Produção Nacional
Revisado por pares
Probiotics and chronic kidney disease
2015; Elsevier BV; Volume: 88; Issue: 5 Linguagem: Inglês
10.1038/ki.2015.255
ISSN1523-1755
AutoresLaetitia Koppe, Denise Mafra, Denis Fouque,
Tópico(s)Gastrointestinal motility and disorders
ResumoProbiotics are the focus of a thorough investigation as a natural biotreatment due to their various health-promoting effects and inherent ability to fight specific diseases including chronic kidney disease (CKD). Indeed, intestinal microbiota has recently emerged as an important player in the progression and complications of CKD. Because many of the multifactorial physiological functions of probiotics are highly strain specific, preselection of appropriate probiotic strains based on their expression of functional biomarkers is critical. The interest in developing new research initiatives on probiotics in CKD have increased over the last decade with the goal of fully exploring their therapeutic potentials. The efficacy of probiotics to decrease uremic toxin production and to improve renal function has been investigated in in vitro models and in various animal and human CKD studies. However to date, the quality of intervention trials investigating this novel CKD therapy is still lacking. This review outlines potential mechanisms of action and efficacy of probiotics as a new CKD management tool, with a particular emphasis on uremic toxin production and inflammation. Probiotics are the focus of a thorough investigation as a natural biotreatment due to their various health-promoting effects and inherent ability to fight specific diseases including chronic kidney disease (CKD). Indeed, intestinal microbiota has recently emerged as an important player in the progression and complications of CKD. Because many of the multifactorial physiological functions of probiotics are highly strain specific, preselection of appropriate probiotic strains based on their expression of functional biomarkers is critical. The interest in developing new research initiatives on probiotics in CKD have increased over the last decade with the goal of fully exploring their therapeutic potentials. The efficacy of probiotics to decrease uremic toxin production and to improve renal function has been investigated in in vitro models and in various animal and human CKD studies. However to date, the quality of intervention trials investigating this novel CKD therapy is still lacking. This review outlines potential mechanisms of action and efficacy of probiotics as a new CKD management tool, with a particular emphasis on uremic toxin production and inflammation. Chronic kidney disease (CKD) is emerging as a major risk factor of cardiovascular disease (CVD). Uremic illness is considered to be due to the accumulation of organic waste products, so-called uremic retention solutes (URSs) that are normally cleared by the kidneys. URS such as phenols and indoles are generated along the gastrointestinal tract (GIT), where the gut microbiota has a significant role in their production1.Evenepoel P. Meijers B.K. Bammens B.R. et al.Uremic toxins originating from colonic microbial metabolism.Kidney Int Suppl. 2009; 114: S12-S19Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar and have been shown to have deleterious effects on the cardiovascular system. A number of treatments targeting URS have been proposed, such as reducing substrates (dietary protein restriction), decreasing absorption (oral adsorbents such as AST-120), increasing clearance by renal replacement therapies (long and/or more efficient dialysis, absorbent membranes, kidney transplantation), and modulating cellular pathways (organic anion transporters and antioxidants).2.Ramezani A. Raj D.S. The gut microbiome, kidney disease, and targeted interventions.J Am Soc Nephrol. 2014; 25: 657-670Crossref PubMed Scopus (445) Google Scholar Unfortunately, most of these treatments display inherent disadvantages (side effects, high cost, unavailability in patients with moderate CKD) and remain limited to experimental studies. The gut microbiota is essential for regulating the normal function of the intestinal barrier: it promotes immunological tolerance to antigens from nutrients or organisms, controls nutrient uptake and metabolism, and prevents propagation of pathogenic organisms.3.Power S.E. O'Toole P.W. Stanton C. et al.Intestinal microbiota, diet and health.Br J Nutr. 2014; 111: 387-402Crossref PubMed Scopus (305) Google Scholar Hence, the concept has emerged that dysregulation of intestinal microbiota may have a significant role in cancer and metabolic and inflammatory digestive disease. Recently, it has been demonstrated that CKD is associated with dysbiotic gut microbiotia.4.Vaziri N.D. Wong J. Pahl M. et al.Chronic kidney disease alters intestinal microbial flora.Kidney Int. 2012; 83: 308-315Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar During CKD, the potential utilization of therapies modulating the gut microbiota such as probiotics has emerged as an attractive strategy to reduce URS and improve CVD. Probiotics, a word derived from Greek meaning ‘for life’, is defined by the World Health Organization5.Food and Agriculture Organsization Guidelines for the Evaluation of Probiotics in Food. Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. Food and Agriculture Organization, London2002Google Scholar as ‘live microorganisms that, when administered in adequate amounts, confer a health benefit on the host’. Probiotics are being increasingly used for various pathologic conditions.6.Ebel B. Lemetais G. Beney L. et al.Impact of probiotics on risk factors for cardiovascular diseases. A review.Crit Rev Food Sci Nutr. 2014; 54: 175-189Crossref PubMed Scopus (68) Google Scholar However, not all probiotics strains are beneficial in all circumstances and the careful selection of specific organisms based on desired clinical outcome is crucial. Over the past 15 years, considerable experimental and clinical data reinforced the hypothesis that probiotics have a therapeutic role in maintaining a metabolically balanced GIT, reducing the progression of CKD and the generation of URS. For the purpose of this review, we will define the mechanisms of the action of probiotics and we will focus on recent developments in probiotics in the field of CKD from both in vitro and in vivo studies. Recent data highlight that uremia is associated with abnormalities in the gastrointestinal mucosa7.Vaziri N.D. Yuan J. Rahimi A. et al.Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation.Nephrol Dial Transplant. 2012; 27: 2686-2693Crossref PubMed Scopus (212) Google Scholar and a disequilibrium in the intestinal ecosystem.4.Vaziri N.D. Wong J. Pahl M. et al.Chronic kidney disease alters intestinal microbial flora.Kidney Int. 2012; 83: 308-315Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar Specifically, these studies demonstrate the presence of aerobic bacteria, such as Firmicutes, Actinobacteria, and Proteobacteria, and fewer anaerobic bacteria, such as Sutterellaceae, Bacteroidaceae, and Lactobacillaceae.4.Vaziri N.D. Wong J. Pahl M. et al.Chronic kidney disease alters intestinal microbial flora.Kidney Int. 2012; 83: 308-315Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar The intestinal dysbiosis may be due to iatrogenic causes or uremia per se as shown in Figure 1. If the consequences of intestinal microbiota dysregulation in the progression and complications of CKD are currently largely unknown, recent studies give new insights. First, besides the passive accumulation of URS due to a reduction in kidney clearance, the modification of the intestinal microbiota in CKD strongly increases transformation of amino acids into URS, e.g., indoxyl-sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine n-oxide (TMAO)1.Evenepoel P. Meijers B.K. Bammens B.R. et al.Uremic toxins originating from colonic microbial metabolism.Kidney Int Suppl. 2009; 114: S12-S19Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar among others. Increased intestinal concentration of uremic toxins may lead to microbial dysbiosis and pathobionts overgrowth. For example, a modification of the GIT biochemical milieu in the presence of locally accumulated uric acid and urea could perturb symbionts overgrowth.8.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. 2015; https://doi.org/10.1093/ndt/gfv095Crossref PubMed Scopus (233) Google Scholar Second, the dysbiosis could participate in immune dysregulation and inflammation in CKD.9.Anders H.-J. Andersen K. Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease.Kidney Int. 2013; 83: 1010-1016Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar Pathobionts trigger the intestinal immune system toward a proinflammatory response by preferentially activating Th17-Th7 cells and increasing the production of lipopolysaccharides (LPSs), a major component of the outer membrane of Gram-negative bacteria. Third, dysbiosis also contributes to an increase in intestinal permeability by disrupting the colonic epithelial tight junction,7.Vaziri N.D. Yuan J. Rahimi A. et al.Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation.Nephrol Dial Transplant. 