Next Article in Journal
Roles of PI3K/AKT/GSK3 Pathway Involved in Psychiatric Illnesses
Next Article in Special Issue
The Therapeutic Implications of the Gut Microbiome and Probiotics in Patients with NAFLD
Previous Article in Journal
Timely Interventions for Children with ADHD through Web-Based Monitoring Algorithms
Previous Article in Special Issue
Gut Microbiota, Fusobacteria, and Colorectal Cancer
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Impact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease

Division of Nephrology, Department of Medicine, University of California-Irvine, Irvine, CA 92697, USA
Department of Internal Medicine, Riverside Community Hospital, University of California-Riverside School of Medicine, Riverside, CA 92501, USA
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA
Authors to whom correspondence should be addressed.
Diseases 2019, 7(1), 21;
Submission received: 21 December 2018 / Revised: 29 January 2019 / Accepted: 8 February 2019 / Published: 13 February 2019
(This article belongs to the Special Issue Gut Microbiome and Human Diseases)


Chronic kidney disease (CKD) is a worldwide major health problem. Traditional risk factors for CKD are hypertension, obesity, and diabetes mellitus. Recent studies have identified gut dysbiosis as a novel risk factor for the progression CKD and its complications. Dysbiosis can worsen systemic inflammation, which plays an important role in the progression of CKD and its complications such as cardiovascular diseases. In this review, we discuss the beneficial effects of the normal gut microbiota, and then elaborate on how alterations in the biochemical environment of the gastrointestinal tract in CKD can affect gut microbiota. External factors such as dietary restrictions, medications, and dialysis further promote dysbiosis. We discuss the impact of an altered gut microbiota on neuroendocrine pathways such as the hypothalamus–pituitary–adrenal axis, the production of neurotransmitters and neuroactive compounds, tryptophan metabolism, and the cholinergic anti-inflammatory pathway. Finally, therapeutic strategies including diet modification, intestinal alpha-glucosidase inhibitors, prebiotics, probiotics and synbiotics are reviewed.

1. Introduction

Chronic kidney disease (CKD) is a major health problem with a high economic burden to healthcare systems all over the world [1,2,3], with a higher global prevalence (11–13%) than diabetes mellitus (8.2%) [3]. It is defined by the presence of a marker of kidney damage such as proteinuria or a reduced estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) for at least three months [4]. A remarkable increase in the incidence of CKD has occurred in recent years because of the rising prevalence of hypertension, obesity, and type 2 diabetes mellitus [2]. Other CKD risk factors include smoking [5], nephron loss due to aging and renal senescence [6,7], congenital anomalies of the anatomy and function of the kidney [8], preterm birth and low birthweight [6], and acute kidney injury [6]. The annual mortality rate attributable to CKD is estimated to be approximately one million cases worldwide [1]. Higher rates of CKD prevalence have been reported from developed areas including Europe, USA, Canada, and Australia in comparison with developing countries such as Saharan Africa and India [9].
Conditions that are caused or accelerated by CKD include cardiovascular diseases (CVD, the leading cause of death in CKD), skin abnormalities [10], anemia [11,12,13], cachexia [12,13], sleep disorders [14], psychosocial distress [2], bone disorders fracture [15], hyperphosphatemia and hyperparathyroidism [16,17], hyperkalemia [17], fluid and acid-base disorders [18], and microbial infections [19]. Specific hormonal, inflammatory, nutritional, and metabolic factors may play critical roles in the pathogenesis and progression of CKD. These factors include pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, reduced albumin level, increased C-reactive protein level, reduced growth hormone-insulin like growth factor-1 axis activity, hyperactivation of the renin-angiotensin aldosterone system, and the promotion of insulin resistance [20].

2. Gut Microbiota and Symbiotic Benefits

There are 1013–1014 microbes including 2000–4000 species, both aerobic and anaerobic, residing in the human gastrointestinal (GI) tract, which is collectively referred to as the gut microbiota [21,22]. The gut microbiota is a dynamic and symbiotic ecosystem that is in constant interaction with the host immune system and metabolism [23]. The commensal or symbiotic gut microbiota contains members of three major domains including bacteria (the most abundant), archaea, and eucarya, and density is highest in the colon [21,24,25]. In total, the number of microbial genes is at least 150-fold more than the human genome [26,27]. These microbes have an extensive impact on their host, mainly relating to metabolic pathways for energy harvesting and the production of short-chain fatty acids (SCFAs) and vitamins [26]; it has been suggested that intestinal microbiota should be considered as an additional organ of the body [22]. Seven to nine phyla of bacteria reside in the mammalian GI tract [26,28]. The major bacterial phyla (including genus-level examples) that are present in the gut of healthy humans are Actinobacteria (Bifidobacterium, Atopobium) [29], Bacteroidetes (Bacteroides, Prevotella), Proteobacteria (Proteobacteria, Burkholderia, Desulfovibrio) and Firmicutes (Clostridium, Eubacterium, Roseburia, Ruminococcus) [21,22,26,30], with Bacteroidetes and Firmicutes being the dominant phyla [31]. Over 50% of healthy individuals share the same 75 bacterial species, and over 90% of colonic bacteria belong to the Bacteroidetes and Firmicutes phyla [27].
The diversity of the human gut microbiota varies depending on gender, ethnicity, immune status, nationality, age, diet, geographic location, alcohol and drug consumption, and smoking [32,33,34]. In healthy subjects, the gut microbiota provides several benefits to the host [23]. The gut microbiota protects against pathogens by the inhibition of their colonization via the production of antibiotics and bacteriocins [24,35], facilitates the absorption of complex carbohydrates and produces various nutrients and micronutrients (SCFAs, amino acids such as lysine and threonine, vitamins such as vitamin K6, group B vitamins [23], biotin, and riboflavin [36]) and plays an effective role in element recycling [37]. Furthermore, intestinal microbiota is involved in the development, maturation, and maintenance of GI motility and in shaping the mucosal immune system and intestinal barrier [24,28].
Enterocytes and colonocytes derive 60–70% of their energy from SCFA oxidation [38,39]. SCFAs produced by the gut microbiota can be found in hepatic, portal, and peripheral blood, and influence lipid, glucose, and cholesterol metabolism in various tissues [39]. SCFAs bind and activate specific receptors, such as G-protein coupled receptors FFAR2 (free fatty acid receptor 2, also called GPR43) and FFAR3 (free fatty acid receptor 3, also called GPR41). These receptors are expressed in immune cells, endocrine cells, the GI tract, adipose tissue and the autonomic nervous system, and regulate the host’s energy homeostasis [40]. SCFAs are also involved in immune system activation through neutrophil chemotaxis and the proliferation of regulatory T lymphocytes (Tregs) [41]. Moreover, SCFAs regulate blood pressure through the olfactory receptor 78 (Olfr78) [42] and Gpr41 [43]. Tregs are essential in the maintenance of immunologic self-tolerance [44,45]. The two known types of Tregs are thymus-derived (tTregs) and peripherally-derived (pTregs), which are mainly colon-derived. SCFAs (with butyrate being the most potent) induce the expansion and differentiation of pTregs in the colon and lymphoid tissue [46]. SCFAs additionally have regulatory effects on neutrophils, antigen presenting cells, effector T cells, and natural killer cells [47,48].
A summary of gut microbiota metabolism resulting in the production of SCFAs is shown in Figure 1.

3. Mechanisms of Gut Dysbiosis in CKD

Changes in the composition and function of the microbiota, which is referred to as dysbiosis, has been reported in numerous illnesses including obesity [49], diabetes mellitus [45,50], asthma [45], non-alcoholic fatty liver disease [51], heart failure [45], Parkinson’s disease [52], inflammatory bowel disease [53], CVD [54], cancers [55,56] and CKD [38]. An increased Firmicutes/Bacteroidetes ratio has been noted in disease states such as obesity [57], hypertension [58], autism [59] and irritable bowel syndrome [60].
The kidney–gut axis refers to the association between CKD and significant changes in the composition of gut microbiota, the GI environment, and gut epithelial barrier permeability [23,61,62,63,64,65]. Uremic patients show the expansion of specific genera and species of aerobic and anaerobic intestinal bacteria compared to healthy persons [66]. Vaziri et al. showed a significant difference in the abundance of 175 bacterial operational taxonomic units (OTUs) between CKD and control animals, with a significant decrease in Lactobacillaceae and Prevotellaceae. They also reported significant differences in the frequency of 190 bacterial OTUs between end stage renal disease (ESRD) patients and healthy individuals [23]. It has been shown in CKD and hemodialysis patient cohorts that the number of Enterobacteriaceae (especially Enterobacter, Klebsiella, and Escherichia), Enterococci, and Clostridium perfringens were notably higher as compared to healthy controls, but with lower numbers of Bifidobacterium, Lactobacillaceae, Bacteroidaceae and Prevotellaceae [67,68,69,70]. Jiang et al. reported that subpopulations of Roseburia and Faecalibacterium prausnitzii (butyrate-producing species) were significantly reduced in the stool of 65 Chinese patients with CKD in comparison with 20 healthy controls [71]. They proposed that the depletion of butyrate-producing bacteria may play a role in inflammation and CKD progression [71].
Pathways that lead to gut dysbiosis in CKD include: (i) dramatic changes in the biochemical environment of the GI tract induced by an influx of urea, uric acid, oxalate, and other retained waste products from the blood, (ii) diet restrictions, and (iii) medications such as phosphate binders and antibiotics.

3.1. Alterations in the GI Tract Biochemical Environment

The influx of urea (the most abundant retained waste product in CKD) and other metabolic toxins into the GI lumen applies a selective pressure favoring the overgrowth of bacteria that produce urease, uricase, indole, and p-cresol forming enzymes [45]. Bacterial urease of the gut microbiota hydrolyzes urea and produce ammonium hydroxide, which raises luminal pH and alters the composition of the microbiota [13,35]. Ammonium hydroxide itself is caustic, and leads to the degradation of tight junction barrier proteins [72,73]. Uric acid is the end product of dietary and endogenous purine metabolism in the liver, which is an efficient pathway for the elimination of nitrogen. Oxalic acid is a potentially toxic compound that is not further metabolized in humans, and circulates in its ionized form as oxalate. Under normal conditions, uric acid and oxalate are excreted in the urine; however, the colon plays a major role in the excretion of these compounds in advanced CKD [23,74,75].

3.2. Diet

CKD patients are often advised to restrict their intake of fruits, vegetables, and high-fiber products in order to avoid potassium overload. This results in a shortage of indigestible carbohydrates, which are essential nutrients for the gut saccharolytic microbiota, the reduced production of microbial-derived SCFAs, and ultimately decreased nutrients for colonocytes and Treg cells. On the other hand, because of a shortage in carbohydrate resources, the increased metabolism of proteins and other nitrogen-containing substances in the GI tract leads to the production and accumulation of toxic end products. The imbalance between saccharolytic (fermentative) and proteolytic (putrefactive) microbiota is associated with detrimental effects in CKD patients [23,61,76]. CKD patients are also often advised to limit cheese and yogurt consumption because of their high phosphorus content, leading to a deficit of probiotic-rich food sources, which in turn causes more biochemical changes in the GI lumen [45].

3.3. Medications

Phosphate binders prescribed to ESRD patients (calcium compounds, sevelamer, lanthanum and iron-based products) bind to phosphorus in the GI tract, and are usually taken with every meal to manage hyperphosphatemia by reducing phosphorus absorption. Alterations in the luminal environment of the GI tract after the long-term consumption of these drugs has been reported [23]. The net benefit/harm balance of iron-containing compounds is controversial; oral iron supplementation to manage chronic anemia in CKD may adversely increase the production of uremic toxins [77]. However, Lau et al. recently reported that ferric citrate (an iron-based phosphate binder) was associated with significant changes in the gut microbiome of CKD rats, including the expansion of a potentially favorable species, Akkermansia muciniphila, which has important roles in mucin degradation and gut barrier integrity [78]. CKD patients are often exposed to antibiotics (for example, to treat vascular access infections), which disrupt the gut microbiota via the loss of key taxa and diversity, shifts in metabolic capacity, and expansion of pathogens [23,79].

