Mol. Nutr. Food Res. 2013, 00, 1–9 1 DOI 10.1002/mnfr.201200714 REVIEW Uremia and chronic kidney disease: The role of the gut microflora and therapies with pro- and prebiotics Luis Vitetta 1 and Glenda Gobe 2 1 Centre for Integrative Clinical and Molecular Medicine, School of Medicine at Princess Alexandra Hospital, The University of Queensland, Brisbane, Australia 2 Centre for Kidney Disease Research, School of Medicine at Princess Alexandra Hospital, The University of Queensland, Brisbane, Australia Uremia is an illness that accompanies kidney failure and chronic kidney disease (CKD). Uremic illness is considered to be due largely to the accumulation of organic waste products that are normally cleared by the kidneys. However, uremic retention solutes are generated in part in the gastrointestinal tract (GIT), with the gut microbiota and the ensuing micro-biometabolome playing a significant role in the proliferation of uremic retention solutes. Toxins generated in, or introduced into the body via the intestine, such as advanced glycation end products, phenols, and indoles, all may contribute to the pathogenesis of CKD. Hence, it is biologically plausible, but not well recognized, that an important participant in the toxic load that contributes to CKD originates in the GIT. The microbiota that colonize the GIT perform a number of func- tions that include regulating the normal development and function of the mucosal barriers; assisting with maturation of immunological tissues, which in turn promotes immunologi- cal tolerance to antigens from foods, the environment, or potentially pathogenic organisms; controlling nutrient uptake and metabolism; and preventing propagation of pathogenic micro- organisms. Here, we develop a hypothesis that probiotics and prebiotics have a therapeutic role in maintaining a metabolically balanced GIT, and reducing progression of CKD and associated uremia. Keywords: Commensal bacteria / Chronic kidney disease / Prebiotics / Probiotics / Uremia Received: October 25, 2012 Revised: December 10, 2012 Accepted: December 18, 2012 1 Introduction In humans, following birth, bacteria colonize all body mu- cosal and extra-mucosal tissue sites that include the gastroin- testinal tract (GIT), mouth, hair, nose, ears, vagina, lungs, and skin, thereby giving rise to site-specific unique micro- biota families [1]. Thousands of bacterial species have been reported to co-inhabit the GIT, with the number residing within the body of the average healthy adult human estimated to outnumber human cells by a factor of approximately 10 to 1 [2]. The microbiota within the human distal GIT repre- Correspondence: Associate Professor Glenda Gobe, Centre for Kidney Disease Research, Building 33, School of Medicine, Princess Alexandra Hospital, The University of Queensland, Ipswich Road, Woolloongabba, Brisbane 4102, Australia E-mail: [email protected]Fax: +61-7-3176-2970 Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; ESKD, end-stage kidney disease; GFR, glomerular filtra- tion rate; GIT, gastrointestinal tract; Th, T-helper cell sent the largest body microbial community. Recent reports suggest that the bacterial load and the products of the intesti- nal microbiota might positively influence disease pathogen- esis [3, 4]. This is particularly relevant to the development of chronic kidney disease (CKD), a disease of increasing impor- tance and health system cost in many societies today. CKD is one of the most common chronic diseases in developed and developing countries, and is often the precursor to end-stage kidney disease (ESKD), the stage at which patients must rely on kidney replacement therapies to survive. As with most human diseases, animal models have ad- vanced our understanding of the role of GIT microflora in human disease, although the complexity of the human pre- cludes that there are animal models that can mimic all the features of a particular human disease in its entirety [5]. There is a lack of studies on the role of the GIT microflora in the de- velopment of kidney disease, in general. Eaton et al. [6] used a germfree mouse model of renal and enteric disease from en- terohemorrhagic Escherichia coli (EHEC) to determine if the probiotic Lactobacillus reuteri (ATCC PTA 6475) was effective in suppressing disease symptoms caused by EHEC, such as C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Uremia and chronic kidney disease: The role of the gut
microflora and therapies with pro- and prebiotics
Luis Vitetta1 and Glenda Gobe2
1 Centre for Integrative Clinical and Molecular Medicine, School of Medicine at Princess Alexandra Hospital, TheUniversity of Queensland, Brisbane, Australia
2 Centre for Kidney Disease Research, School of Medicine at Princess Alexandra Hospital, The University ofQueensland, Brisbane, Australia
Uremia is an illness that accompanies kidney failure and chronic kidney disease (CKD). Uremicillness is considered to be due largely to the accumulation of organic waste products that arenormally cleared by the kidneys. However, uremic retention solutes are generated in part inthe gastrointestinal tract (GIT), with the gut microbiota and the ensuing micro-biometabolomeplaying a significant role in the proliferation of uremic retention solutes. Toxins generated in,or introduced into the body via the intestine, such as advanced glycation end products, phenols,and indoles, all may contribute to the pathogenesis of CKD. Hence, it is biologically plausible,but not well recognized, that an important participant in the toxic load that contributes toCKD originates in the GIT. The microbiota that colonize the GIT perform a number of func-tions that include regulating the normal development and function of the mucosal barriers;assisting with maturation of immunological tissues, which in turn promotes immunologi-cal tolerance to antigens from foods, the environment, or potentially pathogenic organisms;controlling nutrient uptake and metabolism; and preventing propagation of pathogenic micro-organisms. Here, we develop a hypothesis that probiotics and prebiotics have a therapeutic rolein maintaining a metabolically balanced GIT, and reducing progression of CKD and associateduremia.
