The intestinal microbiota, a leaky gut, and ... - Kidney International

mini review

http://www.kidney-international.org & 2013 International Society of Nephrology

The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease Hans-Joachim Anders1, Kirstin Andersen1 and Ba¨rbel Stecher2 1 2

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universita¨t Mu¨nchen, Munich, Germany and Max-von-Pettenkofer Institut, Universita¨t Mu¨nchen, Munich, Germany

Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with systemic inflammation and acquired immunodeficiency, which promote cardiovascular disease, body wasting, and infections as leading causes of death. This phenomenon persists despite dialysis-related triggers of immune deregulation having been largely eliminated. Here we propose a potential immunoregulatory role of the intestinal microbiota in CKD/ESRD. We discuss how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation. Persistent innate immune activation involves the induction of immunoregulatory mediators that suppress innate and adaptive immunity, similar to the concept of ‘endotoxin tolerance’ or ‘immune paralysis’ in advanced sepsis or chronic infections. Renal science has largely neglected the gut as a source of triggers for CKD/ESRD-related immune derangements and complications and lags behind on the evolving microbiota research. Interdisciplinary research activities at all levels are needed to unravel the pathogenic role of the intestinal microbiota in kidney disease and to evaluate if therapeutic interventions that manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRDrelated immune deregulation and to prevent the associated complications. Kidney International (2013) 83, 1010–1016; doi:10.1038/ki.2012.440; published online 16 January 2013 KEYWORDS: C-reactive protein; cytokines; flora; innate immunity; lipopolysaccharide; malnutrition

Correspondence: Hans-Joachim Anders, Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universita¨t Mu¨nchen, Ziemssenstr 1, Mu¨nchen, 80336, Germany. E-mail: [email protected] Received 13 July 2012; revised 27 August 2012; accepted 20 September 2012; published online 16 January 2013 1010

The term microbiota describes the 1013 bacterial cells from 200 to 500 different bacterial species that colonize the outer and inner surfaces of the human body. The intestinal microbiota coevolves with the host for a mutually beneficial coexistence. The bacteria estimate the stable, intestinal nutrient environment, in return providing the host with energy-rich metabolites and vitamins. Moreover, the microbiota induces and maintains immune homeostasis and protects against infection with pathogens.1 The human microbiome just started to be thoroughly characterized owing to the development and continuous improvement of deep sequencing technology as well as national and international funding initiatives (Human Microbiome Project and Metagenomics of the Human Intestinal Tract).2 In addition, studies using germfree and gnotobiotic animal models complement genomic approaches for a deeper understanding of the functions of human gut microbiota and provide a more mechanistic view on host–microbiome interactions. For example, germfree mice display severe immune abnormalities, which relate to an incomplete education of the immune system.3 From the time of the postnatal colonization of the gut, the intestinal microbiota obviously becomes an important element in priming the physiological structure of lymphoid tissues by driving the functional interactions of all elements of the adaptive immune system.1 This applies not only to the mucosaassociated lymphoid tissue of the Peyer’s patches but also to the extraintestinal lymphoid tissues. This implies some leakiness of the intestinal barrier that anatomically separates the intestinal microbiota’s biotope from the host.4 The physiology of enteric absorption of nutrients also seems to involve a certain passage of bacterial components beyond the intestinal barrier as an element of physiological shaping of the immune system and immune responses.5 Recent studies now document that this process also contributes to the manifestations of noncommunicable diseases like autoimmune diseases, chronic heart, or liver disease.6–9 In this review we discuss the potential roles of the intestinal microbiota in the context of kidney disease. The intestinal microbiota’s contribution in urea breakdown or uremic toxin production has been summarized elsewhere.10 Here, we discuss the potential role of the microbiota on systemic inflammation, protein wasting, accelerated Kidney International (2013) 83, 1010–1016

H-J Anders et al.: Microbiota in kidney disease

atherogenesis, and immunosuppression as major determinants of mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD). THE INTESTINAL MICROBIOTA, A ‘SYMBIOTIC ORGAN’