4. Disruption of the Intestinal Epithelial Barrier

Disruption of the intestinal barrier in CKD patients is evidenced by (i) endotoxemia without any evidence of clinical infection [80,81,82], (ii) increased intestinal permeability to polyethylene glycols in CKD humans and animals [83,84], (iii) the detection of GI bacteria in the mesenteric lymph nodes of CKD animals [85], and (iv) histological evidence of chronic inflammation throughout the GI tract (stomach, jejunum, ileum, and colon) [12,86,87]. Urea toxicity, hemodialysis procedure, gut wall edema, inflammation, and oxidative stress are major mechanisms that drive the disintegration of the intestinal barrier [88].

4.1. Urea Toxicity

Urease enzyme is expressed by certain microbiota families i.e., Alteromonadaceae, Cellulomonadaceae, Clostridiaceae, Dermabacteraceae, Enterobacteriaceae, Halomonadaceae, Methylococcaceae, Micrococcaceae, Moraxellaceae, Polyangiaceae, Pseudomonadaceae and Xanthomonadaceae [35]. Urease hydrolyzes urea in the gut to form ammonia (NH3) which is instantly hydrolyzed to ammonium hydroxide (NH4OH). High amounts of ammonia and ammonium hydroxide damage the gut’s epithelial barrier, alter microbiota composition and the luminal biochemical milieu, and result in local and systemic inflammation [35]. A key pathway is the breakdown of epithelial tight junctions via the depletion of occludin, claudin-1 and zona occludens proteins [12,23,72,89]. In CKD rats, decreased expression was at the protein level with mRNA levels remaining constant [12].

4.2. Hemodialysis-Associated Disruption of the Intestinal Barrier

Shi et al. examined three patient cohorts including hemodialysis patients, CKD patients not on dialysis, and healthy controls [90], and detected bacterial DNA in the plasma of 27% of hemodialysis patients and 20% of pre-dialysis CKD patients. The majority of bacteria detected in the blood of ESRD patients was also detected in their stool samples, and were not detected in the dialysate solutions [90]. Hemodialysis is thought to exacerbate the CKD-induced injury of the intestinal epithelial barrier [19,23,35,90,91], which was in part due to bowel ischemia from intradialysis and post-dialysis hypotension, and bowel edema due to intradialysis fluid retention, which may be compounded by hypoalbuminemia [13]. Furthermore, systemic anticoagulation, uremic platelet dysfunction, and a high incidence of GI angiodysplasia in these patients can exacerbate intestinal barrier breakdown [19].

4.3. Gut Wall Inflammation and Oxidative Stress

As described above, the influx of urea in CKD disrupts the intestinal epithelial barrier. The translocation of endotoxin and bacterial fragments into the sub-epithelial tissue leads to local inflammation via the activation of the resident immune system cells (macrophages, dendritic cells, and T cells), the release of pro-inflammatory cytokines and chemokines, and the infiltration of circulating inflammatory cells [13]. Local production and the release of cytokines such as IFN-γ, TNF-α, IL-12, and IL-1β cause the further disruption of intercellular tight junctions by the induction of endocytosis of claudin-1 and occludin proteins, and by increasing myosin light-chain kinase (MLCK) protein expression and activity [92,93,94,95]. MLCK phosphorylates the myosin regulatory light chain, resulting in the contraction of the actin–myosin ring and increased intercellular permeability [96,97].

5. Dysbiosis as a Major Source of Uremic Toxins in CKD

Uremic toxins are classified into three groups: endogenous, exogenous, and microbial-derived [61]. Due to the impaired epithelial barrier in CKD described above, there is a propensity for the translocation of microbe-derived uremic toxins from the GI lumen into the bloodstream. Indoxyl sulfate, p-cresyl sulfate and trimethylamine N-oxide (TMAO) are the major bacterial-derived toxins [98]. A study of 12 healthy and 24 ESRD individuals revealed a significant expansion of bacterial families possessing urease, uricase, and indole and p-cresol forming enzymes, and a reduced number of families possessing SCFA butyrate-forming enzymes [35]. These changes in intestinal microbial metabolism generate uremic toxins, which promote systemic inflammation [35,98].
There are currently five different gut-derived uremic toxins that have been associated with CVD and mortality in CKD: indoxyl sulfate, indole-3 acetic acid, p-cresyl sulfate, TMAO, and phenylacetylglutamine. Indoxyl sulfate and indole-3 acetic acid are protein-bound uremic toxins generated from bacterial tryptophanase, which is expressed by Clostridiaceae, Enterobacteriaceae and Verrucomicrobiaceae [98]. Tryptophanase converts tryptophan to indolic compounds that are absorbed from the colon, and then sulfated in the liver [99]. Deaminase enzymes produced by Bacteroides, Bifidobacterium, Lactobacillus, Enterobacter, and Clostridium genera generate phenols by the conversion of tyrosine and phenylalanine to phenyl acetic acid and p-cresol, and the latter is conjugated by intestinal microbes to p-cresyl sulfate [100]. Trimethylamine is a gut-derived small organic uremic toxin from bacterial metabolism of quaternary amines such as phosphatidylcholine [101] that is absorbed and converted into TMAO by hepatic monooxygenases. Phenylacetylglutamine is another colonic microbial product that is produced from the fermentation of phenylalanine [102]. Indoxyl sulfate, indole-3 acetic acid, and p-cresyl sulfate cannot be efficiently removed by conventional hemodialysis, because they are highly bound to albumin [103,104], whereas TMAO and phenylacetylglutamine are water-soluble and dialyzable.
Indoxyl sulfate, p-cresyl sulfate, and TMAO are associated with increased cardiovascular morbidity and mortality in CKD patients [45,105,106,107]. In animal models, the oral administration of TMAO has been shown to promote atherosclerosis, and leads to tubulointerstitial fibrosis and progressive kidney dysfunction [45,108,109]. Indoxyl sulfate promotes cardiac fibrosis [110,111] and induces oxidative stress in endothelial cells [35,112]. Indoxyl sulfate’s effects may link gut-derived uremic toxins with the muscle that is wasting observed in CKD [113]. Gene expression of the muscle atrophy markers myostatin and atrogin-1 are increased, while muscle protein synthesis is decreased in the presence of indoxyl sulfate, thereby resulting in decreased skeletal muscle mass [114,115]. Aside from the major known gut-derived toxins, many as yet unidentified toxins in ESRD patients are likely derived from GI microbiota [28].

6. The Effect of Dysbiosis on Neuroendocrine Pathways in CKD Patients

The reader is directed to the recent paper by Lau et al. that discussed the impact of gut dysbiosis in CKD on the kidney, cardiovascular, bone, adipocytes, and hematologic systems [98]. In this review, we discuss how gut microbiota influence the neuroendocrine system of the host via the hypothalamic–pituitary–adrenal (HPA) axis [116,117], tryptophan metabolism [118], inducing hormone release [119,120], and the production of neurotransmitters, which are neuroactive and hormone-like compounds [121,122,123], and via the vagus nerve (VN) [124]. Alterations in the normal function of the neuroendocrine system due to gut dysbiosis may play a critical role in the establishment and progression of kidney failure (Figure 2).

6.1. Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is the major neuroendocrine system of the human body that controls various body processes in response to stress. Due to the bidirectional communication between the gut microbiota and the HPA axis, various disorders of the gut microbiota are associated with HPA axis dysregulation and vice versa. Toxic products of gut microbiota such as endotoxin and peptidoglycan are able to cross the intestinal epithelium barrier, especially under conditions of increased permeability such as CKD, and stimulate the HPA axis either directly or via the activation of the immune system [125]. Overactivation of the HPA axis may result in the progression of CKD in type 2 diabetes mellitus patients, where endogenous hypercortisolism has been associated with HPA axis activation and CKD prevalence [126]. There is a feedback loop whereby activation of the HPA axis alters gut microbiota subpopulations and increases gastrointestinal epithelial barrier permeability [127,128].

6.2. Induction of Release of Gut Hormones

Larraufie et al. showed that SCFAs (particularly propionate and butyrate) produced by gut microbiota strongly increase the expression and secretion of peptide-YY (PYY) in cultured intestinal cells [129]. PYY is primarily secreted by enteroendocrine cells located in the distal intestine. It plays an important role in the regulation of food intake and insulin secretion. The effect of SCFAs on the expression of this hormone is attributed to the histone deacetylase inhibitory activity of SCFAs and minor contributions of GPR43 [129]. Due to the role of PYY in appetite and energy expenditure, alterations in the expression and secretion of PYY influence the pathophysiology of obesity and hypertension [130] which are important risk factors for CKD [131,132].

6.3. Production of Neurotransmitters and Neuroactive Compounds

Gut microbiota produce a wide range of local neurotransmitters and neuroactive compounds [123], including gamma aminobutyric acid (GABA) (produced by Lactobacillus and Bifidobacterium), serotonin (produced by Bifidobacterium, Streptococcus, Escherichia, Enterococcus, Lactococcus, and Lactobacillus), tryptamine (produced by Clostridium and Ruminococcus), catecholamine (produced by Escherichia, Bacillus, Saccharomyces, Lactococcus, and Lactobacillus), and acetylcholine (produced by Lactobacillus and Bacillus) [122]. Gut microbiota also modulate the production of neurotransmitters through the regulation of the amount and availability of precursors of neuroactive compounds [133,134]. These local neurotransmitters and neuroactive compounds may have critical roles in the regulation of sodium homeostasis and blood pressure, which influence CKD progression [131,135].

6.4. Tryptophan Metabolism

Serotonin is a key signaling molecule in both the enteric nervous system and the central nervous system, and is a tryptophan metabolite [136,137,138]. Approximately 95% of the serotonin in the body is located in the gut [139]. Therefore, dysbiosis may affect serotonin balance, as microbial tryptophanase activity may limit tryptophan availability to the host [118,140,141]. Bacteria can also synthesize tryptophan through tryptophan synthase [142,143]. Serotonin is involved in the control of epithelial permeability and the modulation of immune responses [144]. Therefore, changes in the composition and/or activity of the gut microbiota may alter gut permeability through effects on serotonin production or availability.

6.5. Bacterial Hormone-Like Compounds

Bacteria use the quorum sensing system to regulate gene expression and communicate with each other [145]. These communications rely on autoinducer molecules, which are hormone-like compounds that control bacterial physiology and metabolism. Moreover, these molecules can modulate host–cell signal transduction. Some autoinducer molecules interact with host hormones to activate signaling pathways [121,146] and some quorum-sensing peptides (QSP) are able to cross the blood–brain barrier. Although the precise pathways of microbiota-hormonal signaling have not yet been exactly characterized, specific species of gut microbiota have been shown to induce specific changes in hormone levels [121,147]. Changes in QSP patterns may aggravate chronic inflammation which is a risk factor for CKD progression [13,148].

6.6. Cholinergic Anti-Inflammatory Pathway

The vagus nerve is the principal component of the parasympathetic nervous system which is composed of 80% afferent and 20% efferent fibers. SCFAs produced by intestinal microbiota may activate vagal chemoreceptors and generate inappropriate responses in the central nervous system (CNS) [149,150,151]. On the other hand, a cholinergic anti-inflammatory pathway through vagus nerve activation may actually reduce peripheral inflammation, inhibit the release of pro-inflammatory cytokines such as TNF-α, and improve intestinal barrier integrity [150,152]. It has been proposed that stimulation of the vagus nerve and activation of the cholinergic anti-inflammatory pathway has an overall protective effect against kidney injury [153]. Heart rate variability is being explored as a marker of gut microbiota-related autonomic dysfunction, as efferent signals from the vagus nerve are predicted to inhibit cytokine production and increase instantaneous heart rate variability [154,155].

7. Strategies to Attenuate Gut Dysbiosis in CKD

7.1. Balanced Diet

Montemurno et al. speculated that the Mediterranean diet—which contains unrefined grains, fruits and vegetables, legumes, nuts, olive oil, fish, and a moderate consumption of red wine—and low amounts of dairy products and red meat may have beneficial gut microbiome effects via providing fiber and antioxidants [156]. On the other hand, a Western diet (rich in animal proteins and fats) stimulates the overgrowth of proteolytic bacteria, which results in dysbiosis, the accumulation of proteolytic-derived uremic toxins such as indoxyl sulfate, and may promote CKD progression [156]. It has been shown that the Mediterranean diet reduces dyslipidemia and protects against lipid peroxidation and inflammation in CKD patients [157]. However, in a cross-sectional study of 276 outpatients who completed a Harvard Food Frequency Questionnaire, the Mediterranean diet score did not correlate with plasma levels of gut-derived uremic toxins including indoxyl sulfate and TMAO [158]. Of note, higher fiber intake in the Dietary Approaches to Stop Hypertension (DASH) diet was associated with a lower incidence of CKD in an elderly Korean population [159].