Received: October 25, 2012Revised: December 10, 2012
Accepted: December 18, 2012
1 Introduction
In humans, following birth, bacteria colonize all body mu-cosal and extra-mucosal tissue sites that include the gastroin-testinal tract (GIT), mouth, hair, nose, ears, vagina, lungs,and skin, thereby giving rise to site-specific unique micro-biota families [1]. Thousands of bacterial species have beenreported to co-inhabit the GIT, with the number residingwithin the body of the average healthy adult human estimatedto outnumber human cells by a factor of approximately 10 to1 [2]. The microbiota within the human distal GIT repre-
Correspondence: Associate Professor Glenda Gobe, Centre forKidney Disease Research, Building 33, School of Medicine,Princess Alexandra Hospital, The University of Queensland,Ipswich Road, Woolloongabba, Brisbane 4102, AustraliaE-mail: [email protected]: +61-7-3176-2970
sent the largest body microbial community. Recent reportssuggest that the bacterial load and the products of the intesti-nal microbiota might positively influence disease pathogen-esis [3, 4]. This is particularly relevant to the development ofchronic kidney disease (CKD), a disease of increasing impor-tance and health system cost in many societies today. CKD isone of the most common chronic diseases in developed anddeveloping countries, and is often the precursor to end-stagekidney disease (ESKD), the stage at which patients must relyon kidney replacement therapies to survive.
As with most human diseases, animal models have ad-vanced our understanding of the role of GIT microflora inhuman disease, although the complexity of the human pre-cludes that there are animal models that can mimic all thefeatures of a particular human disease in its entirety [5]. Thereis a lack of studies on the role of the GIT microflora in the de-velopment of kidney disease, in general. Eaton et al. [6] used agermfree mouse model of renal and enteric disease from en-terohemorrhagic Escherichia coli (EHEC) to determine if theprobiotic Lactobacillus reuteri (ATCC PTA 6475) was effectivein suppressing disease symptoms caused by EHEC, such as
2 L. Vitetta and G. Gobe Mol. Nutr. Food Res. 2013, 00, 1–9
hemolytic-uremic syndrome. Germfree mice that were mono-colonized with EHEC developed weight loss, cecal luminalfluid accumulation, and renal tubular necrosis, the latter of-ten a precondition leading to CKD. Their data indicated thatL. reuteri partially protected mice from disease manifesta-tions of EHEC. In other models of nonrenal human diseases,germfree animals have demonstrated that gut flora and gut-derived toxins play a critical role in the development of liverdisease and certain complications such as portal systemicencephalopathy [7]. In the following hypothesis review, wediscuss how toxic products generated by a dysbiotic GIT maycontribute to uremic syndrome and deterioration of biochem-ical and physiologic functions, with progression to CKD andkidney failure. The review considers the links between GITdysbiosis, uremic toxins, and the pathogenesis of CKD; thehygiene hypothesis, where faulty development of an immunesystem contributes to the development of chronic disease; thecorollary of an overactive immune system through chronicpersistent inflammation, and the development of CKD; andthe potential role of probiotics and prebiotics in minimizingdevelopment of CKD and the associated uremia.