Along its entire length, the orogastric/gastrointestinal tube is colonized with bacteria. In healthy individuals, the phyla Bacteroidetes and Firmicutes contribute 490% of all species, including abundant bacterial genera such as Bacteroides spp., Alistipes spp., Prevotella spp., Porphyromonas spp., Clostridium spp., Dorea spp., Faecalibacterium spp., Eubacterium spp., Ruminococcus spp., and Lactobacillus spp. Other less abundant phyla represent the Actinobacteria (that is, Bifidobacterium spp. and Collinsella spp.), Proteobacteria (that is, Enterobacteriaceae, Sutterella spp., and Helicobacter spp.), Verrucomicrobia (that is, Akkermansia spp.), and methanogenic Archaea.2 Density and relative species composition varies considerably between the different regions of the gastrointestinal tract. The vast majority of bacterial species has a strict anaerobic metabolism; however, some species (that is, the Enterobacteriaceae) are facultative anaerobic. Thus, following the decreasing oxygen tension, bacterial density increases from the stomach (102–104/ml) toward the ileum (106–108/ml), reaching its maximum in the colon (41012 cells/ml). Bacterial colonization in the ileum is kept in check by antimicrobial peptides, expressed by paneth cells in small intestinal crypts. This lowers the density of microbial competitors to ensure resorption of readily available nutrient components by the enterocytes. Persistent dietary components like plant-derived polysaccharides or resistant starches reach the colon where they are degraded by the concerted action of the resident microbial food web. A large number of degraders (that is, Bacteroides) express secreted glycandegrading enzymes freeing mono- and oligosaccharides from complex dietary glycans, starches, or mucin, which are thereafter metabolized in primary fermentation reactions. Products of the primary fermentors include hydrogen and CO2 as well as short-chain fatty acids acetate, butyrate, propionate, and lactate as well as ethanol. Short-chain fatty acids serve as energy source of colonocytes but other bacteria use them as substrate for secondary fermentation reactions. The last link of the chain constitutes hydrogen-consuming sulfate-reducing bacteria as well as methanogens competing for the available hydrogen. Hydrogen is a thermodynamic inhibitor of the primary fermentations; thus, hydrogen consumption plays an important role for the colonic ecosystem. Thus, stability of this ecosystem is maintained by functional diversity, which is mostly driven by oxygen tension and nutrient availability. Despite the beneficial functions of its intestinal microbiota, the host has to keep bacteria outside the body to prevent infection. The 1012 bacterial cells/ml within the colonic lumen are merely separated by a single-layered, highly absorptive epithelium that still prevents bacterial translocation.4 This is guaranteed by the protective mucus Kidney International (2013) 83, 1010–1016

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layer, defensins, and antibacterial lectins shielding the epithelium from direct contact with the bacteria as well as the innate (that is, sensing of microbial patterns by innate immune cells in the lamina propria) and adaptive arms (that is, immunoglobulin A–secreting plasma B cells) of the mucosal immune system.5,11,12 It is still incompletely understood how the mucosal immune system remains largely ignorant toward the autochthonous flora while triggering a subacute response, which maintains the symbiotic equilibrium. However, a disrupted tolerance triggers an overshooting inflammatory response against the microbiota, which can lead to overt pathology and chronic intestinal inflammation, for example, in inflammatory bowel diseases. Experimental studies suggest a defective mucosal barrier (for example, introduced by muc2, Nod2, or interleukin-10 deficiency) or microbiota abnormalities, that is, dysbiosis, to cause inflammatory bowel diseases. In addition, gnotobiotic mouse models revealed that different members of the microbiota induce different types of immune responses. A mixture of anaerobic Clostridium spp. has been demonstrated to induce FoxP3 þ regulatory T cells. Another, yet uncultivated member of the Clostridia, the segmented filamentous bacteria, promotes T helper type 17 cell differentiation.13 Certain members of the normal microbiota harbor a particular pathogenic potential and can cause disease under certain conditions. For this reason, they are termed pathobionts.14 Examples for pathobionts are Helicobacter hepaticus, Bacteroides, and Prevotella spp., as well as g-Proteobacteria that drive experimental colitis. Dysbiosis can be promoted by the inflammation itself, making it difficult to discern cause and consequence of the disease.15,16 Furthermore, the host genotype and environmental factors such as antibiotics can induce dysbiosis.17,18 POTENTIAL IMPACT OF CKD/ESRD ON THE INTESTINAL MICROBIOTA AND BARRIER