2012; 27: 2686-2693Crossref PubMed Scopus (212) Google Scholar which may subsequently lead to translocation of LPS and bacteria into the host’s internal environment. Finally, metagenomic analyses of the microbiota performed in obese populations revealed an increase in Firmicutes and reduced Bacteroidetes similar to what has been described in CKD patients.4.Vaziri N.D. Wong J. Pahl M. et al.Chronic kidney disease alters intestinal microbial flora.Kidney Int. 2012; 83: 308-315Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar It is therefore possible that the modification of intestinal microbiota in CKD might be involved in insulin resistance and dyslipidemia through increased LPS production, modified carbohydrate fermentation or bile acid level and composition.10.Koppe L. Pelletier C.C. Alix P.M. et al.Insulin resistance in chronic kidney disease: new lessons from experimental models.Nephrol Dial Transplant. 2014; 29: 1666-1674Crossref PubMed Scopus (52) Google Scholar, 11.Khan M.T. Nieuwdorp M. Backhed F. Microbial modulation of insulin sensitivity.Cell Metab. 2014; 20: 753-760Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Given that gut-derived uremic toxins, inflammation and insulin resistance contribute to progression of CKD as well as CVD, dysbiosis could have an important role in mortality in CKD.1.Evenepoel P. Meijers B.K. Bammens B.R. et al.Uremic toxins originating from colonic microbial metabolism.Kidney Int Suppl. 2009; 114: S12-S19Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar, 11.Khan M.T. Nieuwdorp M. Backhed F. Microbial modulation of insulin sensitivity.Cell Metab. 2014; 20: 753-760Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 12.Mafra D. Lobo J.C. Barros A.F. et al.Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease.Future Microbiol. 2014; 9: 399-410Crossref PubMed Scopus (107) Google Scholar The term probiotic is often misused, which has led to the marketing of products that exploit this term. In 2014, the International Scientific Association for Probiotics and Prebiotics established a consensus statement clarifying the scope of and the appropriate use for the term ‘probiotic’.13.Hill C. Guarner F. Reid G. et al.Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic.Nat Rev Gastroenterol Hepatol. 2014; 11: 506-514Crossref PubMed Scopus (4195) Google Scholar The consensus definition is that probiotics are natural or genetically modified microorganisms expressing specific exogenous enzymes that are able to survive stomach acid and bile, to increase the colon concentration of symbiotons, and confer a health benefit.5.Food and Agriculture Organsization Guidelines for the Evaluation of Probiotics in Food. Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. Food and Agriculture Organization, London2002Google Scholar Figure 2 summarizes the overall beneficial effects of probiotics and those potentially effective in CKD. Although multiple mechanisms are often represented in a single strain, no individual probiotic would be expected to have all the effects listed in Figure 2. Other effects at the intestinal or the extraintestinal level, including immune and metabolic effects, are more likely to be strain specific.3.Power S.E. O'Toole P.W. Stanton C. et al.Intestinal microbiota, diet and health.Br J Nutr. 2014; 111: 387-402Crossref PubMed Scopus (305) Google Scholar Even though the mechanisms regulating epithelial responses to probiotics are complex and poorly understood, the presumed first target of probiotic action is the intestinal epithelial cell through enhancement of epithelial integrity. Some strains may block pathogen entry into the epithelial cell by providing a physical barrier, referred to as colonization resistance, and competition for a limited niche, thereby excluding a site for replication by pathogens. For example, Lactobacillus helveticus possesses hydrophobic cell surface properties and therefore is able to nonspecifically bind to intestinal cells.14.Johnson-Henry K.C. Hagen K.E. Gordonpour M. et al.Surface-layer protein extracts from Lactobacillus helveticus inhibit enterohaemorrhagic Escherichia coli O157:H7 adhesion to epithelial cells.Cell Microbiol. 2007; 9: 356-367Crossref PubMed Scopus (198) Google Scholar In addition, most probiotics create a mucus barrier by increasing mucin synthesis and secretion from goblet cells.15.Mack D.R. Ahrne S. Hyde L. Wei S. et al.Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro.Gut. 2003; 52: 827-833Crossref PubMed Scopus (472) Google Scholar Probiotics may enhance cell survival and decrease apoptosis during various intestinal assaults.16.Yan F. Cao H. Cover T.L. et al.Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth.Gastroenterology. 