2 Uremic toxins, the GIT and CKD
GIT-produced uremic toxins include advanced glycation endproducts that comprise glycation of proteins, peptides, andamino acids due to excess glucose [8]. Uremic toxins canalso include phenols (e.g., p-cresyl sulfate). GIT fermenta-tion of the amino acids phenylalanine and tyrosine generatesp-cresol and phenol [9,10]. Similarly to phenolic compounds,indoles (e.g., indoxyl sulfate) can be generated by the GITmicrobiota [10]. The biological impact of these molecules hasbeen reported to induce proinflammatory responses, leuko-cyte stimulation, and endothelial dysfunction [11–14]. Hencethe overproduction of proinflammatory molecules in the GITmay play a significant role in maintaining an unregulated in-flammatory state in the GIT [10]. If a dysbiotic and inflamedGIT ensues [15], then the systemic spread of these moleculesbecomes possible, augmenting the likelihood of uremic toxinoverload [16]. Hence a link between the GIT inflammation,dysbiosis, and circulating uremic toxins is established andthis is suggestive of a GIT dysbiosis–renal relationship, par-ticularly for the development of CKD.
The term CKD represents a continuum of chronic changein the kidney [17]. Histological features that might haveoriginally indicated the nature of the primary insult areoverwhelmed by nonspecific tissue changes of chronic pro-gression, including chronic inflammation, tubulointerstitialfibrosis, glomerulosclerosis, and vascular rarefaction. The Na-tional Kidney Foundation’s Kidney Disease Outcomes Qual-ity Initiative (K/DOQI) defines CKD as either kidney damageor a decreased glomerular filtration rate (GFR) of less than 60mL/min/1.73m2 for 3 or more months [18]. The kidney dam-age involves destruction of renal mass with loss of nephrons,apparently irreversible fibrosis, and progressive decline in
Table 1. Classification and description of the different stages ofchronic kidney disease
Stage eGFRa) Description
1 90 mL/min Normal renal function butabnormal urine findings,or structural abnormalities,ora genetic traitindicating kidney disease
2 60–89 mL/min Mildly reduced renalfunction and other findings(as for stage 1)indicate kidney disease
3a 45–59 mL/min Moderately reducedkidney function
3b 30–44 mL/min4 15–29 mL/min Severely reduced
kidney function5 <15 mL/min or Very severe or
on dialysis end-stage kidney failure(sometimes called establishedrenal failure)
a) Measured using the Modification of Diet in Renal Disease for-mula [16]. All estimated glomerular filtration rate (eGFR) valuesare normalized to an average surface area of 1.73 m2.
GFR. Estimated GFR is used to categorize CKD patients intofive progressive stages (Table 1) [19]. CKD may not be de-tectable with decreased GFR until it is moderate (stages 3aand b) or advanced (stages 4 and 5). CKD is closely alignedwith greatly increased rates of cardiovascular disease (CVD),with CKD patients more likely to die from myocardial infarctthan from kidney failure. There is, however, a real need nowto understand the mechanisms of early development and sus-tained progression of CKD, and to develop realistic therapiesthat will decrease its incidence and slow its progression.
There are many reports on cytokine changes in patientsdiagnosed with CKD and ESKD. For example, elevated anddivergent levels of cytokine activity, such as the proinflam-matory units interleukin (IL)-6 and tumor necrosis factor-�,are counterregulated by IL-10 [20]. This complex picture ofcytokine network counterregulation may be one of the keydeterminants in development of CKD. Mechanistically, animportant system that drives the expression of cytokines is theimmune system, predominantly the CD4 T-helper (Th) cells.These cells are classified into two distinct types, namely, thetype-1 (Th1) and type-2 (Th2) arms (Fig. 1) [21–24]. Th1 cellsare involved in innate cell-mediated immunity and produceseveral proinflammatory cytokines, notably tumor necrosisfactor-�, IL-12, and interferon-�. Although Th2 cells are in-volved in humoral immunity and produce cytokines such asIL-4 and IL-5, they also produce IL-6 and thus also have a rolein the systemic inflammatory response. Finally, there is theT-regulatory cell (CD4+/CD25+) that produces IL-10 and iscapable of downregulating both the Th1 and Th2 response.