7.2. Prebiotics

Prebiotics are defined as “selectively fermentable ingredients that induce specific modifications in the composition and/or activity of the gut microbiota, which have beneficial effects for the host health” [160]. Prebiotics resist hydrolysis and host absorption and reach the distal GI tract to stimulate the growth and activity of one or a few bacterial species or genera in the colon that are able to ferment these compounds [160]. Some of the prebiotics that are naturally occurring in many fruits, milk and vegetables are fructooligosaccharides, galactooligosaccharides, resistant starch, and lactulose. Beneficial effects are due to the enhanced microbial production of SCFAs and include (i) improved gut barrier integrity and function, (ii) the modulation of anti-inflammatory, antioxidant, and immune system responses, and (iii) the modulation of glucose and lipid metabolism [66,161,162,163].
Our group previously demonstrated that a high resistant starch diet alters the gut milieu, attenuates oxidative stress and inflammation, and improved kidney function in CKD rats. Vaziri et al. compared a low-fiber diet (amylopectin) versus a high fermentable fiber diet (amylose maize resistant starch, HAMRS2) in rats with adenine-induced CKD [44]. The low-fiber diet group showed interstitial fibrosis, inflammation, tubular damage, the activation of NF-κβ, up-regulation of pro-inflammatory, pro-oxidant, and pro-fibrotic molecules, impaired Nrf2 activity, down-regulation of antioxidant enzymes, reduced creatinine clearance, and the disruption of colonic epithelial tight junctions, while the diet high in resistant starch showed significant improvement across all these parameters [44]. In a follow-up report, Vaziri et al. showed that cecal pH was decreased, while Bacteroidetes/Firmicutes ratio was increased in HAMRS2-fed rats [164]. Moreover, serum and urine indoxyl sulfate decreased 36% and 66% respectively, and urine p-cresol was decreased 47% in HAMRS2-fed rats [164].

7.3. Intestinal Alpha-Glycosidase Inhibition

Intestinal alpha-glucosidase inhibitors including acarbose, voglibose, and miglitol are oral glucose-lowering drugs, which act by inhibiting the conversion of carbohydrates into monosaccharides, thus reducing their intestinal absorption and lowering the blood sugar level [165]. These drugs increase the delivery of undigested carbohydrates to colonic microbiota, thereby increasing SCFA production and lowering luminal pH [166]. Two weeks of acarbose supplementation in mice resulted in increased cecal levels of butyrate and total SCFAs in conjunction with increases in Bacteroidaceae (genus Bacteroides), Rikenellaceae (genus Alistipes), and Lachnospiraceae (genus Blautia) [167]. Interestingly, acarbose supplementation in mice increases lifespan [168,169]. In humans, Zhang et al. reported changes in the proportion and diversity of gut microbiota before and after treatment with acarbose in 52 pre-diabetic patients [170]. In a randomized, double-blind, controlled crossover trial, a total of 107 operational taxonomic units (OTUs) were significantly altered after acarbose treatment. Many of the OTUs that were greatly increased with acarbose therapy belonged to SCFA-producing taxa, including Faecalibacterium, Prevotella, and Lactobacillus [170].
The administration of acarbose significantly reduced p-cresol amounts in the urine, plasma and feces in a group of individuals with normal kidney function [76], and thus may have benefits in terms of lowering microbial-derived uremic toxins in patients with CKD.

7.4. Probiotics

Probiotics are “live microorganisms which confer health beneficial effects when administered in adequate amounts to the host”, and are administered orally to re-establish the intestinal balance of microbiota. Beneficial effects include pH modulation, the production of SCFAs and anti-bacterial compounds, and the inhibition of pathogenic species [156,171].
In a small randomized double-blind controlled study (16–17 patients per group), Borges et al. investigated the effects of probiotic supplementation on the gut microbiota profile and inflammatory markers in hemodialysis patients. A mixture of Streptococcus thermophilus, Lactobacillus acidophilus and Bifidobacterium longum was administered in a capsule containing 30 billion live bacteria, and participants were prescribed three capsules a day of probiotic or placebo for three months. There was no statistically significant difference in the inflammatory markers and gut profile between two groups [172]. A separate group that studied the Renadyl probiotic formulation in dialysis patients similarly reported no difference in inflammatory markers or quality of life scores [173]. It can be argued that the administration of probiotics without modifying the biochemical environment of the GI tract in CKD would not be able to sustain beneficial effects [28].
The classic probiotics that are currently on the market utilize only a small group of organisms. Given that evidence is limited regarding the potential probiotic effects in different disease states, more investigations are needed to find new strains and formulations [174]. A. muciniphila, F. prausnitzii, Bacteroides fragilis, and members of Clostridia clusters IV, XIVa, and XVIII have been considered as a “new generation” of probiotics for treatment of the dysbiosis [175]. F. prausnitzii is a dominant member in normal gut microbiota, and has beneficial effects, including butyrate production, anti-inflammatory effects by reducing T helper 1 (Th1) and Th17 pro-inflammatory cytokines, and lowering the IL-12 and IFNγ production [175]. As discussed previously, butyrate-producing Roseburia and F. prausnitzii species are deficient in CKD patients compared with healthy controls [71]. A. muciniphila, a mucin-degrading member of gut microbiota, improves endotoxemia-induced inflammation through restoration of the gut barrier [175,176].
Bacteroides species are anaerobic commensals in the human GI tract. B. fragilis produces polysaccharide A, which is an immunomodulatory molecule that activates Tregs to boost immunologic tolerance [177]. Eubacterium hallii is an important anaerobic butyrate and propionate producer that lowers mucosal inflammation and oxidative status, strengthens the epithelial barrier function, and produces SCFAs as an energy source for colonocytes [178,179]. Clostridium leptum and coccoides are also exceptional inducers of Tregs in the colon [180]. These species deserve further study in newer probiotic formulations.

7.5. Synbiotics

Synbiotics contain both probiotics and prebiotics and there have been some beneficial effects reported in CKD patients. Rossi et al. utilized prebiotics including inulin, fructooligosaccharides and galactooligosaccharides with probiotics consisting of nine bacterial strains belonging to Lactobacillus, Bifidobacteria, and Streptococcus genera. Synbiotic treatment significantly decreased serum p-cresyl sulfate and improved Bifidobacterium counts in stool. A non-significant decrease in serum indoxyl sulfate was also reported [181]. Nakabayashi et al. studied nine hemodialysis patients who received synbiotic treatment with Lactobacillus casei and Bifidobacterium breve, and galactooligosaccharides as prebiotics. They reported decreased serum p-cresol levels in treated patients, but biomarkers of inflammation and oxidative stress were unchanged [182].
Table 1 is a summary of animal and human investigations of prebiotics/probiotics in CKD.

8. Summary

In the healthy state, gut microbiota provides several benefits to the host. However, in CKD the heavy influx of urea, uric acid, and oxalic acid compounded with the dietary restrictions and administration of phosphate binders, antibiotics, and oral iron supplements leads to changes in the GI biochemical milieu. Ultimately, there is microbial dysbiosis and disruption of the intestinal epithelial barrier. Dialysis, fluid retention, and hypoalbuminemia also contribute to the increased permeability of the intestinal barrier. Translocation of endotoxin and bacterial-derived uremic toxins into the bloodstream leads to the induction of oxidative stress and inflammation. There is a bidirectional relationship whereby inflammation and oxidative stress promote the progression of CKD. Further, gut microbiota affects the brain and neuroendocrine system through several pathways. Prebiotics, new generation probiotics and synbiotics have shown promise in reversing dysbiosis in small studies; however, long-term randomized clinical trials are necessary to confirm the efficacy of these compounds in re-establishing symbiotic flora and slowing the progression of CKD.

Author Contributions

N.H.J. prepared the initial manuscript draft. All authors contributed to writing of the final manuscript.