Various extraintestinal noncommunicable diseases are associated with dysbiosis because they affect intestinal immunity in a way that it can no longer maintain the physiological control of the microbiota.5,7,11,14 Therefore, it is reasonable to assume that the metabolic and hemodynamic alterations of CKD/ESRD also alter the composition and function of the intestinal microbiota (Figure 1). Evolving data now confirm this concept. For example, Vaziri et al.19 characterized the intestinal microbiota of uremic versus nonuremic patients and rats and found uremia to be associated with an increase in intestinal pathobionts. How could CKD affect the gut flora? The potential factors are: metabolic acidosis, retention of uremic toxins, volume overload with intestinal wall congestion, and frequent use of antibiotics and oral iron that promotes pathogen overgrowth. Also, intestinal ischemia induces dysbiosis that may be supported by renin– angiotensin–aldosterone system blockade and/or vascular calcifications. The polymer phosphate binder sevelamer also binds intestinal bacterial products. Furthermore, diet changes 1011

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Healthy kidney

Translocation of bacteria and bacterial products activates systemic inflammation (and CKD/ESRD complications?)

Uremia CKD/ESRD

Uremia induces dysbiosis

Homeostatic signals B cell

Proinflammatory cytokines

DC Macrophage

Intestinal epithelial barrier Intestinal lumen

Defensins, mucus, IgA

Symbiosis: pathobionts are kept in check, barrier integrity maintained

Pathobionts

Dysbiosis: pathobiont overgrowth — promotes loss of barrier integrity

Symbionts

Figure 1 | Hypothetical concept about how a failing kidney and the intestinal microbiota affect each other. (Left part) Under physiological conditions, the predominance of symbiotic bacteria, an intact intestinal barrier, defensins production, mucus integrity, and immunoglobulin A (IgA) secretion support the symbiosis between the host and its gut microbiota. An intramural innate immunity controls pathobiont overgrowth inside the lumen of the intestinal tract. (Right part) The metabolic changes that are associated with the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) change the balance of symbionts and pathobionts in a way that favors pathobiont overgrowth, that is dysbiosis. Pathobiont overgrowth induces inflammation and loss of barrier function that in turn promotes increased translocation of bacterial components and even living bacteria into the host’s internal environment. This process will activate innate immunity characterized by production of proinflammatory cytokines that define a state of systemic inflammation. This process potentially modulates a number of clinically relevant processes in CKD such as the progression of CKD, accelerated atherogenesis, and protein wasting.

have a major impact on microbiota-related immunopathology. For example, a western diet, poor in complex plant polysaccharides, immediately alters the microbiome and T-cell priming in autoimmunity.20 ESRD diet recommendations include the avoidance of phosphate-rich cheese as an important source of symbionts. Soy protein–rich and high fiber–rich diets involve the microbiota to produce shortchain fatty acids with anti-inflammatory properties, which protects from diabetes or progressive atherosclerosis.21 This finding suggests that renal dysfunction modulates the environment inside the intestinal lumen that favors the overgrowth of potentially pathogenic bacterial species, that is, dysbiosis. Further studies are needed to dissect the causative factors for uremia-induced dysbiosis. DOES A LEAKY GUT DRIVE SYSTEMIC INFLAMMATION IN CKD/ESRD?

Renal dysfunction causes not only metabolic derangements but also systemic inflammation as indicated by elevated levels of C-reactive protein, pentraxin-3, and proinflammatory 1012

cytokines.22 Other markers of systemic inflammation are sTWEAK, sTRAIL, S100A12, mannose-binding lectin, activated complement.23 The lipopolysaccharide (LPS)-induced monocyte/macrophage activation and systemic inflammation is the central paradigm of Gram-negative sepsis and, as such, the same phenomenon could explain persistent systemic inflammation in CKD/ESRD.24 In fact, blood monocytes are more activated in ESRD patients and express larger amounts of proinflammatory cytokines.25 The current understanding of systemic inflammation in CKD/ESRD patients includes direct induction by uremic toxins, oxidative stress, cytokine excretion/degradation in the kidney, catheter-related infections, purity of the water/fluids used for dialysis, and the biocompatibility of dialysis membranes.26 Technical innovations like biocompatible dialysis filters, nontoxic tube sterilization as well as ultrapure or biocompatible dialysis fluids reduced potential exogenous triggers of immune activation.26 However, the phenomenon of inflammation persists and remains an unaddressed need and therapeutic target. Somehow, the Kidney International (2013) 83, 1010–1016