Infections, specifically those that infect through endo-toxins, are potent inducers of cytokines such as IL-12 and
Figure 1. Diagrammatic schema of the epithelial cell barrier of the gastrointestinal tract (A) Tight junction and gap junction betweentwo epithelial cells. The zonulin occludin (ZO) translocates away from the cell boundary toward the nucleus reducing the transepithelialresistance allowing pathogens to move between the cells and through the cell wall into the lamina propria. Once the pathogen entersthe lamina propria it is able to move throughout the gastrointestinal system and systemic circulation causing severe inflammation. (B)Lipopolysaccharide (LPS)-mediated pathway of inflammation. (C) Recepteur d’origine nantais (RON)-mediated signaling of the inductionof cytokine production and inflammation. (D) Environmental or pathogenic antigens presenting on the epithelial surface may be detectedand consumed by dendritic cells. The antigen is presented to T-helper (TH) TH0 cells that enter the TH1 or TH2 pathway depending on theantigen. Probiotics help regulate and reduce inflammation by (1) preventing the translocation of ZO to the nucleus helping maintain theintestinal transepithelial electrical resistance and the integrity of gap junctions preventing the migration of pathogens past the epithelialbarrier and (2) by preventing the activation of nuclear factor-�B (NF-�B) caused by pathogens and compounds like LPS and RON. [Figureconstructed from the published data of references [21–24]].
INF-� that stimulate Th1-mediated immunity and also de-crease the production of Th2 inflammatory cytokines, suchas IL-4, IL-5, and IL-13 [25]. Furthermore, a decrease in anti-genic stimulation related to the reduction of childhood in-fections results in a decrease in the levels of regulatory cy-tokines, particularly IL-10. According to the hygiene hypoth-esis [26–28], early avoidance of microbial exposure could ex-plain, on one hand, the increase of Th2 dominant diseases,such as allergy [25], and on the other, a decrease in Th1-dominant diseases such as atherosclerosis [26]. In addition,it could be hypothesized that patients with a predominantTh1 phenotype will be more prone to complications of CKD,such as faster progression to ESKD, development of malnu-trition, and accelerated atherosclerosis and CVD risk [29,30].Recently, it was reported that CKD patients under hemodial-
ysis present with raised inflammatory markers and decreaseof total lymphocyte and CD4+ Th lymphocyte counts whencompared with controls [31]. Uremia itself, while generallysuppressing T-cell function [32], is also associated with al-tered Th balance. Most studies demonstrate Th1 predomi-nance [33, 34], although there are also some reports of Th2predominance [30]. Clearly, further studies are needed to de-termine if alterations in Th balance may predispose to alter-ations in cytokines that might be responsible for the increasedCVD risk in CKD and ESKD.
An enhanced understanding of the Th1/Th2 responseand balance may be useful in disease activity monitoring,even though the concept of Th balance remains contentious.Recent evidence suggests that classic immunomodulatorydrugs, such as cyclosporine and cortisone, do significantly
4 L. Vitetta and G. Gobe Mol. Nutr. Food Res. 2013, 00, 1–9
affect the Th response balance, as is also reported withless potent immunomodulatory drugs such as angiotensin-converting enzyme inhibitors [35], peroxisome proliferator-activated receptor activators [36], and statins [37]. Hence, allof these pharmaceuticals may affect T-cell activation signalsin CKD. Moreover, there may be a significant overlap be-tween Th1 and Th2 activity, with the Th balance shifting asmany disease processes progress, such as is seen in hepatitisC virus-related vasculitis [38].
3 The hygiene hypothesis and CKD
Given that part of the uremic retention of solutes is generatedin the intestines, recently it has been suggested that, as such,the GIT remains a forgotten organ in uremia [39]. The mid-20th century saw a significant increase in the prevalence ofautoimmune diseases [25–28]. This was the stimulus that ledto the formulation of the hygiene hypothesis. Over the pasttwo to three decades the hygiene theory has been tested, fine-tuned, and extensively modified [40]. This now provides abiologically plausible explanation for the trend that connectsdiminished exposure in early childhood to those commensalbacteria that boost immune tissue and metabolic maturation,especially in the GIT.