This research received no external funding


The authors thank Shahram Shahabi for his comments and suggestions.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Rafieian-Kopaei, M.; Beigrezaei, S.; Nasri, H.; Kafeshani, M. Soy protein and chronic kidney disease: An updated review. Int. J. Prev. Med. 2017, 8, 105. [Google Scholar] [PubMed]
  2. Tang, E.; Bansal, A.; Novak, M.; Mucsi, I. Patient-reported outcomes in patients with chronic kidney disease and kidney transplant-Part 1. Front. Med. 2017, 4, 254. [Google Scholar] [CrossRef] [PubMed]
  3. Hill, N.R.; Fatoba, S.T.; Oke, J.L.; Hirst, J.A.; O’Callaghan, C.A.; Lasserson, D.S.; Richard Hobbs, F.D. Global prevalence of chronic kidney disease—A systematic review and meta-analysis. PLoS ONE 2016, 11, e0158765. [Google Scholar] [CrossRef] [PubMed]
  4. Stevens, P.E.; Levin, A. Kidney disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group, M. Evaluation and management of chronic kidney disease: Synopsis of the kidney disease: Improving global outcomes 2012 clinical practice guideline. Ann. Intern. Med. 2013, 158, 825–830. [Google Scholar] [CrossRef] [PubMed]
  5. Xia, J.; Wang, L.; Ma, Z.; Zhong, L.; Wang, Y.; Gao, Y.; He, L.; Su, X. Cigarette smoking and chronic kidney disease in the general population: A systematic review and meta-analysis of prospective cohort studies. Nephrol. Dial. Transplant. 2017, 32, 475–487. [Google Scholar] [CrossRef] [PubMed]
  6. Romagnani, P.; Remuzzi, G.; Glassock, R.; Levin, A.; Jager, K.J.; Tonelli, M.; Massy, Z.; Wanner, C.; Anders, H.J. Chronic kidney disease. Nat. Rev. Dis. Primers 2017, 3, 17088. [Google Scholar] [CrossRef] [PubMed]
  7. Glassock, R.J.; Denic, A.; Rule, A.D. The conundrums of chronic kidney disease and aging. J. Nephrol. 2017, 30, 477–483. [Google Scholar] [CrossRef]
  8. Westland, R.; Schreuder, M.F.; van Goudoever, J.B.; Sanna-Cherchi, S.; van Wijk, J.A. Clinical implications of the solitary functioning kidney. Clin. J. Am. Soc. Nephrol. 2014, 9, 978–986. [Google Scholar] [CrossRef]
  9. Vos, T.; Barber, R.M.; Bell, B.; Bertozzi-Villa, A.; Biryukov, S.; Bolliger, I.; Charlson, F.; Davis, A.; Degenhardt, L.; Dicker, D.; et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015, 386, 743–800. [Google Scholar] [CrossRef]
  10. Thomas, E.A.; Pawar, B.; Thomas, A. A prospective study of cutaneous abnormalities in patients with chronic kidney disease. Indian J. Nephrol. 2012, 22, 116–120. [Google Scholar] [CrossRef]
  11. Kaplan, J.M.; Sharma, N.; Dikdan, S. Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease. Int. J. Mol. Sci. 2018, 19, 389. [Google Scholar] [CrossRef] [PubMed]
  12. Vaziri, N.D.; Yuan, J.; Rahimi, A.; Ni, Z.; Said, H. Subramanian VS. Disintegration of colonic epithelial tight junction in uremia: A likely cause of CKD-associated inflammation. Nephrol. Dial. Transplant. 2012, 27, 2686–2693. [Google Scholar] [CrossRef] [PubMed]
  13. Vaziri, N.D. CKD impairs barrier function and alters microbial flora of the intestine: A major link to inflammation and uremic toxicity. Curr. Opin. Nephrol. Hypertens. 2012, 21, 587–592. [Google Scholar] [CrossRef] [PubMed]
  14. Nigam, G.; Camacho, M.; Chang, E.T.; Riaz, M. Exploring sleep disorders in patients with chronic kidney disease. Nat. Sci. Sleep 2018, 10, 35–43. [Google Scholar] [CrossRef] [Green Version]
  15. Malluche, H.H.; Porter, D.S.; Pienkowski, D. Evaluating bone quality in patients with chronic kidney disease. Nat. Rev. Nephrol. 2013, 9, 671–680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Ketteler, M.; Wanner, C. Chronic kidney disease—Update 2018. Dtsch. Med. Wochenschr. 2018, 143, 169–173. [Google Scholar] [PubMed]
  17. Gilligan, S.; Raphael, K.L. Hyperkalemia and hypokalemia in CKD: Prevalence, risk factors, and clinical outcomes. Adv. Chronic Kidney Dis. 2017, 24, 315–318. [Google Scholar] [CrossRef] [PubMed]
  18. Langston, C. Managing fluid and electrolyte disorders in kidney disease. Vet. Clin. North. Am. Small Anim. Pract. 2017, 47, 471–490. [Google Scholar] [CrossRef] [PubMed]
  19. Vaziri, N.D. Gut microbial translocation in the pathogenesis of systemic inflammation in patients with end-stage renal disease. Dig. Dis. Sci. 2014, 59, 2020–2022. [Google Scholar] [CrossRef] [PubMed]
  20. Slee, A.D. Exploring metabolic dysfunction in chronic kidney disease. Nutr. Metab. (Lond) 2012, 9, 36. [Google Scholar] [CrossRef] [Green Version]
  21. Siezen, R.J.; Kleerebezem, M. The human gut microbiome: Are we our enterotypes? Microb. Biotechnol. 2011, 4, 550–553. [Google Scholar] [CrossRef] [PubMed]
  22. Malnick, S.; Melzer, E. Human microbiome: From the bathroom to the bedside. World J. Gastrointest. Pathophysiol. 2015, 6, 79–85. [Google Scholar] [CrossRef] [PubMed]
  23. Vaziri, N.D.; Wong, J.; Pahl, M.; Piceno, YM.; Yuan, J.; Desantis, T.Z.; Ni, Z.; Nguyen, T.H.; Andersen, G.L. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2013, 83, 308–315. [Google Scholar] [CrossRef] [PubMed]
  24. Gerritsen, J.; Smidt, H.; Rijkers, G.T.; de Vos, W.M. Intestinal microbiota in human health and disease: The impact of probiotics. Genes Nutr. 2011, 6, 209–240. [Google Scholar] [CrossRef] [PubMed]
  25. Selber-Hnatiw, S.; Rukundo, B.; Ahmadi, M.; Akoubi, H.; Al-Bizri, H.; Aliu, A.F.; Ambeaghen, T.U.; Avetisyan, L.; Bahar, I.; Baird, A.; et al. Human gut microbiota: Toward an ecology of disease. Front. Microbiol. 2017, 8, 1265. [Google Scholar] [CrossRef] [PubMed]
  26. Shin, N.R.; Whon, T.W.; Bae, J.W. Proteobacteria: Microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 2015, 33, 496–503. [Google Scholar] [CrossRef]
  27. Qin, J.; Li, R.; Raes, J.; Arumugam, M.; Burgdorf, K.S.; Manichanh, C.; Nielsen, T.; Pons, N.; Levenez, F.; Yamada, T.; et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010, 464, 59–65. [Google Scholar] [CrossRef] [Green Version]
  28. 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. 2016, 31, 737–746. [Google Scholar] [CrossRef]
  29. Turroni, F.; Ribbera, A.; Foroni, E.; van Sinderen, D.; Ventura, M. Human gut microbiota and bifidobacteria: From composition to functionality. Antonie Van Leeuwenhoek 2008, 94, 35–50. [Google Scholar] [CrossRef]
  30. Zoetendal, E.G.; Vaughan, E.E.; de Vos, W.M. A microbial world within us. Mol. Microbiol. 2006, 59, 1639–1650. [Google Scholar] [CrossRef]
  31. Backhed, F.; Ley, R.E.; Sonnenburg, J.L.; Peterson, D.A.; Gordon, J.I. Host-bacterial mutualism in the human intestine. Science 2005, 307, 1915–1920. [Google Scholar] [CrossRef] [PubMed]
  32. Capurso, G.; Lahner, E. The interaction between smoking, alcohol and the gut microbiome. Best Pract. Res. Clin. Gastroenterol. 2017, 31, 579–588. [Google Scholar] [CrossRef] [PubMed]
  33. Wypych, T.P.; Marsland, B.J. Diet hypotheses in light of the microbiota revolution: New perspectives. Nutrients 2017, 9, 537. [Google Scholar] [CrossRef] [PubMed]
  34. Ursell, L.K.; Clemente, J.C.; Rideout, J.R.; Gevers, D.; Caporaso, J.G.; Knight, R. The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J. Allergy Clin. Immunol. 2012, 129, 1204–1208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Wong, J.; Piceno, Y.M.; Desantis, T.Z.; Pahl, M.; Andersen, G.L.; Vaziri, N.D. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am. J. Nephrol. 2014, 39, 230–237. [Google Scholar] [CrossRef] [PubMed]
  36. Rossi, M.; Amaretti, A.; Raimondi, S. Folate production by probiotic bacteria. Nutrients 2011, 3, 118–134. [Google Scholar] [CrossRef] [PubMed]
  37. Carbonero, F.; Benefiel, A.C.; Alizadeh-Ghamsari, A.H.; Gaskins, H.R. Microbial pathways in colonic sulfur metabolism and links with health and disease. Front. Physiol. 2012, 3, 448. [Google Scholar] [CrossRef] [PubMed]
  38. Pahl, M.V.; Vaziri, N.D. The Chronic kidney disease—Colonic axis. Semin. Dial. 2015, 28, 459–463. [Google Scholar] [CrossRef] [PubMed]
  39. den Besten, G.; van Eunen, K.; Groen, A.K.; Venema, K.; Reijngoud, D.J.; Bakker, B.M. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 2013, 54, 2325–2340. [Google Scholar] [CrossRef] [Green Version]
  40. Miyamoto, J.; Kasubuchi, M.; Nakajima, A.; Irie, J.; Itoh, H.; Kimura, I. The role of short-chain fatty acid on blood pressure regulation. Curr. Opin. Nephrol. Hypertens. 2016, 25, 379–383. [Google Scholar] [CrossRef] [PubMed]
  41. Cani, P.D.; Knauf, C. How gut microbes talk to organs: The role of endocrine and nervous routes. Mol. Metab. 2016, 5, 743–752. [Google Scholar] [CrossRef] [PubMed]
  42. Pluznick, J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes 2014, 5, 202–207. [Google Scholar] [CrossRef] [PubMed]
  43. Mell, B.; Jala, V.R.; Mathew, A.V.; Byun, J.; Waghulde, H.; Zhang, Y.; Haribabu, B.; Vijay-Kumar, M.; Pennathur, S.; Joe, B. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol. Genomics 2015, 47, 187–197. [Google Scholar] [CrossRef] [PubMed]
  44. Vaziri, N.D.; Liu, S.M.; Lau, W.L.; Khazaeli, M.; Nazertehrani, S.; Farzaneh, SH.; Kieffer, D.A.; Adams, S.H.; Martin, R.J. High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease. PLoS ONE 2014, 9, e114881. [Google Scholar] [CrossRef] [PubMed]
  45. Lau, W.L.; Vaziri, N.D. The Leaky Gut and Altered Microbiome in Chronic Kidney Disease. J. Ren. Nutr. 2017, 27, 458–461. [Google Scholar] [CrossRef]
  46. Thomas, S.; Izard, J.; Walsh, E.; Batich, K.; Chongsathidkiet, P.; Clarke, G.; Sela, D.A.; Muller, A.J.; Mullin, J.M.; Albert, K.; et al. The host microbiome regulates and maintains human health: A primer and perspective for non-microbiologists. Cancer Res. 2017, 77, 1783–1812. [Google Scholar] [CrossRef] [PubMed]
  47. Kim, C.H.; Park, J.; Kim, M. Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation. Immun. Netw. 2014, 14, 277–288. [Google Scholar] [CrossRef] [PubMed]
  48. Wei, B.; Wingender, G.; Fujiwara, D.; Chen, D.Y.; McPherson, M.; Brewer, S.; Borneman, J.; Kronenberg, M.; Braun, J. Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells. J. Immunol. 2010, 184, 1218–1226. [Google Scholar] [CrossRef]
  49. Kang, Y.; Cai, Y. Gut microbiota and obesity: Implications for fecal microbiota transplantation therapy. Hormones 2017, 16, 223–234. [Google Scholar] [CrossRef] [PubMed]
  50. Weiss, G.A.; Hennet, T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol. Life Sci. 2017, 74, 2959–2977. [Google Scholar] [CrossRef]
  51. Saltzman, E.T.; Palacios, T.; Thomsen, M.; Vitetta, L. Intestinal microbiome shifts, dysbiosis, inflammation, and non-alcoholic fatty liver disease. Front. Microbiol. 2018, 9, 61. [Google Scholar] [CrossRef] [PubMed]
  52. Minato, T.; Maeda, T.; Fujisawa, Y.; Tsuji, H.; Nomoto, K.; Ohno, K.; Hirayama, M. Progression of Parkinson’s disease is associated with gut dysbiosis: Two-year follow-up study. PLoS ONE 2017, 12, e0187307. [Google Scholar] [CrossRef] [PubMed]