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intestinal microbiota, the largest source of potential immunostimulatory bacterial products in the human body, has largely been neglected as the remaining trigger for immune deregulation in CKD/ESRD.27,28 However, the intestinal microbiota is now increasingly recognized as an ‘outside-in’ modifier of the host’s immune system, namely the polarization of T-cell subsets and natural killer T cells.5,14,20,29–31 For example, volume overload in CKD/ESRD should have similar effect on the intestinal wall and its barrier function as volume overload in congestive heart failure. Edematous heart failure patients have high serum endotoxin and cytokine levels that decline upon diuretic therapy.32 Wang et al.33 recently demonstrated that experimental uremia in rats increases bacterial translocation from the gut into mesenteric lymph nodes, liver, and spleen in rats, which was associated with higher levels of serum interleukin-6 and C-reactive protein.33 In 2011, McIntyre et al.34 showed that circulating bacterial endotoxin/LPS levels increase along the stages of CKD and are highest in patients on hemodialysis or peritoneal dialysis, despite the use of the latest dialysis technology. LPS levels were highest in hemodialysis/peritoneal dialysis patients with levels comparable to those of patients with severe liver disease, gut irradiation, and decompensated heart failure. LPS levels were also a strong and independent predictor of mortality.34 LPS originates from the cell wall component of Gramnegative bacteria, and hence, microbiota enriched in g-proteobacteria should be a valid source of circulating LPS. It is also likely that other bacterial products occur at higher serum levels in CKD patients but these are more difficult to quantify. For example, peptidoglycan translocates from the intestinal microflora and can activate bone marrow neutrophils via NOD1 while peptidoglycan injection is sufficient to restore neutrophil function upon microbiota depletion.35 Additional, immunomodulatory effects of the intestinal microbiota include the induction of T helper type 17 cells that can drive immunopathology, for example, in the central nervous system.36 Thus, CKD-related dysbiosis and changes in the intestinal barrier may favor the increased translocation of living bacteria or bacterial products from the intestinal lumen into the circulation, a process that could account for the persistent systemic inflammation in CKD/ESRD.

Toll-like receptor 4 (TLR4) is a mediator of atherosclerosis that may imply that increased LPS/TLR4 signaling could be a driving factor in the accelerated atherogenesis of CKD/ESRD patients.38 The same mechanism could drive the progression of CKD because increased TLR-mediated activation of intrarenal immune cells has been demonstrated to accelerate CKD progression.39,40 This would imply that circulating bacterial products activate tissue macrophages and other immune cells, for example, inside the kidney or the vascular wall, to produce proinflammatory mediators and turn a silent or smoldering disease process into active tissue inflammation and additional immunopathology. In addition, colonic bacteria generate uremic toxins such as aphenylacetyl-l-glutamine, 5-hydroxyindole, indoxyl glucuronide, p-cresol sulfate, and indoxyl sulfate, which contribute to ESRD complications.41,42 As such, gut flora–directed interventions might beneficially affect the uremic state. Support for this concept comes from studies that have tested the effects of intestinal microbiota–related interventions on uremia and CKD/ESRD complications.43–45 For example, the oral intake of nonpathogenic Sprosarcina pasteurii improved renal function parameters and prolonged the lifespan of uremic rats.43 In addition, neutralizing the bacteria-derived uremic toxin indoxyl sulfate inside the gut also delayed the progression of CKD and of cardiovascular disease in uremic rats.44 Finally, a clinical pilot study with the same indoxyl sulfate–binding agent in predialysis CKD patients demonstrated an improved 5-year survival with this treatment.45 Together, the microbiota represents the largest endogenous source of immmunostimulatory elements that could account for persistent activation of the innate immune system and systemic inflammation in CKD/ESRD. Dysbiosis is likely to occur given the multiple metabolic derangements in uremia. The intestinal barrier function in uremia has not yet been carefully studied but the fact that circulating LPS levels increase with CKD stage suggests a link between intestinal barrier and renal dysfunction. At this point, it remains speculative but intriguing to imagine that uremic microbiota and an impaired intestinal barrier could account for inflammation and drive the accelerated atherogenesis, protein catabolism, and body wasting in CKD/ESRD.