2007; 132: 562-575Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar In fact, soluble factors secreted by Lactobacillus rhamnosus were found to activate protein kinase B in a phosphatidylinositol-3′-kinase-dependent manner and prevent cytokine-induced apoptosis in human and mouse intestinal cells.16.Yan F. Cao H. Cover T.L. et al.Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth.Gastroenterology. 2007; 132: 562-575Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar Lactobacillus rhamnosus is able to produce soluble proteins (p40 and p75), which protect the intestinal barrier from hydrogen peroxide–induced insult.17.Seth A. Yan F. Polk D.B. Rao R.K. Probiotics ameliorate the hydrogen peroxide–induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G1060-G1069Crossref PubMed Scopus (303) Google Scholar Other probiotics maintain intestinal integrity by increasing the intercellular apical epithelial tight junction via the upregulation of zonula occludens-1 expression or by preventing epithelial tight junction protein redistribution.18.Mennigen R. Nolte K. Rijcken E. et al.Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1140-G1149Crossref PubMed Scopus (372) Google Scholar The protective effects of probiotics on intestinal function have been confirmed in in vivo studies using Citrobacter rodentium infection in a mouse model of bacterial-induced infectious colitis.19.Fanning S. Hall L.J. Cronin M. et al.Bifidobacterial surface-exopolysaccharide facilitates commensal-host interaction through immune modulation and pathogen protection.Proc Natl Acad Sci USA. 2012; 109: 2108-2113Crossref PubMed Scopus (383) Google Scholar This observation should be considered in clinical studies in CKD patients who frequently present with a chronic inflammation of the GIT and where probiotics could enhance the mucosal barrier function. Several studies have confirmed that probiotics might reduce digestive infection.3.Power S.E. O'Toole P.W. Stanton C. et al.Intestinal microbiota, diet and health.Br J Nutr. 2014; 111: 387-402Crossref PubMed Scopus (305) Google Scholar This is of particular interest as CKD patients are at higher risk of Clostridium difficile infection.20.Keddis M.T. Khanna S. Noheria A. et al.Clostridium difficile infection in patients with chronic kidney disease.Mayo Clin Proc. 2012; 87: 1046-1053Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Indeed, some probiotic strains have been shown to produce elaborated antibacterial compounds referred to as bacteriocins or antimicrobial peptide. Antimicrobial peptides may act as colonizing peptides, facilitating the competition of a probiotic with the resident microbiota, as killing peptides eliminating pathogens, or serve as signaling peptides for other bacteria or the immune system. Along the same line, lactic acid-producing Lactobacilli exert antimicrobial effects by reducing the local pH in the gut lumen.21.Fayol-Messaoudi D. Berger C.N. Coconnier-Polter M.-H. et al.pH-, Lactic acid-, and non-lactic acid-dependent activities of probiotic Lactobacilli against Salmonella enterica Serovar Typhimurium.Appl Environ Microbiol. 2005; 71: 6008-6013Crossref PubMed Scopus (208) Google Scholar Lactobacillis salivarus produces an in vivo bacteriocin that has been shown to significantly protect mice against infection with the invasive foodborne pathogen Listeria monocytogenes.22.Corr S.C. Li Y. Riedel C.U. et al.Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118.Proc Natl Acad Sci USA. 2007; 104: 7617-7621Crossref PubMed Scopus (615) Google Scholar Finally, Lactobacillus fermentum stimulates human β-defensin mRNA expression and protein secretion in the intestine.23.Schlee M. Harder J. Koten B. et al.Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2.Clin Exp Immunol. 2008; 151: 528-535Crossref PubMed Scopus (281) Google Scholar Other probiotics could influence gene expression of microbial pathogens and thereby reduce their hostility. For instance, Lactobacillus acidophilus may interfere with the virulence gene expression of enterohemorrhagic Escherichia coli O157:H7.24.Medellin-Pena M.J. Wang H. Johnson R. et al.Probiotics affect virulence-related gene expression in Escherichia coli O157:H7.Appl Environ Microbiol. 2007; 73: 4259-4267Crossref PubMed Scopus (175) Google Scholar Probiotics could prevent the binding of enteric pathogens to mucosal surfaces by obscuring the receptor-binding sites, thus preventing pathogens from invading the host and allowing for an increased clearance of the pathogen from the GIT.25.Linden S.K. Sutton P. Karlsson N.G. et al.Mucins in the mucosal barrier to infection.Mucosal Immunol. 2008; 1: 183-197Crossref PubMed Scopus (779) Google Scholar By decreasing the presence of pathobionts, probiotics have proven that it is possible to enhance both innate and adaptive arms of the host immune system.26.Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut.Nat Rev Immunol. 2008; 8: 411-420Crossref PubMed Scopus (811) Google Scholar For instance, some probiotic strains have the ability to promote the differentiation of B cells and increase the production of secretory IgA. Polymeric IgA sticks to the mucus layer overlying the gut epithelium and binds to pathogenic microorganisms, thereby reducing their ability to gain access to the endothelial cells. Other probiotic strains stimulate the innate immune system by signaling to dendritic cells, which then travel to mesenteric lymph nodes where they induce regulatory T cells (FoxP3+) and the production of anti-inflammatory cytokines (interleukin-10 and transforming growth factor-β). For example, Saccharomyces boulardii was shown to reduce intestinal inflammation through modulation of the T-cell response and reduced trafficking of Th1 cells, which resulted in a reduction of the proinflammatory cytokine interferon-γ.27.Dalmasso G. Cottrez F. Imbert V. et al.Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes.Gastroenterology. 2006; 131: 1812-1825Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar The relative serum cytokine profiles have been reported to predict the ability of the probiotic strains to have an impact on disease outcome.28.O’Mahony L. McCarthy J. Kelly P. et al.Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.Gastroenterology. 2005; 128: 541-551Abstract Full Text Full Text PDF PubMed Scopus (1168) Google Scholar Probiotics can also modulate the activation of the proinflammatory nuclear factor-κB to slow down the deleterious LPS flow and decrease interleukin-8 secretion, which is a potent neutrophil chemoattractant to sites of intestinal injury.26.Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut.Nat Rev Immunol. 2008; 8: 411-420Crossref PubMed Scopus (811) Google Scholar However, there are also reports that some strains of probiotics are able to activate nuclear factor-κB and increase levels of the proinflammatory cytokine directly or through the increase of ammonia and ammonium hydroxide (NH3/NH4OH) production. These discrepancies serve to further emphasize the strain-specific effects of probiotics on the host26.Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut.Nat Rev Immunol. 2008; 8: 411-420Crossref PubMed Scopus (811) Google Scholar (Figure 3). Numerous reports have demonstrated that manipulating the gut microbiota with probiotics, particularly Lactobacillus strains, have beneficial effects such as improving glucose homeostasis and reducing inflammation and hepatic steatosis.29.Delzenne N.M. Neyrinck A.M. Backhed F. et al.Targeting gut microbiota in obesity: effects of prebiotics and probiotics.Nat Rev Endocrinol. 2011; 7: 639-646Crossref PubMed Scopus (580) Google Scholar Probiotics may modify the bile acid profile in the gut. Sayin et al. clearly demonstrated that colonization by a transformed bacterium that increases bile salt hydrolase activity influences host metabolic processes by decreasing the abundance of tauro-beta-muricholic acid, a potent antagonist of farnesoid X receptor, resulting in a fibroblast growth factor 15/19–mediated regulation of hepatic cholesterol synthesis and improved metabolic perturbations.30.Sayin S.I. Wahlstrom A. Felin J. et al.Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.Cell Metab. 2013; 17: 225-235Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar Because numerous well-known probiotics exhibit bile salt hydrolase activity, this may partially account for their metabolic effects.31.Begley M. Hill C. Gahan C.G.M. Bile salt hydrolase activity in probiotics.Appl Environ Microbiol. 2006; 72: 1729-1738Crossref PubMed Scopus (798) Google Scholar Some probiotics are able to increase bacteria that express the β-fructofuranosidase and increase the beneficial short-chain fatty acid production through carbohydrate fermentation. Recent studies showed that Akkermansia muciniphila increases short-chain fatty acids and improves glucose/insulin homeostasis and lipid metabolism by binding to the specific G–protein–coupled receptors 41/43, enhancing glucagon-like peptide-1, and peptide YY production by enteroendocrine cells or anti-inflammatory action on immune cell production.32.Everard A. Belzer C. Geurts L. et al.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.Proc Natl Acad Sci USA. 2013; 110: 9066-9071Crossref PubMed Scopus (2729) Google Scholar Finally, the reduction of pathobionts by probiotics decreases LPS production, which may in turn improve inflammation and glucose homeostasis.29.Delzenne N.M. Neyrinck A.M. Backhed F. et al.Targeting gut microbiota in obesity: effects of prebiotics and probiotics.Nat Rev Endocrinol. 