text Full Text PDF PubMed Google Scholar With low-fiber intake the supply of carbohydrates to the colon microbes is low.34.Elia M. Cummings J.H. Physiological aspects of energy metabolism and gastrointestinal effects of carbohydrates.Eur J Clin Nutr. 2007; 61: S40-S74Crossref PubMed Scopus (137) Google Scholar With limited substrate for fermentation, microbial growth is reduced and the volume of the stool, of which microbes make up a major portion, is reduced. The amount of amino acids needed for synthesis of microbial protein is thus reduced, so that an increased portion of the proteins and peptides delivered to the colon is converted into uremic solutes. A prolonged transit time through the colon, which results in part from lesser microbial growth, promotes conversion of amino acids to uremic wastes.35.Stephen A.M. Wiggins H.S. Cummings J.H. Effect of changing transit time on colonic microbial metabolism in man.Gut. 1987; 28: 601-609Crossref PubMed Scopus (137) Google Scholar Increasing dietary fiber intake is predicted to have the opposite effects and to limit the conversion of amino acids to uremic solutes while increasing microbial growth. Higher fiber intake could account for the observation that urinary excretion of indoxyl sulfate and p-cresol sulfate is lower in vegetarians than in people eating an unrestricted diet. In dialysis patients, supplementing the diet with 10–20g/day of non-digestible carbohydrates was recently shown to lower plasma levels of p-cresol sulfate, which should encourage further efforts in this direction.31.Meijers B.K. De Preter V. Verbeke K. et al.p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin.Nephrol Dial Transplant. 2009; 25: 219-224Crossref PubMed Scopus (184) Google Scholar An interesting, but as yet unexplained, finding is that production of the colon-derived solutes indoxyl sulfate and p-cresol sulfate appears to be lower in patients on peritoneal dialysis than in patients on hemodialysis.36.Pham N.M. Recht N.S. Hostetter T.H. et al.Removal of the protein-bound solutes indican and p-cresol sulfate by peritoneal dialysis.Clin J Am Soc Nephrol. 2008; 3: 85-90Crossref PubMed Scopus (69) Google Scholar Another potential means to reduce the daily load of colon-derived solutes is to administer sorbents that bind to microbial metabolites. The carbon-based sorbent AST-120 reduces plasma levels of indoxyl sulfate and can also reduce levels of p-cresol sulfate and other solutes.20.Kikuchi K. Itoh Y. Tateoka R. et al.Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci. 2010; 878: 2997-3002Crossref PubMed Scopus (93) Google Scholar Clinical interest in AST-120 is currently focused on testing whether it can slow the progression of renal insufficiency. However, sorbents could also be used to lower solute levels and improve health in dialysis patients. Other maneuvers that could reduce the production of colon-derived solutes include treatment with laxatives to reduce transit time and antibiotics or ‘probiotic’ bacterial strains to alter the microbial population.6.Evenepoel P. Meijers B.K. Bammens B.R. et al.Uremic toxins originating from colonic microbial metabolism.Kidney Int Suppl. 2009; 76 (Suppl 114): S12-S19Abstract Full Text Full Text PDF Scopus (270) Google Scholar,32.De Preter V. Hamer H.M. Windey K. et al.The impact of pre- and/or probiotics on human colonic metabolism: does it affect human health?.Mol Nutr Food Res. 2011; 55: 46-57Crossref PubMed Scopus (102) Google Scholar A particularly exciting possibility is that new knowledge of the colon microbiome will permit redirection of solute production by genetic manipulation of colon microbes.37.Goodman A.L. Kallstrom G. Faith J.J. et al.Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice.Proc Natl Acad Sci USA. 2011; 108: 6252-6257Crossref PubMed Scopus (430) Google Scholar An attractive feature of all these potential treatments is that they could lower solute levels without the burden of increasing dialysis duration and/or frequency. The liver and kidney together provide the body with an organic waste disposal system. Remarkably similar symptoms, including prominent encephalopathy, are caused by failure of either organ. Efforts to control uremic symptoms by reducing solute production largely ended with the development of dialysis. Hepatic encephalopathy, however, is still treated by maneuvers designed to suppress waste solute production. These maneuvers, moreover, are directed exclusively toward solutes made by colon microbes. Their initial target was ammonia, but other colon-derived solutes are thought also to contribute to hepatic encephalopathy, and the severity of symptoms is not well correlated with the plasma level of any known solute. The maneuvers that have been used to reduce solute production in liver failure include colectomy, restriction of dietary protein, and administration of non-digestible carbohydrates, laxatives, sorbents, antibiotics, and probiotics. These are the same maneuvers that could be used to reduce colon-derived solute production in renal failure, as described above. For many years, these maneuvers were used in the liver failure without proof of their efficacy. But controlled trials have recently established that the nonabsorbed disaccharide lactulose and the antibiotic rifaxamin maintain remission from hepatic encephalopathy.38.Riordan S.M. Williams R. Gut flora and hepatic encephalopathy in patients with cirrhosis.N Engl J Med. 2010; 362: 1140-1142Crossref PubMed Scopus (56) Google Scholar Trials of maneuvers to suppress colon-derived solute production in renal failure may have to be larger and/or longer, given that symptoms of solute retention in dialysis patients are less severe. However, the successful trials in the liver failure show that chronic suppression of colon-derived solute production is feasible and can be beneficial. The alternative to suppressing solute production is to improve solute removal by dialysis. How easily this can be accomplished depends on the nature of the solute and its distribution in the body.39.Meyer T.W. Sirich T.L. Hostetter T.H. Dialysis cannot be dosed.Semin Dial. 2011; 24: 471-479Crossref PubMed Scopus (34) Google Scholar Indoxyl sulfate and p-cresol sulfate, the two best known colon-derived solutes, both bind to plasma albumin. This binding is avid but reversible. More than 90% of the solute in the plasma is bound to albumin at any instant, but the bound portion is in rapid equilibrium with the free portion. Because only free solutes are available for diffusion through the dialysis membrane, the clearances for indoxyl sulfate and p-cresol sulfate are only a small fraction of the urea clearance during conventional dialysis. However, the clearance of the bound solutes can be greatly increased by increasing the dialysate flow and size of the dialyzer.40.Meyer T.W. Leeper E.C. Bartlett D.W. et al.Increasing dialysate flow and dialyzer mass transfer area coefficient to increase the clearance of protein-bound solutes.J Am Soc Nephrol. 2004; 15: 1927-1935Crossref PubMed Scopus (81) Google Scholar,41.Luo F.J. Patel K.P. Marquez I.O. et al.Effect of increasing dialyzer mass transfer area coefficient and dialysate flow on clearance of protein-bound solutes: a pilot crossover trial.Am J Kidney Dis. 2009; 53: 1042-1049Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The clearance of bound solutes can also be increased by combining high-volume ultrafiltration with hemodialysis and by use of sorbents.42.Meijers B.K. Bammens B. Verbeke K. et al.A review of albumin binding in CKD.Am J Kidney Dis. 2008; 51: 839-850Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar,43.Meert N. Waterloos M.A. Van Landschoot M. et al.Prospective evaluation of the change of predialysis protein-bound uremic solute concentration with postdilution online hemodiafiltration.Artif Organs. 2010; 34: 580-585Crossref PubMed Scopus (51) Google Scholar Application of these techniques could reduce the time-averaged concentrations of bound solutes without increasing either the duration or frequency of dialysis. The extent of protein binding has not been evaluated for the majority of colon-derived solutes, but some of those listed in Table 1, such as p-cresol glucuronide and α-N-phenylacetyl-glutamine, are known not to be protein bound. For these solutes, suppression of production could provide a simpler means to lower solute levels than increasing dialytic removal. Recent studies have documented wide variability in the plasma levels of uremic solute levels among individual patients with the same degree of renal insufficiency, suggesting that solute production is variable and should be susceptible to manipulation.44.Eloot S. Schepers E. Barreto D.V. et al.Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins.Clin J Am Soc Nephrol. 2011; 6: 1266-1273Crossref PubMed Scopus (61) Google Scholar Colon microbes produce a large number of organic compounds that are foreign to mammalian cell metabolism. Some of these compounds are absorbed in the colon and then normally excreted from the body by the kidneys. The possibility that accumulation of these compounds contributes to uremic toxicity is strong enough to warrant trials of the clinical effect of lowering their levels in the plasma.
Referência(s)