DOES A LEAKY GUT CONTRIBUTE TO CKD PROGRESSION AND CKD COMPLICATIONS?

DOES A LEAKY GUT INDUCE SYSTEMIC IMMUNOSUPPRESSION IN CKD/ESRD?

Persistent systemic inflammation is an independent predictor of poor survival in CKD.22 It is thought that systemic inflammation drives certain CKD/ESRD complications that determine overall mortality, for example, the accelerated atherogenesis as well as protein catabolism and body wasting. Bacterial products activate pattern-recognition receptors on many different cell types including vascular endothelial cells, dendritic cells, and macrophages inside and outside the kidney.37 This could link the translocation of bacterial products from the gut of CKD/ESRD patients to a number of different disease contexts. For example, the LPS receptor

Despite systemic inflammation, uremia is also a state of acquired immunodeficiency, accounting for fatal infections in CKD/ESRD. Uremia suppresses not only innate host defense against pathogens but also crystal-induced inflammation, as gout attacks become less intense even though hyperuricemia and urate crystals should activate the NLRP3 inflammasome.46 Blood monocytes express less TLRs, costimulatory molecules, and reactive oxygen species release, and phagocytic activity is impaired in neutrophils and monocytes as compared with nonuremic controls23,47 (Table 1). Uremia also impairs antigen-specific adaptive

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Table 1 | Abnormal innate and adaptive immunity in CKD/ESRD Elements of persistent inflammation

Elements of acquired immunodeficiency

Innate immunity Higher white blood counts including many leukocytes with a distinct proinflammatory phenotype characterized byy yincreased production of proinflammatory cytokines (neutrophils and macrophages)52 yreactive oxygen species production inducing oxidative stress and endothelial dysfunction52 ydecreased functional capacity of immunoregulatory cell types (e.g., regulatory T cells)56 ygranule release (granulocytes)56 Activation of nonimmune cells, for example, adhesion molecule expression in endothelial cells52 Suppression of endogenous antioxidant and cytoprotective defense systems63 Increased complement activation23

Innate immunity Phenotype switch of many immune cells towards phenotypes characterized byy ybeing refractory to proinflammatory stimuli but producing anti-inflammatory mediators ydecreased phagocytic function (granulocytes and macrophages)53–55 yimpaired antigen-presentation (dendritic cells, macrophages, and B cells)54,57–60 ydepletion and dysfunction of plasmacytoid dendritic cells61,62 yoverexpression of scavenger and c-lectin receptors (antigen-presenting cells)23 yoverexpression of immunoregulatory factors like IRAK-M inhibiting TLR signaling

Adaptive immunity yimpaired ratio of CD4/CD8 T cells64,65 yless B cells, defective B-cell maturation, enhanced B-cell apoptosis, impaired antibody production, and isotype switch54 yincreased T-cell apoptosis64,66 yTh1/Th2 ratio shifted toward Th2 T cells66 ydepletion of naive and central memory CD4 þ and CD8 þ T cells66 Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease; IRAK-M, interleukin-1 receptor-associated kinase-M; TLR, Toll-like receptor; Th1/Th2, T helper type 1 and 2.