  53. Moustafa, A.; Li, W.; Anderson, E.L.; Wong, E.H.M.; Dulai, P.S.; Sandborn, W.J.; Biggs, W.; Yooseph, S.; Jones, M.B.; Venter, J.C.; et al. Genetic risk, dysbiosis, and treatment stratification using host genome and gut microbiome in inflammatory bowel disease. Clin. Transl. Gastroenterol. 2018, 9, e132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Carding, S.; Verbeke, K.; Vipond, D.T.; Corfe, B.M.; Owen, L.J. Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis. 2015, 26, 26191. [Google Scholar] [CrossRef] [PubMed]
  55. Raskov, H.; Burcharth, J.; Pommergaard, H.C. Linking gut microbiota to colorectal cancer. J. Cancer 2017, 8, 3378–3395. [Google Scholar] [CrossRef] [PubMed]
  56. Lopez, A.; Hansmannel, F.; Kokten, T.; Bronowicki, J.P.; Melhem, H.; Sokol, H.; Peyrin-Biroulet, L. Microbiota in digestive cancers: Our new partner? Carcinogenesis 2017, 38, 1157–1166. [Google Scholar] [CrossRef]
  57. Koliada, A.; Syzenko, G.; Moseiko, V.; Budovska, L.; Puchkov, K.; Perederiy, V.; Gavalko, Y.; Dorofeyev, A.; Romanenko, M.; Tkach, S.; et al. Association between body mass index and Firmicutes/Bacteroidetes ratio in an adult Ukrainian population. BMC Microbiol. 2017, 17, 120. [Google Scholar] [CrossRef] [Green Version]
  58. Adnan, S.; Nelson, J.W.; Ajami, N.J.; Venna, V.R.; Petrosino, J.F.; Bryan, R.M., Jr.; Durgan, D.J. Alterations in the gut microbiota can elicit hypertension in rats. Physiol. Genomics 2017, 49, 96–104. [Google Scholar] [CrossRef]
  59. Strati, F.; Cavalieri, D.; Albanese, D.; De Felice, C.; Donati, C.; Hayek, J.; Jousson, O.; Leoncini, S.; Renzi, D.; Calabrò, A.; et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017, 5, 24. [Google Scholar] [CrossRef]
  60. Chung, C.S.; Chang, P.F.; Liao, C.H.; Lee, T.H.; Chen, Y.; Lee, Y.C.; Wu, M.S.; Wang, H.P.; Ni, Y.H. Differences of microbiota in small bowel and faeces between irritable bowel syndrome patients and healthy subjects. Scand. J. Gastroenterol. 2016, 51, 410–419. [Google Scholar] [CrossRef]
  61. Vaziri, N.D.; Suematsu, Y.; Shimomura, A. Uremic toxins and gut microbiome. Nihon Jinzo Gakkai Shi 2017, 535–544. [Google Scholar]
  62. Jiang, S.; Xie, S.; Lv, D.; Wang, P.; He, H.; Zhang, T.; Zhou, Y.; Lin, Q.; Zhou, H.; Jiang, J.; et al. Alteration of the gut microbiota in Chinese population with chronic kidney disease. Sci. Rep. 2017, 7, 2870. [Google Scholar] [CrossRef] [PubMed]
  63. Cigarran Guldris, S.; Gonzalez Parra, E.; Cases Amenos, A. Gut microbiota in chronic kidney disease. Nefrologia 2017, 37, 9–19. [Google Scholar] [CrossRef] [PubMed]
  64. Liu, Y.; Li, J.; Yu, J.; Wang, Y.; Lu, J.; Shang, E.X.; Zhu, Z.; Guo, J.; Duan, J. Disorder of gut amino acids metabolism during CKD progression is related with gut microbiota dysbiosis and metagenome change. J. Pharm. Biomed. Anal. 2018, 149, 425–435. [Google Scholar] [CrossRef]
  65. Rossi, M.; Johnson, D.W.; Campbell, K.L. The kidney-gut axis: Implications for nutrition care. J. Ren. Nutr. 2015, 25, 399–403. [Google Scholar] [CrossRef]
  66. Ramezani, A.; Raj, D.S. The gut microbiome, kidney disease, and targeted interventions. J. Am. Soc. Nephrol. 2014, 25, 657–670. [Google Scholar] [CrossRef]
  67. Hida, M.; Aiba, Y.; Sawamura, S.; Suzuki, N.; Satoh, T.; Koga, Y. Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis. Nephron 1996, 74, 349–355. [Google Scholar] [CrossRef]
  68. De Angelis, M.; Montemurno, E.; Piccolo, M.; Vannini, L.; Lauriero, G.; Maranzano, V.; Gozzi, G.; Serrazanetti, D.; Dalfino, G.; Gobbetti, M.; et al. Microbiota and metabolome associated with immunoglobulin A nephropathy (IgAN). PLoS ONE 2014, 9, e99006. [Google Scholar] [CrossRef]
  69. Wang, F.; Jiang, H.; Shi, K.; Ren, Y.; Zhang, P.; Cheng, S. Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients. Nephrology (Carlton) 2012, 17, 733–738. [Google Scholar] [CrossRef]
  70. Wang, F.; Zhang, P.; Jiang, H.; Cheng, S. Gut bacterial translocation contributes to microinflammation in experimental uremia. Dig. Dis. Sci. 2012, 57, 2856–2862. [Google Scholar] [CrossRef]
  71. Jiang, S.; Xie, S.; Lv, D.; Zhang, Y.; Deng, J.; Zeng, L.; Chen, Y. A reduction in the butyrate producing species Roseburia spp. and Faecalibacterium prausnitzii is associated with chronic kidney disease progression. Antonie van Leeuwenhoek 2016, 109, 1389–1396. [Google Scholar] [CrossRef] [PubMed]
  72. Vaziri, N.D.; Yuan, J.; Norris, K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am. J. Nephrol. 2013, 37, 1–6. [Google Scholar] [CrossRef] [PubMed]
  73. Lau, W.L.; Vaziri, N.D. Urea, a true uremic toxin: The empire strikes back. Clin. Sci. 2017, 131, 3–12. [Google Scholar] [CrossRef] [PubMed]
  74. Fathallah-Shaykh, S.A.; Cramer, M.T. Uric acid and the kidney. Pediatr. Nephrol. 2014, 29, 999–1008. [Google Scholar] [CrossRef] [PubMed]
  75. Ermer, T.; Eckardt, K.U.; Aronson, P.S.; Knauf, F. Oxalate, inflammasome, and progression of kidney disease. Curr. Opin. Nephrol. Hypertens. 2016, 25, 363–371. [Google Scholar] [CrossRef] [PubMed]
  76. Poesen, R.; Meijers, B.; Evenepoel, P. The colon: An overlooked site for therapeutics in dialysis patients. Semin. Dial. 2013, 26, 323–332. [Google Scholar] [CrossRef]
  77. Kortman, G.A.M.; Reijnders, D.; Swinkels, D.W. Oral iron supplementation: Potential implications for the gut microbiome and metabolome in patients with CKD. Hemodial. Int. 2017, 21, S28–S36. [Google Scholar] [CrossRef]
  78. Lau, W.L.; Vaziri, N.D.; Nunes, A.C.F.; Comeau, A.M.; Langille, M.G.I.; England, W.; Khazaeli, M.; Suematsu, Y.; Phan, J.; Whiteson, K. The phosphate binder ferric citrate alters the gut microbiome in rats with chronic kidney disease. J. Pharmacol. Exp. Ther. 2018, 367, 452–460. [Google Scholar] [CrossRef]
  79. Vangay, P.; Ward, T.; Gerber, J.S.; Knights, D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe 2015, 17, 553–564. [Google Scholar] [CrossRef]
  80. Gonçalves, S.; Pecoits-Filho, R.; Perreto, S.; Barberato, S.H.; Stinghen, A.E.; Lima, E.G.; Fuerbringer, R.; Sauthier, S.M.; Riella, M.C. Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol. Dial. Transplant. 2006, 21, 2788–2794. [Google Scholar] [CrossRef] [Green Version]
  81. Szeto, C.C.; Kwan, B.C.; Chow, K.M.; Lai, K.B.; Chung, K.Y.; Leung, C.B.; Li, P.K. Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clin. J. Am. Soc. Nephrol. 2008, 3, 431–436. [Google Scholar] [CrossRef] [PubMed]
  82. Raj, D.S.; Carrero, J.J.; Shah, V.O.; Qureshi, A.R.; Barany, P.; Heimburger, O.; Lindholm, B.; Ferguson, J.; Moseley, P.L.; Stenvinkel, P. Soluble CD14 levels, interleukin 6, and mortality among prevalent hemodialysis patients. Am. J. Kidney Dis. 2009, 54, 1072–1080. [Google Scholar] [CrossRef] [PubMed]
  83. Magnusson, M.; Magnusson, K.E.; Sundqvist, T.; Denneberg, T. Increased intestinal permeability to differently sized polyethylene glycols in uremic rats: Effects of low- and high-protein diets. Nephron 1990, 56, 306–311. [Google Scholar] [CrossRef] [PubMed]
  84. Magnusson, M.; Magnusson, K.E.; Sundqvist, T.; Denneberg, T. Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure. Gut 1991, 32, 754–759. [Google Scholar] [CrossRef] [PubMed]
  85. de Almeida Duarte, J.B.; de Aguilar-Nascimento, J.E.; Nascimento, M.; Nochi, R.J., Jr. Bacterial translocation in experimental uremia. Urol. Res. 2004, 32, 266–270. [Google Scholar] [CrossRef] [PubMed]
  86. Vaziri, N.D.; Dure-Smith, B.; Miller, R.; Mirahmadi, M.K. Pathology of gastrointestinal tract in chronic hemodialysis patients: An autopsy study of 78 cases. Am. J. Gastroenterol. 1985, 80, 608–611. [Google Scholar] [PubMed]
  87. Vaziri, N.D.; Yuan, J.; Nazertehrani, S.; Ni, Z.; Liu, S. Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction. Am. J. Nephrol. 2013, 38, 99–103. [Google Scholar] [CrossRef]
  88. Ritz, E. Intestinal-renal syndrome: Mirage or reality? Blood Purif. 2011, 31, 70–76. [Google Scholar] [CrossRef]
  89. Vaziri, N.D.; Goshtasbi, N.; Yuan, J.; Jellbauer, S.; Moradi, H.; Raffatellu, M.; Kalantar-Zadeh, K. Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium. Am. J. Nephrol. 2012, 36, 438–443. [Google Scholar] [CrossRef]
  90. Shi, K.; Wang, F.; Jiang, H.; Liu, H.; Wei, M.; Wang, Z.; Xie, L. Gut bacterial translocation may aggravate microinflammation in hemodialysis patients. Dig. Dis. Sci. 2014, 59, 2109–2117. [Google Scholar] [CrossRef]
  91. Bossola, M.; Sanguinetti, M.; Scribano, D.; Zuppi, C.; Giungi, S.; Luciani, G.; Torelli, R.; Posteraro, B.; Fadda, G.; Tazza, L. Circulating bacterial-derived DNA fragments and markers of inflammation in chronic hemodialysis patients. Clin. J. Am. Soc. Nephrol. 2009, 4, 379–385. [Google Scholar] [PubMed]
  92. Nusrat, A.; Turner, J.R.; Madara, J.L. Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: Nutrients, cytokines, and immune cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2000, 279, G851–G857. [Google Scholar] [CrossRef] [PubMed]
  93. Al-Sadi, R.; Boivin, M.; Ma, T. Mechanism of cytokine modulation of epithelial tight junction barrier. Front. Biosci. (Landmark Ed.) 2009, 14, 2765–2778. [Google Scholar] [CrossRef] [PubMed]
  94. Bruewer, M.; Samarin, S.; Nusrat, A. Inflammatory bowel disease and the apical junctional complex. Ann. N. Y. Acad. Sci. 2006, 1072, 242–252. [Google Scholar] [CrossRef]
  95. Shen, L.; Turner, J.R. Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: Tight junction dynamics exposed. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, G577–G582. [Google Scholar] [CrossRef] [PubMed]
  96. Lorentz, C.A.; Liang, Z.; Meng, M.; Chen, C.W.; Yoseph, B.P.; Breed, E.R.; Mittal, R.; Klingensmith, N.J.; Farris, A.B.; Burd, E.M.; et al. Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis. Mol. Med. 2017, 23, 155–165. [Google Scholar] [CrossRef] [PubMed]
  97. Cunningham, K.E.; Turner, J.R. Myosin light chain kinase: Pulling the strings of epithelial tight junction function. Ann. N. Y. Acad. Sci. 2012, 1258, 34–42. [Google Scholar] [CrossRef] [PubMed]
  98. Lau, W.L.; Savoj, J.; Nakata, M.B.; Vaziri, N.D. Altered microbiome in chronic kidney disease: Systemic effects of gut-derived uremic toxins. Clin. Sci. (Lond) 2018, 132, 509–522. [Google Scholar] [CrossRef]
  99. Jourde-Chiche, N.; Dou, L.; Cerini, C.; Dignat-George, F.; Vanholder, R.; Brunet, P. Protein-bound toxins--update 2009. Semin. Dial. 2009, 22, 334–339. [Google Scholar] [CrossRef]
  100. Martinez, A.W.; Recht, N.S.; Hostetter, T.H.; Meyer, T.W. Removal of P-cresol sulfate by hemodialysis. J. Am. Soc. Nephrol. 2005, 16, 3430–3436. [Google Scholar]
  101. Ufnal, M.; Zadlo, A.; Ostaszewski, R. TMAO: A small molecule of great expectations. Nutrition 2015, 31, 1317–1323. [Google Scholar] [PubMed]
  102. Zimmerman, L.; Jörnvall, H.; Bergström, J. Phenylacetylglutamine and hippuric acid in uremic and healthy subjects. Nephron 1990, 55, 265–271. [Google Scholar] [PubMed]
  103. Niwa, T.; Takeda, N.; Tatematsu, A.; Maeda, K. Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography. Clin. Chem. 1988, 34, 2264–2267. [Google Scholar] [PubMed]