A gradual change in the frequency of childhood infec-tions has occurred in industrialized countries that have beenaffected by better living and sanitation conditions and theintroduction of antibiotics [41, 42]. In contrast, in developingcountries, exposure to crowded living conditions and poorsanitation, less access to antibiotics and inefficient vacci-nation programs have lead to a higher prevalence of infec-tions occurring in the early phase of life [43]. The deficitin early childhood infections subsequently enhances the risk,for later life GIT inflammatory problems that can disrupt nor-mal/regulated GIT inflammatory responses and increases thesusceptibility to developing autoimmune diseases [15,25,28].The hypothesis proposed that there was reduced exposureto infections in early childhood owing to a combination ofdiminishing family size and better personal hygiene, whichmight then go on to increase the risk of developing allergicdiseases [15, 25, 28]. The interface of the microbial environ-ment with the innate immune system could be significantlymodulated so that its ability to impart instructions to adap-tive or regulatory immune or inflammatory responses wouldbe adversely affected, particularly when such interactions oc-curred in utero and or were presaged in early life. Bach [25]documented this trend, highlighting that an epidemic of bothgastrointestinal autoimmune diseases where the immune re-sponse was dominated by Th1 cells (such as type 1 diabetesmellitus, Crohn’s disease, and multiple sclerosis) or aller-gic diseases where the immune response was dominated byTh2 cells (such as asthma, allergic rhinitis, and atopic der-matitis) were becoming increasingly prevalent in Westerncommunities.
Evolution has naturally bestowed the human species withimmune and inflammatory regulatory mechanisms activatedby interactions with both the external and internal microbialenvironments. These then serve to fine-tune both Th1 andTh2 antigen-driven effector responses [42]. The innate im-mune system senses the environment and accordingly mod-ulates the T regulatory arm, the ultimate keeper of the balancebetween antigen tolerance and responsiveness. The efficiencyof the regulatory interface in its current state would, paradox-ically, be jeopardized by a decrease in the microbial burdenwith which the immune system has coevolved [43].
Studies exploring the molecular mechanisms that mightunderpin the hygiene hypothesis have focused mostly on theinteractions between bacterial products and Toll-like recep-tors, the main transducers of microbial signals to the innateimmune system and critical regulators of CD4 T-cell acti-vation and regulation [43, 44]. Therapeutically, a recent re-view has highlighted how, in those individuals with chronichelminth infections, there is often an association with a re-duced prevalence of inflammatory disorders, including aller-gic diseases [45]. Mechanistically, it was reported that by in-ducing or expanding regulatory B cells with helminthes, thismay open novel avenues for the treatment of inflammatorydiseases, such as allergic asthma.
4 Chronic inflammation and CKD
The hygiene hypothesis is not always supported, as is thecase with reports regarding infection, and development ofchronic diseases like CKD, in some Indigenous communi-ties. These communities are often predisposed to increasedmicrobial contact and chronic infections at an early age, yetthey have a high incidence of CKD in adult life [46]. Reasonsare thought to include living in places where sanitation ispoor, lack of fresh food accessibility and usage, high alcoholand tobacco usage, and concurrent presence of other diseasesthat increase the incidence of CKD, such as diabetes and hy-pertension. It is thought that low level, persistent, inflamma-tion contributes to their higher rates of CKD development,and this hypothesis has been supported by investigations inanimal models [47, 48].
In the examples discussed previously, the immune dys-function that is proposed by the hygiene hypothesis may beoverwhelmed by extra sources of microbial stimulation inthe environment. An additional consideration, however, isthat as well as adverse lifestyle practices, protection againstchronic inflammation as a cause of CKD may depend onthe development of a healthy GIT biota through breast feed-ing. This practice is reduced in many Indigenous communi-ties [49]. In Australia, e.g., these factors have strong correla-tions to the increased incidence of adult-onset renal failure inIndigenous communities [50]. There is substantial evidencefor the nutritional and health benefits of breastfeeding [50],including protection against allergic diseases, gastrointesti-nal infection, and respiratory and ear infections [49, 51–53].
Participants’ nutritional status, assessed as serumalbumin, body weight, caloric intake, mid-armmuscle area, and appetite improved modestly, butnot significantly
Probiotic treatment changed small bowelpathobiology by modifying metabolic actions ofsmall bowel bacterial overgrowth, reducing in vivogeneration of toxins and carcinogens andpromoting nutrition with no adverse side effects.
Prospective pilot RDBPcrossover trial [45]
CKD stages 3 and 4Canada (n = 13)
6 months ↓BUN [probiotic (−2.93 mmol/L versus placebo (4.52mmol/L) p = 0.002
S. thermophilus KB27L. acidophilus KB31B. longum KB35Dose: KIBOW biotics 90
billion CFUs/day
↓Moderate mean uric acid concentration duringprobiotic period (24.70 mmol/L) versus placeboperiod (50.62 mmol/L) p = 0.050
Changes in serum creatinine concentration wereinsignificant
No gastrointestinal nor infectious complications werenoted in any subject with improved QOL.
Prospective pilot RDBPcrossover trial conductedin four countries [46]
S. thermophilusL. acidophilusB. longumDose: KIBOW biotics 90
6 months ↓BUN levels in 29 patients (63%, p < 0.05)↓Creatinine levels in 20 patients (43%, p > 0.05)↓Uric acid levels in 15 patients (33%, p > 0.05)Almost all subjects expressed a perceived substantial
overall improvement in QOL (86%, p < 0.05)Supplement was well tolerated and safe during the
entire trial period at all sites.
Single center,nonrandomized,open-label phase I/IIstudy [47]
4 weeks ↓p-Cresyl sulfate serum concentrations at 4 weeks by20% (intention to treat, p = 0.01; per protocol, p =0.03)
p-Cresyl sulfate generation rates were reduced (p =0.007)
In contrast, neither indoxyl sulfate generation rates (p= 0.9) nor serum concentrations (p = 0.4) weresignificantly changed.
Open-label single armstudy [48]
L. casei ShirotaB. breve Yakult
galacto-oligosaccharidesas prebiotics
Dose: 1 × 108 CFU/mLprobiotics and 1.67 g ofprebiotic three times aday for 2 weeks.
Hemodialysis (HD)patients (n = 8)
Japan
4 weeks (2 weeks ofpretreatmentobservation and 2weeks oftreatment)
During pretreatment observation period, HD patientswith a high serum p-cresol level tended to havehard stools with difficulty in defecation
With SYN treatment, stool quantity increasedsignificantly and hard, muddy, or soft stools tendedto be replaced by normal ones
The serum p-cresol level also decreased significantly.
BUN, blood-urea-nitrogen; CFU, colony-forming units; HD, hemodialysis; QOL, quality of life.
Human milk provides the neonate with advantages [51–53]that include the efficient protection against infections andthe active stimulation of the development of the infant’simmune system. The major host defense system is pro-vided via secretory IgA antibodies produced in the mam-
mary glands by lymphocytes, through migration from themother’s gut mucosa. As a consequence, breast feeding thatis commenced directly after delivery is reported to providean excellent defense against microbes normally meeting theneonate and needed to induce development of its immune
6 L. Vitetta and G. Gobe Mol. Nutr. Food Res. 2013, 00, 1–9
system [49, 50]. Breast milk also contains numerous compo-nents that enhance the infant’s host defense as well as thecapacity to develop tolerance, helping to avoid allergic reac-tivity to foods and long-term adverse health sequelae [54].Furthermore, it has been reported that the development ofwidespread obesity and the metabolic syndrome that includesraised body mass index, blood pressure, blood glucose, andtriglyceride levels; and insulin resistance, and disordered uricacid metabolism, most closely parallels the renal disease epi-demic [55]. These combined factors from birth and over timemay have a strong association with GIT dysbiosis supportinguremia.
5 Probiotics, prebiotics, and their roles inminimizing CKD
Probiotics have been defined as living organisms in food anddietary supplements that, upon ingestion, can improve thehealth of the host beyond their inherent basic nutritional con-tent [56]. In comparison, prebiotics are nondigestible food in-gredients that stimulate the growth and/or activity of bacteriain the GIT [15]. A synbiotic preparation is one that combinesprobiotics with prebiotics.
The preceding discussion supports the physiologically rea-sonable postulate that the GIT may be the primary contributorto the syndrome of uremia. It is increasingly recognized thatbacterial metabolism and its ensuing metabolites, such asphenols, indoles, and amines, may significantly contribute touremic toxicity [57]. Moreover, it has been also documentedthat the GIT microbiota may be the key factor that main-tains the GIT in a chronic inflammatory state, as evidencedin patients with CKD [58].
Animal studies have shown that uremic toxins may pro-mote progression of chronic renal failure by damaging tubu-lar cells [59]. This study suggested the potential benefit ofearly intervention to remove various uremic toxins, therebydelaying the onset of ESKD in patients with progressive CKD.An additional, blinded, placebo-controlled preclinical study,using the 5/6th nephrectomized Sprague Dawley rats as achronic renal failure model [60] demonstrated that after 16weeks of treatment with mixed probiotic regimens, there wasprolongation of the lifespan of uremic rats. Moreover thestudy documented a reduction in blood urea nitrogen levels,concluding that supplementation of probiotics to uremic ratsslowed the progression of azotemia, which then was corre-lated to the prolonged lifespan of the uremic rats [60]. A ther-apy that consists of a multistrain probiotic may, therefore,have a potential biological therapy to reduce uremic toxinconcentrations and produce subsequent clinical benefits.