immunity as evident from insufficient priming of antigenspecific T/B-cell responses upon vaccination48 and a depletion of naive and memory T cell and B cells.47 Furthermore, the disease activity of chronic autoimmune diseases declines with progression of CKD, and disease flares are infrequent in ESRD. Immunodeficiency in CKD/ESRD is associated with an induction of anti-inflammatory cytokines such as interleukin-10,23 but the miracle of concomitant systemic inflammation and immunodeficiency in CKD/ ESRD has not yet been solved. However, concomitant inflammation and immunodeficiency is a well-known phenomenon, for example, upon persistent immune activation with bacterial products. The current understanding of sepsis or chronic infections such as tuberculosis or leishmaniosis also involves concomitant inflammation and immunodeficiency.24,49 In early sepsis, bacterial products activate TLRs and inflammasomes of immune (and nonimmune) cells to secrete proinflammatory mediators via nuclear factor-kB signaling.24 In bacterial sepsis, this phase accounts for cytokine storm, fever, inflammation, and shock. Persistent TLR activation, however, induces a subsequent refractory state, a phenomenon similar to that of ‘endotoxin tolerance’ or also named ‘compensatory antiinflammatory syndrome.’50 This process involves the upregulation of several intra- and extracellular anti-inflammatory mediators as depicted in Figure 2.49–51 Therefore, impaired host defense and secondary infections dominate mortality in more advanced sepsis.49,50 One may speculate that when an impaired intestinal barrier and an increased translocation of bacterial products would be sufficient to trigger systemic inflammation, then this persistent process would also induce 1014

subsequent counterregulatory mechanisms that suppress innate and adaptive immunity. At the single-cell level, newly generated immune cells would undergo a transient phase of activation followed by a subsequent refractory phase that explains the paradox concomitance of inflammation and immunodeficiency at the systemic level. Currently, there are no data to support this concept for the uremic state, but the new understanding of how endotoxin tolerance determines immunity in the different phases of sepsis is based on this concept.50 SUMMARY AND PERSPECTIVES

The intestinal microbiota evolves as an important element in the education and regulation of the immune system that also has previously unexpected roles for the manifestations of several noncommunicable diseases. It seems reasonable to speculate the same for CKD. It is likely that uremia will directly or indirectly affect the composition of the intestinal microbiota as well as the intestinal barrier. An increased translocation of bacterial products across the intestinal barrier will activate innate immunity, which could provide an explanation for the systemic inflammation that is associated with CKD and ESRD. It remains to be demonstrated whether persistent bacterial leakage from the gut triggering the phenomenon of ‘endotoxin tolerance’ may explain the concomitant acquired immunodeficiency of CKD/ESRD patients. Renal science lags far behind on the evolving microbiota research and should no longer neglect the gut as a potential trigger for the deregulated immune system in kidney disease. Interdisciplinary research activities at all levels are needed to unravel the pathogenetic role of the Kidney International (2013) 83, 1010–1016

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Transient endotoxin exposure TLR activation

NF-κB

Subsequent immune deactivation

NF-κB

Release of proinflammatory cytokines

Systemic inflammation

Induction of multiple negative regulators of TLR signaling Lymphocyte apoptosis upon activation

Phagocytosis of apoptotic cells by phagocytes

NF-κB p50/50 homodimers

Secretion of anti-inflammatory mediators (e.g., IL-10, TGF-β)

microRNA

Inhibition of TLR and IL-1 receptor pathway

Phenotype switch toward anti-inflammatory macrophages

Endotoxin tolerance = refractory innate immune state

Epigenetic regulation (histone deacetylation/methylation)

Persistent endotoxin exposure

Figure 2 | ‘Endotoxin tolerance’ or transient versus persistent activation of innate immunity. Transient activation of, for example, Toll-like receptors (TLRs) stimulates nuclear factor (NF)-kB-dependent secretion of proinflammatory cytokines that triggers systemic inflammation. Repeated or persistent TLR stimulation of monocytes and macrophages induces ‘tolerance’ or ‘compensatory anti-inflammatory syndrome’ that defines a refractory status of the innate immune system. It appears that in chronic kidney disease/end-stage renal disease (CKD/ESRD), both elements of innate immune activation and acquired immunosuppression coexist because some leukocytes are massively activated whereas others remain deactivated. This results in the clinical syndrome of persistent inflammation accompanied by an immunosuppressive state. IL, interleukin; TGF-b, transforming growth factor-b.

intestinal microbiota in kidney disease and to evaluate if therapeutic interventions to manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRD-related immune deregulation and to prevent ESRD complications.

12. 13. 14.

15.

DISCLOSURE

All the authors declared no competing interests. ACKNOWLEDGMENTS

16.

17.

H–JA is funded by the Deutsche Forschungsgemeinschaft GRK1202. 18.

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