2011; 7: 639-646Crossref PubMed Scopus (580) Google Scholar Of note, probiotics could also help for synthesizing key vitamins such as vitamin K and B vitamins.2.Ramezani A. Raj D.S. The gut microbiome, kidney disease, and targeted interventions.J Am Soc Nephrol. 2014; 25: 657-670Crossref PubMed Scopus (445) Google Scholar To date high-quality interventional trials investigating probiotic treatment in CKD are lacking. Surrogate end points have been studied, such as changes in serum concentration or urinary excretion of biomarkers, e.g., URS or cytokines. However, studies investigating the impact of probiotics on clinical end points (e.g., CVD or mortality) have not been conducted so far. Moreover, the quality, size, and design of trials are not sufficient enough to justify the wide use of probiotics. Strict control of dietary intake as well as appropriate selection and dose of probiotic strains should be performed in order to compare trials. Experimental and clinical studies using probiotic formulations in CKD are summarized in Table 1.Table 1Animal and human studies reporting the use of probiotics in chronic kidney diseaseFirst author and yearProbioticsStudyResultsStudies in CKD patientsViramontes-Hörner D et al.42.Viramontes-Hörner D. Márquez-Sandoval F. Martín-del-Campo F. et al.Effect of a Symbiotic Gel (Lactobacillus acidophilus+Bifidobacterium lactis+Inulin) on presence and severity of gastrointestinal symptoms in hemodialysis patients.J Ren Nutr. 2015; 25: 284-291Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarSynbiotic: Lactobacillus acidophilus and Bifidobacterium lactis+prebiotic (inulin)Multicenter, double-blinded, placebo-con-trolled, randomized, clinical n =42; HDDietary advice (30–35 kcal/kg/day and protein 1.1–1.2 g/kg/day)Vitamins and omega-3 fatty acids supple-mentation2 monthsSafeImprove gastrointestinal symptomsTrend to decrease plasma C-reactive protein levelsWang et al.40.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: 423-430Crossref PubMed Scopus (123) Google ScholarBifobacterium bifidum A218, Bifidobacterium catenulatum A302, Bifidobacterium longum A101, and Lactobacillus plantarum A87Single-center, double-blind, placebo-controlled, randomizedn=39, peritoneal dialysis patients6 months↓ Serum TNF-α, IL-5, IL-6, and LPSPreservation of residual renal functionRossi et al.37.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: 106Crossref PubMed Scopus (38) Google ScholarSynbiotic: Lactobacillus, Bifidobacteria and Streptococcus genera+prebiotic (inulin, fructo-oligosaccarides, and galacto-oligosaccarides)Single-center, double-blind, placebo-con-trolled, randomized cross-over trialn=37; CKD stage 4–56 weeks, with a 4-week washout before cross-over. Dietary advice (protein 0.8 g/kg BW/d) Single-center, double-blind, placebo-controlled n =18, HDIn process, primary outcomes: level of ISSecondary outcomes: levels of PCS; LPS,TMAO, inflammation, and oxidative stressmarkers; renal function; quality of lifeCruz-Mora J et al.52.Cruz-Mora J. Martínez-Hernández N.E. Martín del Campo-López F. et al.Effects of a symbiotic on gut microbiota in mexican patients with endstage renal disease.J Ren Nutr. 2014; 24: 330-335Abstract Full Text Full Text PDF PubMed Scopus (7) Google ScholarSynbiotic: Lactobacillus acidophilus and Bifidobacterium lactis+prebiotic (inulin)Increases Bifidobacterial counts in fecal sam-plesReduction of Lactobacilli counts in fecal samplesImprove gastrointestinal symptomsSlowing of progression of kidney diseasePavan et al. 47.Pavan M. Influence of prebiotic and probiotic supplementation on the progression of chronic kidney disease.Minerva Urol Nefrol. 2014; PubMed Google ScholarSynbiotic: prebiotic+probioticProspective observation placebo-controlled, randomized trial n=24; CKD stage 3–4 12 month Dietary advice (protein 0.8 g/kg BW/d)Guida et al.55.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: 1043-1049Abstract Full Text Full Text PDF PubMed Scopus (107) Google ScholarSynbiotic: Lactobacillus plantarum, Lactobacillus casei subsp. rhamnosus, Lactobacillus gas-seri, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus salivarius Lactobacillus sporogenes, and Strep-tococcus thermophilus +, prebiotic (inulin and tapioca-resistant starch)Single-center, double-blind, placebo-con-trolled, randomized cross-over trial. n =30; CKD stage 3–44 weeks↓Plasma p-cresolNatarajan et al.41.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: 568571PubMed Goog
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