  104. Vanholder, R.; De Smet, R.; Glorieux, G.; Argilés, A.; Baurmeister, U.; Brunet, P.; Clark, W.; Cohen, G.; De Deyn, P.P.; Deppisch, R.; et al. Review on uremic toxins: Classification, concentration, and interindividual variability. Kidney Int. 2003, 63, 1934–1943. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Liabeuf, S.; Barreto, D.V.; Barreto, F.C.; Meert, N.; Glorieux, G.; Schepers, E.; Temmar, M.; Choukroun, G.; Vanholder, R.; Massy, Z.A. European Uraemic Toxin Work Group (EUTox). Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol. Dial. Transplant. 2010, 25, 1183–1191. [Google Scholar] [PubMed]
  106. Barreto, F.C.; Barreto, D.V.; Liabeuf, S.; Meert, N.; Glorieux, G.; Temmar, M.; Choukroun, G.; Vanholder, R.; Massy, Z.A. European Uremic Toxin Work Group (EUTox). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 2009, 4, 1551–1558. [Google Scholar] [CrossRef]
  107. Wang, Z.; Klipfell, E.; Bennett, B.J.; Koeth, R.; Levison, B.S.; Dugar, B.; Feldstein, A.E.; Britt, E.B.; Fu, X.; Chung, Y.M.; et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011, 472, 57–63. [Google Scholar] [CrossRef] [Green Version]
  108. Prokopienko, A.J.; Nolin, T.D. Microbiota-derived uremic retention solutes: Perpetrators of altered nonrenal drug clearance in kidney disease. Expert Rev. Clin. Pharmacol. 2018, 11, 71–82. [Google Scholar] [CrossRef]
  109. Stubbs, J.R.; House, J.A.; Ocque, A.J.; Zhang, S.; Johnson, C.; Kimber, C.; Schmidt, K.; Gupta, A.; Wetmore, J.B.; Nolin, T.D.; et al. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J. Am. Soc. Nephrol. 2016, 27, 305–313. [Google Scholar] [CrossRef]
  110. Lekawanvijit, S.; Adrahtas, A.; Kelly, D.J.; Kompa, A.R.; Wang, B.H.; Krum, H. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur. Heart J. 2010, 31, 1771–1779. [Google Scholar] [CrossRef] [Green Version]
  111. Yisireyili, M.; Shimizu, H.; Saito, S.; Enomoto, A.; Nishijima, F.; Niwa, T. Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats. Life Sci. 2013, 92, 1180–1185. [Google Scholar] [CrossRef] [PubMed]
  112. Wing, M.R.; Patel, S.S.; Ramezani, A.; Raj, D.S. Gut microbiome in chronic kidney disease. Exp. Physiol. 2016, 101, 471–477. [Google Scholar] [CrossRef] [PubMed]
  113. Wang, X.H.; Mitch, W.E. Mechanisms of muscle wasting in chronic kidney disease. Nat. Rev. Nephrol. 2014, 10, 504–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Enoki, Y.; Watanabe, H.; Arake, R.; Sugimoto, R.; Imafuku, T.; Tominaga, Y.; Ishima, Y.; Kotani, S.; Nakajima, M.; Tanaka, M.; et al. Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci. Rep. 2016, 6, 32084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Sato, E.; Mori, T.; Mishima, E.; Suzuki, A.; Sugawara, S.; Kurasawa, N.; Saigusa, D.; Miura, D.; Morikawa-Ichinose, T.; Saito, R.; et al. Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease. Sci. Rep. 2016, 6, 36618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Sudo, N.; Chida, Y.; Aiba, Y.; Sonoda, J.; Oyama, N.; Yu, X.N.; Kubo, C.; Koga, Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 2004, 558, 263–275. [Google Scholar] [CrossRef] [Green Version]
  117. Mudd, A.T.; Berding, K.; Wang, M.; Donovan, S.M.; Dilger, R.N. Serum cortisol mediates the relationship between fecal Ruminococcus and brain N-acetylaspartate in the young pig. Gut Microb. 2017, 8, 589–600. [Google Scholar] [CrossRef]
  118. O’Mahony, S.M.; Clarke, G.; Borre, Y.E.; Dinan, T.G.; Cryan, J.F. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav. Brain Res. 2015, 277, 32–48. [Google Scholar] [CrossRef]
  119. Tan, J.; McKenzie, C.; Potamitis, M.; Thorburn, A.N.; Mackay, C.R.; Macia, L. The role of short-chain fatty acids in health and disease. Adv. Immunol. 2014, 121, 91–119. [Google Scholar]
  120. Arentsen, T.; Raith, H.; Qian, Y.; Forssberg, H.; Diaz Heijtz, R. Host microbiota modulates development of social preference in mice. Microb. Ecol. Health Dis. 2015, 26, 29719. [Google Scholar] [CrossRef]
  121. Neuman, H.; Debelius, J.W.; Knight, R.; Koren, O. Microbial endocrinology: The interplay between the microbiota and the endocrine system. FEMS Microbiol. Rev. 2015, 39, 509–521. [Google Scholar] [CrossRef] [PubMed]
  122. Kim, N.; Yun, M.; Oh, Y.J.; Choi, H.J. Mind-altering with the gut: Modulation of the gut-brain axis with probiotics. J. Microbiol. 2018, 56, 172–182. [Google Scholar] [CrossRef] [PubMed]
  123. Afsar, B.; Vaziri, N.D.; Aslan, G.; Tarim, K.; Kanbay, M. Gut hormones and gut microbiota: Implications for kidney function and hypertension. J. Am. Soc. Hypertens 2016, 10, 954–961. [Google Scholar] [CrossRef] [PubMed]
  124. Bravo, J.A.; Forsythe, P.; Chew, M.V.; Escaravage, E.; Savignac, H.M.; Dinan, T.G.; Bienenstock, J.; Cryan, J.F. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. USA 2011, 108, 16050–16055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Farzi, A.; Frohlich, E.E.; Holzer, P. Gut microbiota and the neuroendocrine system. Neurotherapeutics 2018, 15, 5–22. [Google Scholar] [CrossRef]
  126. Asao, T.; Oki, K.; Yoneda, M.; Tanaka, J.; Kohno, N. Hypothalamic-pituitary-adrenal axis activity is associated with the prevalence of chronic kidney disease in diabetic patients. Endocr. J. 2016, 63, 119–126. [Google Scholar] [CrossRef] [Green Version]
  127. de Punder, K.; Pruimboom, L. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. Front. Immunol. 2015, 6, 223. [Google Scholar] [CrossRef]
  128. Kelly, J.R.; Kennedy, P.J.; Cryan, J.F.; Dinan, T.G.; Clarke, G.; Hyland, N.P. Breaking down the barriers: The gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front. Cell Neurosci. 2015, 9, 392. [Google Scholar] [CrossRef]
  129. Larraufie, P.; Martin-Gallausiaux, C.; Lapaque, N.; Dore, J.; Gribble, F.M.; Reimann, F.; Blottiere, H.M. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 2018, 8, 74. [Google Scholar] [CrossRef] [Green Version]
  130. Shih, P.A.; Wang, L.; Chiron, S.; Wen, G.; Nievergelt, C.; Mahata, M.; Khandrika, S.; Rao, F.; Fung, M.M.; Mahata, S.K.; et al. Peptide YY (PYY) gene polymorphisms in the 3’-untranslated and proximal promoter regions regulate cellular gene expression and PYY secretion and metabolic syndrome traits in vivo. J. Clin. Endocrinol. Metab. 2009, 94, 4557–4566. [Google Scholar] [CrossRef]
  131. VanDeVoorde, R.G.; Mitsnefes, M.M. Hypertension and CKD. Adv. Chronic Kidney Dis. 2011, 18, 355–361. [Google Scholar] [CrossRef]
  132. Stenvinkel, P.; Zoccali, C.; Ikizler, T.A. Obesity in CKD--what should nephrologists know? J. Am. Soc. Nephrol. 2013, 24, 1727–1736. [Google Scholar] [CrossRef] [PubMed]
  133. Desbonnet, L.; Garrett, L.; Clarke, G.; Kiely, B.; Cryan, J.F.; Dinan, T.G. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010, 170, 1179–1188. [Google Scholar] [CrossRef]
  134. Yano, J.M.; Yu, K.; Donaldson, G.P.; Shastri, G.G.; Ann, P.; Ma, L.; Nagler, C.R.; Ismagilov, R.F.; Mazmanian, S.K.; Hsiao, E.Y. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015, 161, 264–276. [Google Scholar] [CrossRef] [PubMed]
  135. Gregg, L.P.; Hedayati, S.S. Management of traditional cardiovascular risk factors in CKD: What are the data? Am. J. Kidney Dis. 2018, 72, 728–744. [Google Scholar] [CrossRef] [PubMed]
  136. Jimenez, E.; Ladero, V.; Chico, I.; Maldonado-Barragan, A.; Lopez, M.; Martin, V.; Fernández, L.; Fernández, M.; Álvarez, M.A.; Torres, C.; et al. Antibiotic resistance, virulence determinants and production of biogenic amines among enterococci from ovine, feline, canine, porcine and human milk. BMC Microbiol. 2013, 13, 288. [Google Scholar] [CrossRef]
  137. Lyte, M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics. Bioessays 2011, 33, 574–581. [Google Scholar] [CrossRef]
  138. Shishov, V.A.; Kirovskaia, T.A.; Kudrin, V.S.; Oleskin, A.V. Amine neuromediators, their precursors, and oxidation products in the culture of Escherichia coli K-12. Prikl Biokhim Mikrobiol. 2009, 45, 550–554. [Google Scholar] [CrossRef]
  139. Camilleri, M. Serotonin in the gastrointestinal tract. Curr. Opin. Endocrinol. Diabetes Obes. 2009, 16, 53–59. [Google Scholar] [CrossRef]
  140. Lee, J.H.; Lee, J. Indole as an intercellular signal in microbial communities. FEMS Microbiol. Rev. 2010, 34, 426–444. [Google Scholar] [CrossRef] [Green Version]
  141. Li, G.; Young, K.D. Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan. Microbiology 2013, 159, 402–410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Raboni, S.; Bettati, S.; Mozzarelli, A. Tryptophan synthase: A mine for enzymologists. Cell Mol. Life Sci. 2009, 66, 2391–2403. [Google Scholar] [CrossRef] [PubMed]
  143. Yanofsky, C. RNA-based regulation of genes of tryptophan synthesis and degradation, in bacteria. RNA 2007, 13, 1141–1154. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Daneman, R.; Rescigno, M. The gut immune barrier and the blood-brain barrier: Are they so different? Immunity 2009, 31, 722–735. [Google Scholar] [CrossRef] [PubMed]
  145. Park, H.; Shin, H.; Lee, K.; Holzapfel, W. Autoinducer-2 properties of kimchi are associated with lactic acid bacteria involved in its fermentation. Int. J. Food Microbiol. 2016, 225, 38–42. [Google Scholar] [CrossRef] [PubMed]
  146. Karavolos, M.H.; Winzer, K.; Williams, P.; Khan, C.M. Pathogen espionage: Multiple bacterial adrenergic sensors eavesdrop on host communication systems. Mol. Microbiol. 2013, 87, 455–465. [Google Scholar] [CrossRef] [PubMed]
  147. Bellezza, I.; Peirce, M.J.; Minelli, A. Cyclic dipeptides: From bugs to brain. Trends Mol. Med. 2014, 20, 551–558. [Google Scholar] [CrossRef] [PubMed]
  148. Modaresi, A.; Nafar, M.; Sahraei, Z. Oxidative stress in chronic kidney disease. Iran. J. Kidney Dis. 2015, 9, 165–179. [Google Scholar] [PubMed]
  149. Marietta, E.; Horwath, I.; Taneja, V. Microbiome, immunomodulation, and the neuronal system. Neurotherapeutics 2018, 15, 23–30. [Google Scholar] [CrossRef] [PubMed]
  150. Bonaz, B.; Bazin, T.; Pellissier, S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front. Neurosci. 2018, 12, 49. [Google Scholar] [CrossRef]
  151. Raybould, H.E. Gut chemosensing: Interactions between gut endocrine cells and visceral afferents. Auton Neurosci. 2010, 153, 41–46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Tracey, K.J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Investig. 2007, 117, 289–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Edwards, J.K. Acute kidney injury: Vagus nerve stimulation may prevent AKI. Nat. Rev. Nephrol. 2016, 12, 376. [Google Scholar] [CrossRef] [PubMed]
  154. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur. Heart J. 1996, 17, 354–381. [Google Scholar]
  155. Bonaz, B.; Sinniger, V.; Pellissier, S. Vagal tone: Effects on sensitivity, motility, and inflammation. Neurogastroenterol. Motil. 2016, 28, 455–462. [Google Scholar] [CrossRef]
  156. Montemurno, E.; Cosola, C.; Dalfino, G.; Daidone, G.; De Angelis, M.; Gobbetti, M. What would you like to eat, Mr CKD microbiota? A mediterranean diet, please! Kidney Blood Press Res. 2014, 39, 114–123. [Google Scholar] [CrossRef] [PubMed]