There is a deficit of relevant clinical trials in the scien-tific literature. Table 2 lists some of these trials. An early,small, open-labeled trial showed efficacy in hemodialysispatients [61]. This clinical study employed a single strain,namely Lactobacillus acidophilus, and it reported significantreductions in uremic toxins (in the blood) and carcinogens
(in the bowel) versus no treatment. Probiotic treatment wasalso associated with a change in small bowel pathobiologyby modifying metabolic actions of small bowel bacterial over-growth. This was also associated with reduced in vivo gen-eration of toxins and carcinogens and promoted nutritionwith no adverse side effects. Recently, two pilot studies of6-month duration have demonstrated that a multistrain pro-biotic (from a proprietary source) was partly efficacious andsafe in stage 3 and 4 CKD (Table 2) [62, 63].
Small participant studies with synbiotics have also shownefficacy [64, 65]. In a small trial with hemodialysis patientsfrom Belgium, it was reported that the prebiotic oligofructose-inulin significantly reduced p-cresyl sulfate generation ratesand serum concentrations in hemodialysis patients [64]. Afurther small study from Japan that investigated a synbiotictreatment on serum levels of p-cresol in hemodialysis pa-tients reported that treatment with the synbiotic preparationmay be anticipated to reduce the toxic effect of p-cresol inhemodialysis patients [65]. The study reported that that ure-mic toxin, p-cresol, was associated with constipation and thatthe synbiotic treatment resulted in normalization of bowelhabits and a decrease of serum p-cresol levels in that seriesof hemodialysis patients.
6 Conclusions
CKD is a long-term condition with a gradual loss of kidneyfunction over time. The failure to properly colonize the GITand trigger the effective maturation of GIT mucosal sitesduring the neonatal period may seed an adverse milieu forlater life kidney disease. Schepers and colleagues [39] haverecently proposed that the gut is the forgotten organ in kid-ney disease and uremia. They argue that, apart from the roleof the GIT as a route by which uremic toxins or their precur-sors enter the body, the small and large bowel may also actas active participants through the maintenance of a dysbioticstate. A dysbiotic state has been characterized by a disruptionof homeostatic balance. Diseases such as Crohn’s disease,chronic periodontitis, and bacterial vaginosis are regarded tooriginate from disruptions of the local homeostatic balance.The overproduction of toxins that are generated in the GIT,such as advanced glycation end products, indoles, and phe-nols, may have a close link to antagonistic GIT microbiomeprofiles. This effect could then be linked to adverse changesin the composition of the GIT bacterial milieu that leads tothe continuous production of uremic toxins, thereby exacer-bating the uremic load on the kidneys.
The human-microbial GIT interface may be seen as anecosystem that participates in a variety of important roles inhuman health and disease. An early review has reported thata number of factors associated with modern Western livinghave a detrimental impact on the microflora of the GIT [66].Factors such as overprescription of antibiotics and analgesicmedications, psychological and physical stress, and certaindietary components have been found to contribute to GIT
dysbiosis [67,68]. Inappropriate lifestyle nutritional practicesseeded in childhood and promoted during adulthood, maycontribute to the continued disruption of the homeostaticbalance of the GIT toward a dysbiotic uremic burden thatincreases the risk of kidney failure. Certainly, the increasedincidence of kidney disease in Australian Indigenous com-munities would tend to support this premise [50, 69]. Main-taining this ecosystem in a balanced state may be an impor-tant requisite for the downregulation of uremic toxin loadproduction in the small and large bowel. If adverse metabolicdisruption persists, upregulation of uremic toxins may thenlead to CKD and other metabolic syndrome sequelae thateventually promote kidney failure. In this hypothesis review,we suggest that the administration of a multistrain probioticformulation, with or without prebiotics, for bowel-based toxicsolute extraction is a biologically plausible pharmacobiotictherapy for CKD. Restructuring the GIT microbial commu-nity by rescuing from a proinflammatory or dysbiotic statemay prove beneficial in reducing the uremic load producedin the gut and its escape to the systemic circulation.
Potential conflict of interest statement: Luis Vitetta has re-ceived National Institute of Complementary Medicine and Na-tional Health and Medical Research Council of Australia com-petitive funding and Industry support for research into probiotics.Glenda Gobe has declared no conflict of interest.
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