  157. Mekki, K.; Bouzidi-bekada, N.; Kaddous, A.; Bouchenak, M. Mediterranean diet improves dyslipidemia and biomarkers in chronic renal failure patients. Food Funct. 2010, 1, 110–115. [Google Scholar] [CrossRef]
  158. Pignanelli, M.; Just, C.; Bogiatzi, C.; Dinculescu, V.; Gloor, G.B.; Allen-Vercoe, E.; Reid, G.; Urquhart, B.L.; Ruetz, K.N.; Velenosi, T.J.; et al. Mediterranean diet score: Associations with metabolic products of the intestinal microbiome, carotid plaque burden, and renal function. Nutrients 2018, 10, 779. [Google Scholar] [CrossRef]
  159. Lee, H.S.; Lee, K.B.; Hyun, Y.Y.; Chang, Y.; Ryu, S.; Choi, Y. DASH dietary pattern and chronic kidney disease in elderly Korean adults. Eur. J. Clin. Nutr. 2017, 71, 755–761. [Google Scholar] [CrossRef]
  160. Esgalhado, M.; Kemp, J.A.; Damasceno, N.R.; Fouque, D.; Mafra, D. Short-chain fatty acids: A link between prebiotics and microbiota in chronic kidney disease. Future Microbiol. 2017, 12, 1413–1425. [Google Scholar] [CrossRef]
  161. Salehi-Abargouei, A.; Ghiasvand, R.; Hariri, M. Prebiotics, prosynbiotics and synbiotics: Can they reduce plasma oxidative stress parameters? A systematic review. Probiotics Antimicrob Proteins 2017, 9, 1–11. [Google Scholar] [CrossRef] [PubMed]
  162. Valcheva, R.; Dieleman, L.A. Prebiotics: Definition and protective mechanisms. Best Pract. Res. Clin. Gastroenterol. 2016, 30, 27–37. [Google Scholar] [CrossRef] [PubMed]
  163. Slavin, J. Fiber and prebiotics: Mechanisms and health benefits. Nutrients 2013, 5, 1417–1435. [Google Scholar] [CrossRef] [PubMed]
  164. Kieffer, D.A.; Piccolo, B.D.; Vaziri, N.D.; Liu, S.; Lau, W.L.; Khazaeli, M.; Nazertehrani, S.; Moore, M.E.; Marco, M.L.; Martin, R.J.; Adams, S.H. Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats. Am. J. Physiol Renal Physiol. 2016, 310, F857–F871. [Google Scholar] [CrossRef] [PubMed]
  165. DiNicolantonio, J.J.; Bhutani, J.; O’Keefe, J.H. Acarbose: Safe and effective for lowering postprandial hyperglycaemia and improving cardiovascular outcomes. Open Heart 2015, 2, e000327. [Google Scholar] [CrossRef] [PubMed]
  166. Weaver, G.A.; Tangel, C.T.; Krause, J.A.; Parfitt, M.M.; Jenkins, P.L.; Rader, J.M.; Lewis, B.A.; Miller, T.L.; Wolin, M.J. Acarbose enhances human colonic butyrate production. J. Nutr. 1997, 127, 717–723. [Google Scholar] [CrossRef] [PubMed]
  167. Xu, G.D.; Cai, L.; Ni, Y.S.; Tian, S.Y.; Lu, Y.Q.; Wang, L.N.; Chen, L.L.; Ma, W.Y.; Deng, S.P. Comparisons of effects on intestinal short-chain fatty acid concentration after exposure of two glycosidase inhibitors in mice. Biol. Pharm. Bull. 2018, 41, 1024–1033. [Google Scholar] [CrossRef]
  168. Harrison, D.E.; Strong, R.; Allison, D.B.; Ames, B.N.; Astle, C.M.; Atamna, H.; Fernandez, E.; Flurkey, K.; Javors, M.A.; Nadon, N.L.; et al. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 2014, 13, 273–282. [Google Scholar] [CrossRef]
  169. Strong, R.; Miller, R.A.; Antebi, A.; Astle, C.M.; Bogue, M.; Denzel, M.S.; Fernandez, E.; Flurkey, K.; Hamilton, K.L.; Lamming, D.W.; et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 2016, 15, 872–884. [Google Scholar] [CrossRef] [Green Version]
  170. Zhang, X.; Fang, Z.; Zhang, C.; Xia, H.; Jie, Z.; Han, X.; Chen, Y.; Ji, L. Effects of acarbose on the gut microbiota of prediabetic patients: A randomized, double-blind, controlled crossover trial. Diabetes Ther. 2017, 8, 293–307. [Google Scholar] [CrossRef]
  171. Ranganathan, N.; Ranganathan, P.; Friedman, E.A.; Joseph, A.; Delano, B.; Goldfarb, D.S.; Tam, P.; Rao, A.V.; Anteyi, E.; Musso, C.G. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Adv. Ther. 2010, 27, 634–647. [Google Scholar] [CrossRef] [PubMed]
  172. Borges, N.A.; Carmo, F.L.; Stockler-Pinto, M.B.; de Brito, J.S.; Dolenga, C.J.; Ferreira, D.C.; Nakao, L.S.; Rosado, A.; Fouque, D.; Mafra, D. Probiotic supplementation in chronic kidney disease: A double-blind, randomized, placebo-controlled trial. J. Ren. Nutr. 2018, 28, 28–36. [Google Scholar] [CrossRef] [PubMed]
  173. Natarajan, R.; Pechenyak, B.; Vyas, U.; Ranganathan, P.; Weinberg, A.; Liang, P.; Mallappallil, MC.; Norin, A.J.; Friedman, E.A.; Saggi, S.J. Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients. Biomed. Res. Int. 2014, 2014, 568571. [Google Scholar] [CrossRef] [PubMed]
  174. Neef, A.; Sanz, Y. Future for probiotic science in functional food and dietary supplement development. Curr. Opin. Clin. Nutr. Metab. Care 2013, 16, 679–687. [Google Scholar] [CrossRef] [PubMed]
  175. El Hage, R.; Hernandez-Sanabria, E.; Van de Wiele, T. Emerging trends in “smart probiotics”: Functional consideration for the development of novel health and industrial applications. Front. Microbiol. 2017, 8, 1889. [Google Scholar] [CrossRef] [PubMed]
  176. Li, J.; Lin, S.; Vanhoutte, P.M.; Woo, C.W.; Xu, A. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in apoe-/-mice. Circulation 2016, 133, 2434–2446. [Google Scholar] [CrossRef]
  177. Troy, E.B.; Kasper, D.L. Beneficial effects of Bacteroides fragilis polysaccharides on the immune system. Front. Biosci. 2010, 15, 25–34. [Google Scholar] [CrossRef]
  178. Engels, C.; Ruscheweyh, H.J.; Beerenwinkel, N.; Lacroix, C.; Schwab, C. The common gut microbe eubacterium hallii also contributes to intestinal propionate formation. Front. Microbiol. 2016, 7, 713. [Google Scholar] [CrossRef]
  179. Cani, P.D.; Van Hul, M. Novel opportunities for next-generation probiotics targeting metabolic syndrome. Curr. Opin. Biotechnol. 2015, 32, 21–27. [Google Scholar] [CrossRef]
  180. Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331, 337–341. [Google Scholar] [CrossRef]
  181. Rossi, M.; Johnson, D.W.; Morrison, M.; Pascoe, E.M.; Coombes, J.S.; Forbes, J.M.; Szeto, C.C.; McWhinney, B.C.; Ungerer, J.P.; Campbell, K.L. Synbiotics easing renal failure by improving gut microbiology (synergy): A randomized trial. Clin. J. Am. Soc. Nephrol. 2016, 11, 223–231. [Google Scholar] [CrossRef] [PubMed]
  182. Nakabayashi, I.; Nakamura, M.; Kawakami, K.; Ohta, T.; Kato, I.; Uchida, K.; Yoshida, M. Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: A preliminary study. Nephrol. Dial. Transplant. 2011, 26, 1094–1098. [Google Scholar] [CrossRef] [PubMed]
  183. Andrade-Oliveira, V.; Amano, M.T.; Correa-Costa, M.; Castoldi, A.; Felizardo, R.J.; de Almeida, D.C.; Bassi, E.J.; Moraes-Vieira, P.M.; Hiyane, M.I.; Rodas, A.C.; Peron, J.P.; et al. Gut bacteria products prevent aki induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 2015, 26, 1877–1888. [Google Scholar] [CrossRef] [PubMed]
  184. Bliss, D.Z.; Stein, T.P.; Schleifer, C.R.; Settle, R.G. Supplementation with gum arabic fiber increases fecal nitrogen excretion and lowers serum urea nitrogen concentration in chronic renal failure patients consuming a low-protein diet. Am. J. Clin. Nutr. 1996, 63, 392–398. [Google Scholar] [CrossRef] [PubMed]
  185. Younes, H.; Egret, N.; Hadj-Abdelkader, M.; Remesy, C.; Demigne, C.; Gueret, C.; Deteix, P.; Alphonse, J.C. Fermentable carbohydrate supplementation alters nitrogen excretion in chronic renal failure. J. Ren. Nutr. 2006, 16, 67–74. [Google Scholar] [CrossRef] [PubMed]
  186. Sirich, T.L.; Plummer, N.S.; Gardner, C.D.; Hostetter, T.H.; Meyer, T.W. Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 2014, 9, 1603–1610. [Google Scholar] [CrossRef]
  187. Xie, L.M.; Ge, Y.Y.; Huang, X.; Zhang, Y.Q.; Li, J.X. Effects of fermentable dietary fiber supplementation on oxidative and inflammatory status in hemodialysis patients. Int. J. Clin. Exp. Med. 2015, 8, 1363–1369. [Google Scholar]
  188. Poesen, R.; Evenepoel, P.; de Loor, H.; Delcour, J.A.; Courtin, C.M.; Kuypers, D.; Augustijns, P.; Verbeke, K.; Meijers, B. The influence of prebiotic arabinoxylan oligosaccharides on microbiota derived uremic retention solutes in patients with chronic kidney disease: A randomized controlled trial. PLoS ONE 2016, 11, e0153893. [Google Scholar] [CrossRef]
  189. Ranganathan, N.; Patel, B.; Ranganathan, P.; Marczely, J.; Dheer, R.; Chordia, T.; Dunn, S.R.; Friedman, E.A. Probiotic amelioration of azotemia in 5/6th nephrectomized Sprague-Dawley rats. Sci. World J. 2005, 5, 652–660. [Google Scholar] [CrossRef]
  190. Ranganathan, N.; Patel, B.G.; Ranganathan, P.; Marczely, J.; Dheer, R.; Pechenyak, B.; Dunn, S.R.; Verstraete, W.; Decroos, K.; Mehta, R.; et al. In vitro and in vivo assessment of intraintestinal bacteriotherapy in chronic kidney disease. ASAIO J. 2006, 52, 70–79. [Google Scholar] [CrossRef]
  191. Prakash, S.; Chang, T.M. Microencapsulated genetically engineered live E. coli DH5 cells administered orally to maintain normal plasma urea level in uremic rats. Nat. Med. 1996, 2, 883–887. [Google Scholar] [CrossRef] [PubMed]
  192. Lippi, I.; Perondi, F.; Ceccherini, G.; Marchetti, V.; Guidi, G. Effects of probiotic VSL#3 on glomerular filtration rate in dogs affected by chronic kidney disease: A pilot study. Can. Vet. J. 2017, 58, 1301–1305. [Google Scholar] [PubMed]
  193. Ranganathan, N.; Friedman, E.A.; Tam, P.; Rao, V.; Ranganathan, P.; Dheer, R. Probiotic dietary supplementation in patients with stage 3 and 4 chronic kidney disease: A 6-month pilot scale trial in Canada. Curr. Med. Res. Opin. 2009, 25, 1919–1930. [Google Scholar] [CrossRef] [PubMed]
  194. Taki, K.; Takayama, F.; Niwa, T. Beneficial effects of Bifidobacteria in a gastroresistant seamless capsule on hyperhomocysteinemia in hemodialysis patients. J. Ren. Nutr. 2005, 15, 77–80. [Google Scholar] [CrossRef] [PubMed]
  195. Takayama, F.; Taki, K.; Niwa, T. Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis. Am. J. Kidney Dis. 2003, 41, S142–S145. [Google Scholar] [CrossRef] [PubMed]
  196. Ando, Y.; Miyata, Y.; Tanba, K.; Saito, O.; Muto, S.; Kurosu, M.; Homma, S.; Kusano, E.; Asano, Y. Effect of oral intake of an enteric capsule preparation containing Bifidobacterium longum on the progression of chronic renal failure. Nihon Jinzo Gakkai shi. 2003, 45, 759–764. [Google Scholar] [PubMed]
  197. Simenhoff, M.L.; Dunn, S.R.; Zollner, G.P.; Fitzpatrick, M.E.; Emery, S.M.; Sandine, W.E.; Ayres, J.W. Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus. Miner. Electrol. Metab. 1996, 22, 92–96. [Google Scholar]
  198. Wang, I.K.; Wu, Y.Y.; Yang, Y.F.; Ting, I.W.; Lin, C.C.; Yen, T.H.; Chen, J.H.; Wang, C.H.; Huang, C.C.; Lin, H.C. The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: A randomised, double-blind, placebo-controlled trial. Benef. Microb. 2015, 6, 423–430. [Google Scholar] [CrossRef] [PubMed]
  199. Miranda Alatriste, P.V.; Urbina Arronte, R.; Gomez Espinosa, C.O.; Espinosa Cuevas Mde, L. Effect of probiotics on human blood urea levels in patients with chronic renal failure. Nutr. Hosp. 2014, 29, 582–590. [Google Scholar] [PubMed]
  200. Tao, S.; Tao, S.; Cheng, Y.; Liu, J.; Ma, L.; Fu, P. Effects of probiotic supplements on the progression of chronic kidney disease: A meta-analysis. Nephrology 2018. [Google Scholar] [CrossRef] [PubMed]
  201. Jia, L.; Jia, Q.; Yang, J.; Jia, R.; Zhang, H. Efficacy of probiotics supplementation on chronic kidney disease: A systematic review and meta-analysis. Kidney Blood Press Res. 2018, 43, 1623–1635. [Google Scholar] [CrossRef] [PubMed]
  202. Dehghani, H.; Heidari, F.; Mozaffari-Khosravi, H.; Nouri-Majelan, N.; Dehghani, A. Synbiotic supplementations for azotemia in patients with chronic kidney disease: A randomized controlled trial. Iran. J. Kidney Dis. 2016, 10, 351–357. [Google Scholar] [PubMed]
  203. Pavan, M. Influence of prebiotic and probiotic supplementation on the progression of chronic kidney disease. Minerva Urol. Nefrol. 2016, 68, 222–226. [Google Scholar] [PubMed]
  204. Guida, B.; Germano, R.; Trio, R.; Russo, D.; Memoli, B.; Grumetto, L.; Barbato, F.; Cataldi, M. Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: A randomized clinical trial. Nutr. Metab. Cardiovasc. Dis. 2014, 24, 1043–1049. [Google Scholar] [CrossRef] [PubMed]
  205. McFarlane, C.; Ramos, C.I.; Johnson, D.W.; Campbell, K.L. Prebiotic, probiotic, and synbiotic supplementation in chronic kidney disease: A systematic review and meta-analysis. J. Ren. Nutr. 2018, 30191–30192, 1051–2276. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Metabolism of amino acids and carbohydrates by gut microbiota. Complex carbohydrates are converted to monosaccharides and oligosaccharides, and then fermented to hydrogen (H2), carbon dioxide (CO2), ethanol, and short-chain fatty acids (SCFAs). SCFAs serve as a major source of energy for colonocytes and regulatory T lymphocytes (Tregs), or are converted to acetyl coenzyme-A (Acetyl-CoA), H2, and CO2. The deamination and decarboxylation of amino acids leads to the formation of ammonia, SCFAs, phenolic compounds, nitrosamines and hydrogen sulfide (H2S).
Figure 1. Metabolism of amino acids and carbohydrates by gut microbiota. Complex carbohydrates are converted to monosaccharides and oligosaccharides, and then fermented to hydrogen (H2), carbon dioxide (CO2), ethanol, and short-chain fatty acids (SCFAs). SCFAs serve as a major source of energy for colonocytes and regulatory T lymphocytes (Tregs), or are converted to acetyl coenzyme-A (Acetyl-CoA), H2, and CO2. The deamination and decarboxylation of amino acids leads to the formation of ammonia, SCFAs, phenolic compounds, nitrosamines and hydrogen sulfide (H2S).
Diseases 07 00021 g001
Figure 2. The effect of gut dysbiosis on neuroendocrine pathways in chronic kidney disease. The altered gut microbiota can lead to the activation of the hypothalamic–pituitary–adrenal (HPA) axis; increased serotonin via changes in tryptophan metabolism; the production of neurotransmitters, neuroactive compounds, and quorum sensing peptides; and decreased vagus nerve stimulation via decreased the production of short-chain fatty acids (SCFAs). Ultimately, the HPA axis activation, chronic systemic inflammation, and alterations in sodium and blood pressure hemostasis promote CKD progression.
Figure 2. The effect of gut dysbiosis on neuroendocrine pathways in chronic kidney disease. The altered gut microbiota can lead to the activation of the hypothalamic–pituitary–adrenal (HPA) axis; increased serotonin via changes in tryptophan metabolism; the production of neurotransmitters, neuroactive compounds, and quorum sensing peptides; and decreased vagus nerve stimulation via decreased the production of short-chain fatty acids (SCFAs). Ultimately, the HPA axis activation, chronic systemic inflammation, and alterations in sodium and blood pressure hemostasis promote CKD progression.
Diseases 07 00021 g002
Table 1. Studies that examined prebiotics and/or probiotics in patients or animals with chronic kidney disease.
Table 1. Studies that examined prebiotics and/or probiotics in patients or animals with chronic kidney disease.
SpeciesDietary InterventionStudy TypeOutcomesReferences
MiceShort-chain fatty acids (acetate, propionate, and butyrate, pH 7.4 diluted in PBS)Pilot studyDelayed progression of chronic kidney disease.
Improved mitochondrial biogenesis.
Reduced local and systemic inflammation, cellular oxidative stress, cell infiltration/activation and apoptosis.
RatAmylose maize resistant starchOriginal research studyAttenuation of oxidative stress and inflammation.
Delayed progression of chronic kidney disease.
RatHigh amylose maize-resistant starch type 2 (HAMRS2)Original research studyReduction in serum and urine indoxyl sulfate levels.
Reduction in urine p-cresol level.
Improvements in kidney function indexes and amelioration of chronic kidney disease outcomes.
HumanGum arabic (highly fermentable fiber)Clinical trialSignificant decrease in serum urea nitrogen.
Significant increase in fecal bacterial mass and fecal nitrogen content.
HumanFermentable carbohydrateClinical trialSignificant increase in stool nitrogen excretion.
Significant decrease in the urinary nitrogen excretion.
Unchanged total nitrogen excreted by the two routes.
Significant decrease in plasma urea levels.
HumanResistant starchClinical trialSignificant reduction in plasma indoxyl sulfate.
Insignificant reduction in plasma p-cresyl sulfate.
HumanSoluble dietary fiberClinical trialSignificant decrease in total cholesterol (TC), low-density lipoprotein (LDL), and TC: LDL ratio.
Significant decrease in malondialdehyde, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and C-reactive protein levels.
No changes in triglycerides, high-density lipoprotein, Cu–Zn superoxide dismutase, and glutathione peroxidase levels.
HumanArabinoxylan oligosaccharides Clinical trialNo significant effect on serum p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate and phenylacetylglutamine.
Small, albeit significant decrease in serum trimethylamine N-oxide.
No change in the urinary excretion of p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate phenylacetylglutamine, and trimethylamine N-oxide.
No significant change in homeostatic model assessment.
No influence on microbiota-derived uremic retention solutes and insulin resistance.
Rat Various combinations of Bacillus pasteurii, Sporolac, Kibow cocktail, CHR Hansen Cocktail, and EconormPilot studyImproved survival.
Reduction in blood urea nitrogen levels.
Delayed progression of chronic kidney disease.
RatSoil-borne alkalophilic urease-positive bacterium Sporosarcina pasteuriiPilot studyReduced blood urea nitrogen levels.
Improved survival.
RatEscherichia coli DH5 given with urease Original research studyReduction of the high plasma urea level to normal[191]
DogVSL#3 supplementationOriginal research studySignificant increase in estimated glomerular filtration rate.[192]
HumanL. acidophilus, S. thermophilus and B. longumClinical trialSignificant reduction in blood urea nitrogen levels.
Improved quality-of-life scores.
HumanL. acidophilus, S. thermophilus, B. longumClinical trialSignificant reduction of blood urea nitrogen.
Moderate reduction in uric acid levels.
Insignificant changes in serum creatinine.
Improved quality of life scores.
HumanB. longumClinical trialSignificant decrease in predialysis serum levels of homocysteine, indoxyl sulfate, and triglycerides.[194]
HumanB. longumClinical trialReduction in serum indoxyl sulfate.[195]
HumanB. longumClinical trialDelayed progression of chronic kidney disease.[196]
HumanLebenin (antibiotic-resistant lactic acid bacteria)Clinical trialReduction in levels of uremic toxins (especially the plasma level of indican).[67]
HumanL. acidophilusClinical trialReduction of serum dimethylamine and nitrosodimethylamine.
Improved nutritional status.
HumanStreptococcus thermophilus, Lactobacillus acidophilus and Bifidobacteria longumClinical trialSignificant increase in serum urea nitrogen.
Reduction in fecal pH.
No effect on inflammatory markers and gut microbiome profile.
HumanBifobacterium bifidum, Bifidobacterium catenulatum, Bifidobacterium longum and Lactobacillus plantarumClinical trialSignificant reduction in serum TNF-α, IL-5, IL-6, and endotoxin.
Significant increase in serum IL-10 levels.
HumanS. thermophilus, L. acidophilus, and B. longumClinical trialNon-significant improvement in quality-of-life scores.
Non-significant reduction of serum indoxyl glucuronide and C-reactive protein.
HumanLactobacillus casei shirotaClinical trial>10% decrease in serum urea concentrations.[199]
HumanProbioticsMeta-analysisSignificant reduction in urea level in non-dialysis patients but no change in dialysis patients.
No effects on uric acid, C-reactive protein, creatinine, and estimated glomerular filtration rate.
HumanProbioticsMeta-analysisDecrease in p-cresyl sulfate.
Increase in IL-6.
No effects on serum creatinine, blood urine nitrogen, C-reactive protein and hemoglobin levels.
HumanPrebiotics; galactooligosaccharides
Probiotics: Lactobacillus casei strain Shirota and Bifidobacterium breve strain Yakult
Clinical trialSignificant decrease in serum p-cresol level.
Normalization of bowel habits.
HumanPrebiotics: inulin high performance, fructo-oligosaccharides, and galactooligosaccharides
Probiotics: Lactobacillus, Bifidobacteria, and Streptococcus species
Clinical trialSignificant decrease in serum p-cresyl sulfate.
Favorable modification of the stool microbiome.
HumanPrebiotics: Fructooligosaccharides
Probiotics: Lactobacilus casei, Lactobacilus acidophilus, Lactobacilus bulgarigus, Lactobacilus rhamnosus, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus thermophilus
Clinical trialSignificant reduction in blood urea nitrogen levels.[202]
HumanPrebiotics: Fructooligosaccharides
Probiotics: Streptococcus thermophiles, Lactobacillus acidophilus, Bifidobacterium longum
Clinical trialSignificant lowering of the rate of decline in estimated glomerular filtration rate.[203]
HumanCommercial symbiotic formulation: Probinul neutroClinical trialSignificant reduction in total plasma p-cresol level.[204]
HumanPrebiotic and ProbioticsMeta-analysisSynbiotic interventions significantly increased Bifidobacterium in gut microbiota, but had little or no effect on serum urea nitrogen, indoxyl sulfate, and p-cresyl sulfate.
Prebiotic supplementation may slightly reduce serum urea concentration.

Share and Cite

MDPI and ACS Style

Jazani, N.H.; Savoj, J.; Lustgarten, M.; Lau, W.L.; Vaziri, N.D. Impact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease. Diseases 2019, 7, 21.

AMA Style

Jazani NH, Savoj J, Lustgarten M, Lau WL, Vaziri ND. Impact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease. Diseases. 2019; 7(1):21.

Chicago/Turabian Style

Jazani, Nima H., Javad Savoj, Michael Lustgarten, Wei Ling Lau, and Nosratola D. Vaziri. 2019. "Impact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease" Diseases 7, no. 1: 21.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop