GUT MICROBIOTA IN CHRONIC KIDNEY DISEASE

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VOLUME 58 , ISSUE 3 (Oct 2019) > List of articles

GUT MICROBIOTA IN CHRONIC KIDNEY DISEASE

Magdalena Nalewajska / Jarosław Przybyciński / Małgorzata Marchelek-Myśliwiec / Violetta Dziedziejko * / Kazimierz Ciechanowski

Keywords : intestinal barrier, dysbiosis, gut microflora, microbiota, chronic kidney disease

Citation Information : Postępy Mikrobiologii - Advancements of Microbiology. Volume 58, Issue 3, Pages 237-245, DOI: https://doi.org/10.21307/PM-2019.58.3.237

License : (CC-BY-NC-ND 4.0)

Received Date : December-2018 / Accepted: May-2019 / Published Online: 05-October-2019

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ABSTRACT

In health, the relationship between gut microflora and the host is of a mutualistic kind. Microbiota offers many benefits to the host, including harvesting energy, regulating host immunity, and the synthesis of vitamins. Alteration in gut microflora can lead to homeostasis disruption and development of various diseases. Dysbiosis is commonly observed in chronic kidney disease (CKD). Nutrient processing by gut microbiota results in the production of some uremic toxins, and these accumulate in CKD causing deleterious effects. Increased permeability of the intestinal barrier, which is also seen in CKD contributes to the development of the uremic state. These factors are associated with chronic inflammation and oxidative stress and therefore are involved in CKD-related complications, including disease progression, cardiovascular disease, anemia, mineral-metabolism, and insulin resistance. This review describes connections between altered gut microflora and development of CKD and its complications, as well as possible therapeutic options.

1. Microbiota – short characteristic. 2. Mechanisms leading to alterations in gut microbiota and their effects on intestinal barrier permeability. 3. Causes of chronic kidney disease progression related to gut microbiota alterations. 4. Complications of chronic kidney disease related to gut microbiota alterations. 4.1. Cardiovascular disease. 4.2. Anemia. 4.3. Bone metabolism disorders. 4.4. Insulin resistance in CKD. 5. Therapeutic options. 6. Summary

Translated

Streszczenie: Mikrobiota jelitowa w prawidłowych warunkach pozostaje w symbiozie z organizmem gospodarza. Bakterie jelitowe odgrywają istotną rolę w fermentacji składników pokarmowych, stymulują układ odpornościowy i wytwarzają witaminy. Zaburzenie składu flory jelitowej może prowadzić do zaburzeń homeostazy ustroju i rozwoju wielu chorób. Zaburzenie składu mikrobioty jelitowej obserwowane jest m.in. u pacjentów z przewlekłą chorobą nerek (PChN). W wyniku rozkładu resztek pokarmowych powstają substancje toksyczne, które kumulują się u pacjentów z obniżoną filtracją kłębuszkową i wywołują szkodliwe dla organizmu działania. Zjawisko to nasila się dodatkowo w wyniku zwiększonej przepuszczalności bariery jelitowej, co obserwuje się w PChN. Nadmierna produkcja toksyn i zwiększone ich wchłanianie w jelicie prowadzą do nasilenia reakcji zapalnych i stresu oksydacyjnego, co skutkuje rozwojem powikłań PChN, takich jak: progresja choroby, choroby sercowo-naczyniowe, anemia, zaburzenia gospodarki wapniowo-fosforanowej i powikłania metaboliczne. W tej pracy przedstawiono związek zmienionej flory jelitowej z rozwojem przewlekłej choroby nerek i jej powikłań oraz potencjalne możliwości terapeutyczne.

1. Mikrobiota – krótka charakterystyka. 2. Mechanizmy doprowadzające do jakościowych i ilościowych zmian mikrobioty jelit w przewlekłej chorobie nerek i ich wpływ na strukturę bariery jelitowej. 3. Przyczyny progresji przewlekłej choroby nerek związane z zaburzeniem mikrobioty jelitowej. 4. Powikłania przewlekłej choroby nerek związane ze zmianą mikrobioty jelitowej. 4.1. Choroby sercowo-naczyniowe. 4.2. Anemia. 4.3. Zaburzenia metabolizmu kostnego. 4.4. Insulinooporność w przewlekłej chorobie nerek. 5. Możliwości terapeutyczne. 6. Podsumowanie

1. Microbiota – short characteristic

Microorganisms inhabiting the human organism are currently referred to as a microbiota (formerly – micro-flora) and the set of their genomes is called a micro-biome. It includes not only bacteria but also fungi, viruses and archaea. A microbiota colonizes, among others, the skin, the upper respiratory tract, the auditory meatus, the genital tract and the entire human gastrointestinal testinal tract. In the human gastrointestinal tract, there are 1014 microorganisms, which is equal to 10-fold number of eukaryotic cells in which microbial cells constitute 1.5–2 kg of human body weight. The greatest number and diversity of microorganisms occur in the large intestine [55]. Scientific research conducted in the last few years has shown that microorganisms have the ability to communicate (cross-talk) between each other and the host cells. The diverse network of connections and transmission of signals creates a complicated ecosystem which is also the basis for maintaining the state of the host’s metabolic and immune homeostasis.

The first contact with microorganisms takes place already in foetal life. The presence of the DNA of bacteria whose contact with the foetus stimulates its immune system [64] has been confirmed in the placenta. In the postnatal period, the composition of the microbiota is affected by: the mode of delivery (caesarean section vs. natural birth), diet, hygiene or the necessity of taking antibiotics. The full development of human intestinal microbiota is observed in adulthood [34].

The composition of intestinal microbiota varies between individuals, and homogeneous microbiota exists within small populations. The possibility of carrying out thorough genetic tests allowed for isolating and accurate characterisation of the so-called enterotypes, or permanent systems of intestinal microbiomes. Enterotypes are characteristic for a given host and differ in the type of dominant bacteria. Three enterotypes have been distinguished in humans: Bacteroides, Prevotella and Ruminococcus [3]. These include the following bacteria: Bacteroides, Prevotella, Ruminococcus, Faecalibacterium, Eubacterium, Lactobacillus, Clostridium, Dorea [44]. A given enterotype affects the composition of the entire intestinal flora by inhibiting or promoting the growth of other bacteria; it also specializes in the synthesis of specific compounds [54]. Bacteroides produces biotin, Prevotella – thiamine, and Ruminococcus specializes in the synthesis of heme [48]. Genomic diversity amongst enterotypes leads to variability in the functioning of metabolic pathways, including differences in obtaining energy from food [54]. It resulted in the creation of a hypothesis whereby knowledge of the enterotype of a given host will allow the selection of a personalized diet, as well as medications [10].

In healthy condition, the bacteria of intestinal flora remain in symbiosis with the host, which means the phenomenon of two different species coexisting, beneficial to both sides. In the intestine, there are conditions favouring growth of anaerobic bacteria which convert the non-absorbed carbohydrates supplied with food through the process of fermentation. The energy-yielding nutrients produced therefrom are later used by the host’s cells. Short-chain fatty acids (SCFA) are the most important of these products. The butyrate formed in the course of their biochemical transformation is the main energy substrate for enterocytes. Its appropriate concentration determines the correct metabolism of these cells, and thus the maintenance of the integrity of the intestinal barrier [11]. The intestinal barrier through the presence of tight junctions and the transmembrane transport system enables complex communication between the host and the intestinal microbiota, mainly in the immune system. Proteins that build tight junctions are primarily: the peripheral membrane protein ZO-1(zonula occludens – 1 ZO1) and the proteins connecting the membranes of neighbouring cells (transmembrane proteins) – occludin and claudin [58].

A change in the environment in which a microbiota exists: the presence of toxins, diet, antibiotic therapy, stress or medications taken cause the dominant bacteria and the compounds synthesized by them to change, which leads to damaging the intestinal barrier. This is the case, among others, in chronic kidney disease [2].

2. Mechanisms leading to alterations in gut microbiota and their effects on intestinal barrier permeability

Chronic kidney disease (CKD) is a condition with a complex aetiology. The most common causes of this disease are lifestyle diseases: diabetes and hypertension. Its development is also promoted by immunological and genetic diseases as well as congenital malformations. The severity of this disease is assessed, among others, by the decrease in glomerular filtration rate (GFR) and is divided into five stages. In stage I of CKD, glomerular filtration is not yet impaired but morphological changes in the kidneys may appear, e.g. urolithiasis, cysts. In stage II, GFR falls below 89 ml/min/1.73 m2, however it is higher than 60 ml/min/1.73 m2. Stage III is characterized by a further reduction in glomerular filtration and is between 59 and 30 ml/min/1.73 m2. Stage IV is GFR between 29–15 ml/min/1.73 m2, and the last stage is V, in which GFR falls below 15 ml/min/1.73 m2 [7].

The essence of CKD is not only the retention of uremic toxins, impaired production of erythropoietin, calcium-phosphate management disorders and lack of the active form of vitamin D, but also persistent inflammation. Its source is, among others, impaired integrity of the intestinal barrier, which occurs in uraemia [48]. In this situation, the pro-inflammatory molecules and bacterial toxins leak from the gastrointestinal tract into the bloodstream of the host. What is most often listed in this case is bacterial lipopolysaccharides (LPS), integral components of the outer membrane of Gram-negative bacteria and cyanobacteria, which play a key role in bacteria life processes, but also constitute their main pathogenic factor [5]. The presence of the fragments and metabolites of bacteria outside the intestinal lumen induces and sustains an inflammatory response. This pathomechanism is also superimposed by: a decreased clearance of cytokine, intravenous iron administration in patients undergoing dialysis and finally the haemodialysis procedure itself (use of filtration membranes, dialysis fluids) [7]. As previously mentioned, in the case of CKD, there is an accumulation of a number of uremic toxins, including urea and uric acid. It has been observed that their presence in the gastrointestinal tract lumen results in both quantitative and qualitative changes in the intestinal microbiota. Their excessive concentration makes them become alternative metabolic substrates for bacteria. The bacteria possessing urease, uricase and p-cresol-forming enzymes (Alteromondacea, Cellulomondacea, Clostridiacea, Dermabacteracea, Enterobacteriacea, Halomonadacea, Methylocaccaceae, Micrococcaceae, Moraxellaceae, Polyangiaceae, Pseudomonadaceace and Xanthomonadaceae) are beginning to dominate. On the other hand, those that metabolize non-absorbable carbohydrates (Bifidobacterium and Lactobacillus) [11, 62] are dying. Urease breaks down urea into ammonia. The increase in the synthesis of ammonia contributes to the increase of pH, and thus leads to damage to tight junctions in the intestinal epithelial cells and the destruction of the intestinal barrier [59]. In a study carried out by Vaziri et al., it was proved that the metabolic changes result in the impairment of function and the destruction of proteins by – and the intramembranes forming part of tight junctions – ZO1 protein, claudin and occluding [59].

Other, coexisting factors that adversely affect the integrity of the intestinal barrier include: swelling of the intestinal wall which occurs in CKD, excessive use of diuretics, aggressive ultrafiltration during haemodialysis, gastrointestinal bleeding, infiltration of the intestinal epithelial lamina propria by lymphocytes [17, 19, 33, 37]. Uremic toxins inhibit activity and reduce the number of transmembrane transporters, which is very important from the clinical point of view, because it may lead to changes in the pharmacokinetics of certain drugs and impair their metabolism in CKD patients [31].

The type of diet and eating habits in this group of patients should be mentioned as well. They have a huge impact on the content of the intestinal flora. Often this disease is accompanied by a lack of appetite, nausea and reluctance to accept certain foods [6]. Patients with CKD should control the amount of fluid intake and also limit the consumption of proteins and products rich in phosphorus and potassium to prevent hyperphosphatemia and hyperkalaemia. Unfortunately, this also involves limiting the consumption of vegetables and fruit. This is not beneficial because it has been proved that a diet rich in fibre and low in red meat, sodium and simple sugars increases the survival rate of patients with CKD [23, 24].

3. Causes of chronic kidney disease progression related to gut microbiota alterations

When glomerular filtration rate (GFR) decreases, adverse metabolic processes are accelerated. Indoxyl sulphate (IS) is the final product of the degradation of tryptophan in indol pathway. The first stage of this pathway is initiated by tryptophanase – an enzyme synthesized by Escherichia coli bacterium which is part of the intestinal flora. As a result of this process indole is formed, which is absorbed into the bloodstream through the intestinal barrier and undergoes sulfonation in the liver. Under the right conditions, IS is excreted from the organism with urine [37]. IS concentrations observed in patients with CKD with impaired renal filtration function are higher than in healthy subjects – basing on research conducted the relationship between IS concentration and the progression of kidney disease and the development of vascular complications has been demonstrated [28]. With the use of the established cell lines and animal models, the negative influence of IS on the proximal cells of the renal tubules causing their progressive damage has been proved. Interstitial fibrosis and glomerulosclerosis have also been observed [37]. A study conducted by Leong et al. confirmed that in patients with CKD in stages I–IV the risk of the progression of kidney disease associated with high levels of IS is increased [28].

Trimethylamine N-oxide (TMAO) is also included in the group of uremic toxins. It originates from choline, phosphatidylcholine and L-carnitine, supplied with food, with the participation of intestinal bacteria [8]. In the study conducted by Hoyles et al., it was observed that Enterobacteriacea metabolizes TMAO trimethylamine oxide most effectively [20]. High concentrations of TMAO are associated with an increased risk of the development and progression of kidney disease, which was confirmed, among others, in the Framingham Heart Study with the participation of 1,500 participants [46]. In turn, in studies conducted on mice, the influence of TMAO on the development of tubulointerstitial fibrosis and increased collagen deposition in the kidneys has been demonstrated [8].

4. Complications of chronic kidney disease related to gut microbiota alterations

4.1. Cardiovascular disease

Cardiovascular diseases (CVD) are one of the major causes of mortality among CKD patients. A relationship between high levels of uremic toxins in the blood serum of patients with CKD and the risk of CVD occurrence has been demonstrated [60]. P-cresol sulphate (PCS) is a product of the metabolism of tyrosine and phenylalanine and, apart from indoxyl sulphate (IS) described above, it is the main compound affecting the occurrence of CVD in patients with CKD [30]. In the meta-analysis, a positive correlation has been found between IS and PCS concentration and mortality among CKD patients; high concentration of PCS, but not IS was associated with an increased risk of CVD in the CKD group [30]. In the work previously published by Sato et al., plasmatic IS concentrations were determined in patients with coronary artery disease and decreased glomerular filtration rate (GFR). With the use of echocardiography, it was confirmed that in patients with higher IS concentrations, left ventricular diastolic dysfunction was greater than in patients with lower concentrations [50]. In other studies, IS was associated with an increased risk of coronary calcification and restenosis after coronary stent implantation [21, 56]. In 2018, Claro et al. demonstrated that IS and PCS are independent prognostic factors for total mortality among CKD patients. The results of the study confirmed the key role of uremic toxins in the pathogenesis of CVD in the mechanism of inflammatory reaction in patients with impaired renal function [9]. Trimethylamine N-oxide (TMAO), in turn, influences the development of atherosclerosis by accumulation of cholesterol in macrophages. High levels of TMAO in plasma are associated with an increased risk of significant cardiovascular events, regardless of the typical CVD risk factors [60].

4.2. Anemia

Indoxyl sulphate interferes with the synthesis of erythropoietin and intensifies erythropoietin (programmed red blood cell death), leading to the decrease in haemoglobin concentration in patients with CKD [1, 38].

4.3. Bone metabolism disorders

CKD is associated with renal osteodystrophy. It has a complex aetiology, but its source is primarily secondary hyperparathyroidism and deficiency of the active form of vitamin D (1.25 (OH)2D3). Recent studies have indicated the negative effect of uremic toxins, which are subject to changes under the influence of altered intestinal microbiota, on metabolic changes taking place in bone tissue in this group of patients. In vitro studies have shown that the indoxyl sulphate (IS) mentioned above inhibits stem cell differentiation towards osteoblasts, osteoblast proliferation and alkaline phosphatase (ALP) activity [15]. The exact mechanism of action of IS in this case is not known, but there are indications that it is related to the production of free radicals and oxidative stress [15]. Another problem in people with CKD is parathyroid hormone (PTH) impairment. The concentration of PTH increases with the decrease of GFR and is an expression of the organism’s defence against the decrease in calcium concentration. Can the change in the composition of a microbiota be one of the mechanisms which impair the response of bone tissue cells to the action of PTH? Indoxyl sulphate appears to reduce the production of PTH-dependent intracellular cAMP and reduce the expression of the PTH receptor gene in osteoblasts [15]. It also inhibits the differentiation of osteoclasts and reduces bone resorption [61]. The results of in vivo studies coincide with the results of preclinical studies. In a cross-sectional study, in which 47 dialysed patients participated, it was found that the concentration of indoxyl sulphate showed a negative correlation with bone markers – ALP and ALP bone fraction [18]. It is currently believed that, among others, IS may contribute to the development of adynamic bone disease in CKD patients, i.e. a form of renal osteodystrophy where bone turnover is reduced. One of the features is the inadequate low PTH concentration in relation to the decreased GFR [15]. Other uremic toxins associated with a microbial metabolism disorder which have an impact on bone metabolism are p-cresol sulphate (PCS) and nitric oxide synthetase inhibitor (ADMA) [15]. In vitro studies have shown the association of high PCS concentrations, both with aberrant osteoblast differentiation and proliferation, decrease in their survival rate, a PTH-dependent cAMP mediated transmission disorder and a reduction in PTH receptor expression. ADMA inhibits the differentiation of osteoblasts [15].

4.4. Insulin resistance in CKD

In 1980, in the work of DeFronzo et al., insulin resistance (IR) was proved to occur in patients with CKD [12]. The phenomenon of insulin resistance in patients with CKD appears already in the early stages of the disease and progresses with the decrease in glomerular filtration [53]. IR is an important, negative phenomenon in CKD as it is associated with an increased risk of developing cardiovascular diseases. The pathogenesis of IR in CKD is multifactorial. The importance of reduced physical activity, chronic inflammation, oxidative stress, vitamin D deficiency, development of metabolic acidosis, and CKD anaemia in the development of IR has been proved [52, 53]. The changed composition of intestinal microbiota is another link in the emergence of insulin resistance [26]. In 2004, Backhed et al. demonstrated that the transplantation of the microbiota from the intestinal gut of overweight mice to conventionally grown GF (germfree) mice, resulted in a significant increase in adipose tissue content and insulin resistance just within the first 14 days of observation, despite the reduction of intake food [4]. It has also been proved that in comparison to mice without obesity, overweight mice are observed to have a 50% reduction in Bacteroides and a proportional increase in the abundance of Firmicutes. The change of intestinal microbiota in obese animals has an impact on greater use of energy from food than is the case of lean individuals [29, 57]. Metabolic toxins produced by the microbiota and accumulated in the bodies of CKD patients may also contribute to the development of IR [26]. In the studies by McCaleb et al., rat adipocytes were isolated and incubated with serum from CKD, obese, and type 2 diabetics respectively – adipocytes exhibited reduced glucose uptake in CKD patients, which was not observed in patients with diabetes or obesity [32]. Thus, the existence of uremic-specific molecules, which exhibit insulin-resistant activity, was suggested. In another study, a decrease in plasma glucose concentration and insulin requirement was observed in patients with CKD after reduction of protein intake with food, confirming the key role of end products of intestinal protein degradation in the development of insulin resistance [47] . Among these compounds, p-cresol sulphate (PCS) seems to be the most important. Chronic administration of PCS to mice with normal renal function was associated with the development of insulin resistance and ectopic redistribution of fat cells [27]. Importantly, after administration of the compound, PCS concentration was comparable to that occurring in patients with end-stage kidney disease. Ectopic redistribution of lipids in skeletal muscle, liver, myocardium (lipid overload theory) is responsible for disturbed phosphorylation of the IRS-1 receptor substrate in tyrosine residues, blocking the intracellular signalling pathway and thus causing insulin resistance [40].

5. Therapeutic options

In recent years, the significant impact of the microbiome on human health has been recognized. This led to the flourishing of research into the therapeutic possibilities of diseases through exerting an impact on bacterial flora. This also applies to chronic kidney disease. The use of prebiotics, probiotics, and synbiotics is one of the proven methods of therapeutic interventions in the case of symbiosis disorders. Prebiotics are specific nutrients, containing demainly fibre, oligosaccharides, such as inulin. They promote the growth of beneficial intestinal bacteria and by changing the pH, they affect the intestinal barrier status and also increase the activity of intestinal hormones such as GLP-1 (glucagon-like peptide-1). Probiotics are selected strains of microorganisms, able to survive in the human body and exert a beneficial effect on health. They must be characterised by the ability to adhere to the intestinal epithelium so that they are not removed from them in a short time (e.g. during diarrhoea). In addition, they must be resistant to hydrochloric acid contained in the stomach, digestive enzymes, bile acids. The preparation combining probiotics and prebiotics is called a synbiotic [48, 51]. Probiotics may be of natural origin, e.g. fermented products – mainly dairy products, such as yogurt or kefir, pickled products, or commercially produced preparations taken orally [16]. Although they have been used for many years and are generally considered safe, they may also have pathogenic significance. Cases of generalized infections caused by various probiotic strains have been reported. Most cases were associated with Saccharomyces boulardi and cerevisae fungemia. However, bacterial infections caused by Lactobacillus, Bacillus subtilis, and Bifidobacterium breve strains have also been found. In the literature one can also find descriptions of endocarditis caused by probiotic Streptococcus strains. Some of these cases may have been the result of the transfer of bacteria to the area of intravenous puncture through the hands of the staff, who previously administered probiotics. Another negative aspect may be altered metabolism in the intestinal lumen. Administration of a probiotic increases the intestinal epithelial oxygen requirement or increases the formation of lactate, which can lead to dangerous complications. Moreover, in theory, probiotics may overstimulate the intestinal immune system or spread antibiotic-resistant genes among other intestinal bacteria. As of now, these fears have not been justified [13]. To date, numerous studies have been carried out using a variety of bacterial strains, mainly of the genera Lactobacillus, Streptococcus and Bifidobacterium and prebiotics [48]. The action of probiotics is complex and specific to individual bacterial strains. It consists, among others, in sealing barrier joints, increasing mucin production, and protecting enterocytes from apoptosis. In addition to the intestinal barrier protective effect, they have an antagonistic effect on the pathogenic intestinal flora by secreting bacteriocins and competition in occupying intestinal niches. The stimulating effect on immunity and the formation of regulatory lymphocytes is also important[25]. A significant reduction in the levels of harmful metabolites, such as cresol compounds, indoxyl sulphate, or urea nitrogen (BUN, blood urea nitrogen), has been obtained in studies. In one of the studies, an increase in glomerular filtration was observed after prebiotics were applied. The examined patients with chronic kidney disease first consumed 1.6 g of fibre per day for 2 weeks. Then the dietary fibre supply was increased to 23 g per day for 4 weeks. The disadvantage of this study was the small number of participants – 13 people, although a statistically significant decrease in creatinine was obtained, persisting for at least up to 4 weeks after the end of the nutritional intervention [49]. These effects are achieved mainly by creating a suitable environment for the growth of sucrose bacteria at the expense of proteolytic substances, increased absorption of nitrogen compounds by the intestinal flora, lower production of harmful metabolites, and their excretion with stool. An appropriate diet increases the production of short-chain fatty acids, possessing the capacity for “sealing” the intestine [48]. Fatty acids also have a direct metabolic and immunomodulatory effect by directly impacting the FFAR1, FFAR2, and FFAR3 receptors. In this way, they increase leptin levels, stimulate the activity of regulatory lymphocytes, and reduce the amount of reactive forms of oxygen [14]. Other potentially beneficial effects of prebiotics depend on the activation of glucagon-like peptide-1 (GLP-1), the YY peptide (PYY-anorexigenic neuropeptide), and other intestinal hormones. They consist in lowering body weight, improving lipid metabolism, and reducing insulin resistance [51]. However, a study conducted in the population of peritoneal dialysis patients proved a lower level of proinflammatory cytokines and endotoxin after a 6-month period of consuming probiotics from the strains of Bifidobacterium and Lactobacillus [39]. The analysis of the NHANES cohort indicates a lower severity of albuminuria in people consuming probiotics and yogurt, at least 3 times a week. Unfortunately, in the study based on completing nutrition questionnaires, no specific type of probiotics was indicated [39, 63]. In studies on rats, it has been proved to slow down the progression of kidney disease, and even to prolong the survival after the use of probiotics of the strains of Bacilluspasteurii or Lactobacillus sporogenes [39, 51].

There are also numerous observational and interventional studies on humans and animals, proving the benefits of taking an increased amount of fibre. It may have both the form of oligosaccharides or resistant starch. A large observational study on a population of approximately 14,000 confirmed the reduction of the signs of inflammation and overall mortality along with an increase in fibre intake [36, 45]. On the other hand, the results of some studies do not confirm the benefits of using fibre in CKD. In a randomized, double-blind study involving 40 patients with CKD in stage III–IV, the therapeutic effect of arabinoxylan administered over 4 weeks was not proved [42]. Arabinoxylan is a compound derived from the walls of plant cells, mainly cereal products, being a polymer of arabinose and xylose.

Currently, the most promising results are obtained through the use of synbiotics. Studies using different bacterial strains combined with inulin and other probiotics have led to a decrease in the concentration of toxic metabolites, mainly p-cresol sulphate, inflammatory parameters, and even a slowdown in CKD progression. The research was conducted on various groups of patients, both dialyzed and remaining in the third and fourth stage of CKD. After the application of the strains of Lactobacillus acidophilus, a decrease in the serum concentration of dimethylamine was obtained, whereas after the administration of Bifidobacterium longum – a decrease in the serum concentration of indoxyl sulphate, homocysteine, and triacylglycerols. The disadvantage of these studies is the relatively small number of examined groups (up to 40 people) and they require confirmation in a larger population [39]. A recently published meta-analysis of randomized trials using probiotics in patients with stage III–V CKD indicates a reduction in p-cresol sulphate and an increase in the concentration of interleukin-6. The use of probiotic did not have a significant statistical effect on the concentration of creatinine, nitrogen in urea, and other toxins, or on the concentration of haemoglobin and C-reactive protein (CRP). The meta-analysis was based on eight studies, covering a total of 261 patients. Patients received eight different probiotic preparations at different doses. Among the administered bacterial strains, there were: Lactobacillus: acidophilus, gasseri, bulgaricus, plantarum, casei, salivarius, sporogenes, Bifidobacterium: bifidum, longum, infantis, breve, and Streptococcus thermophilus [22].

An interesting possibility for treating microbiota disorders is the modification of the bacterial genome used in the form of probiotics in order to adjust their metabolism to give the greatest benefits to CKD patients. In theory, it is possible to deliver bacteria with a modified genome to the gastrointestinal tract of patients, equipped with enzymes breaking down uremic toxins. Currently, there are no practical tests assessing such possibilities [39, 41, 51].

Other potential possibilities of exerting influence include the use of antibiotics which kill abnormal intestinal flora or inhibitors of fermentation of undigested carbohydrates, such as acarbose, which leads to the inhibition of the digestion of polysaccharides by intestinal cells, providing an energy substrate for intestinal bacteria [48]. The use of rifaximin, a broad-spectrum bactericidal antibiotic, has a proven effect of reducing the production of trimethylamine oxide by removing intestinal bacteria. More specific effects can be obtained by blocking bacterial enzymes such as TMA – lyase and tryptophanase, to prevent the production of toxins without a bactericidal effect. So far, however, there has been a lack of studies proving the safety and efficacy of such procedure in humans [43]. Lubiprostone, a CIC-2 chloride channel activator used in the treatment of constipation, may also contribute to restoring the intestinal microbial balance by multiplying bacteria of the genus Lactobacillus and Prevotella [39].

Yet another approach is proposed which does not directly affect the intestinal microbiota, but rather counteracts the negative effects of uremic toxin formation. It involves the use of substances which bind harmful metabolites in the digestive tract. Studies have been carried out using a carbon compound called AST-120 with respect to the activity of sevelamer hydrochloride. A reduction in the concentration of indoxyl sulphate in the blood was observed; moreover, administration of AST-120 to patients with ESRD during the pre-dialysis period led to a reduction in overall mortality in this group of patients [48].

Among the new potential therapies impacting the intestinal microbiome there is also canagliflozin. This antidiabetic medication, in addition to blocking SGLT-2 glucose transporters in the renal tubules, also has a weak inhibitory effect on SGD-1, sodium-dependent glucose transporters and SGLT-1 galactose found in the intestines. A study on mice with renal failure indicates that canagliflozin inhibits the absorption of carbohydrates in the initial section of the small intestine, leading to their greater concentration in the final section of the small intestine and large intestine. This affects the development of potentially beneficial bacteria, e.g. of the genus Bifidobacterium. The production of short-chain fatty acids is increased and the formation of p-cresol sulphate and, to a lesser extent, indoxyl sulphate is clearly reduced. This opens up new possibilities and the need for research on SGLT-1 inhibitors as a drug restoring intestinal eubiotism [35].

6. Summary

In recent years, there has been a growing interest in intestinal microbiota in the context of its impact on human health. Thanks to the development of bioinformatics and progress in the field of DNA sequencing techniques, the relationship between altered intestinal microbiota and the occurrence of many diseases, including chronic kidney disease, has been proved. Altered intestinal flora stimulates the production of metabolic toxins and increases their absorption in the intestine, which in turn leads to the progression of kidney disease and the development of its complications. It is believed that restoring the normal intestinal flora in these patients can slow down the disease and reduce the risk of complications. The results of preclinical studies on potential therapeutic options are promising, however, there is still a need for clinical trials in large populations to establish unambiguous treatment strategies in patients with chronic kidney disease. Perhaps in the future, modifying the composition of the intestinal flora will allow better treatment and control of kidney diseases.

Acknowledgments

The article was translated by EURO-ALPHABET from Polish into English under agreement 659 / P-DUN / 2018 and funded by the Ministry of Science and Higher Education.

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  8. Castillo-Rodriguez E., Sanchez-Niño M.D. et al.: Impact of altered intestinal microbiota on chronic kidney disease progression. Toxins, 10, doi: 10.3390/toxins10070300 (2018)
    [CROSSREF]
  9. Claro L.M., Pécoits-Filho R. et al.: The impact of uremic toxicity induced inflammatory response on the cardiovascular burden in chronic kidney disease. Toxins, 10, doi: 10.3390/toxins10100384 (2018)
    [CROSSREF]
  10. Costea P.I., Bork P. et al.: Enterotypes in the landscape of gut microbial community composition. Nat. Microbiol. 3, 8–16 (2018)
    [PUBMED] [CROSSREF]
  11. Cummings J.H., Macfarlane G.T.: Collaborative JPEN-Clinical Nutrition Scientific Publications Role of intestinal bacteria in nutrient metabolism. JPEN-Parenter Enter. 21, 357–365 (1997)
    [CROSSREF]
  12. DeFronzo R.A., Alvestrand A., Smith D., Hendler R., Hendler E., Wahren J.: Insulin resistance in uremia. J. Clin. Invest. 67, 563–568 (1981)
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  13. Doron S., Snydman D.R.: Risk and Safety of Probiotics. Clin. Infect. Dis. 60, 129–34 (2015)
    [CROSSREF]
  14. 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. 12, 1413–1425 (2017)
    [CROSSREF]
  15. Fujii H., Goto S., Fukagawa M.: Role of uremic toxins for kidney, cardiovascular, and bone dysfunction. Toxins, 10, doi: 10.3390/toxins10050202 (2018)
    [CROSSREF]
  16. George Kerry R., Patra J.K., Gouda S., Park Y., Shin H.S., Das G.: Benefaction of probiotics for human health: A review. J. Food Drug. Anal. 26, 927–939 (2018)
    [CROSSREF]
  17. Gerson L.B.: Causes of gastrointestinal hemorrhage in patients with chronic renal failure. Gastroenterology 145, 895–897 (2013)
    [CROSSREF]
  18. Goto S., Fujii H., Hamada Y., Yoshiya K., Fukagawa M.: Association Between Indoxyl Sulfate and Skeletal Resistance in Hemodialysis Patients. Ther. Apher. Dial. 14, 417–423 (2010)
    [CROSSREF]
  19. Cigarran Guldris S., Gonzalez Parra E., Cases Amenós A.: Gut microbiota in chronic kidney disease. Nefrología (English Edition) 37, 9–19 (2017)
    [CROSSREF]
  20. Hoyles L., Dumas M.E. et al.: Metabolic retroconversion of tri-methylamine N-oxide and the gut microbiota. Microbiome 6, 73 (2018)
    [CROSSREF]
  21. Hsu C.C., Lu Y.C., Chiu C.A., Yu T.H., Hung W.C., Wang C.P., Lu L.F., Chung F.M., Lee Y.J., Tsai I.T: Levels of indoxyl sulfate are associated with severity of coronary atherosclerosis. Clin. Invest. Med. 36, E42–49 (2013)
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  22. 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 43,1623–1635 (2018)
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  23. Kelly J.T., Palmer S.C., Wai S.N., Ruospo M., Carrero J.J., Campbell K.L., Strippoli G.F.M.: Healthy dietary patterns and risk of mortality and ESRD in CKD: A meta-analysis of cohort studies. Clin. J. Am. Soc. Nephrol. 12, 272–279 (2017)
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  24. Koppe L., Fouque D., Soulage C.O.: The role of gut microbiota and diet on uremic retention solutes production in the context of chronic kidney disease. Toxins, 10, doi: 10.3390/toxins10040155 (2018)
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  25. Koppe L., Mafra D., Fouque D.: Probiotics and chronic kidney disease. Kidney Int. 88, 958–966 (2015)
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  26. Koppe L., Pelletier C.C., Alix P.M., Kalbacher E., Fouque D., Soulage C.O., Guebre-Egziabher F.: Insulin resistance in chronic kidney disease: new lessons from experimental models. Nephrol. Dial. Transplant 29, 1666–1674 (2014)
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  27. Koppe L., Soulage C.O. et al.: p-Cresyl sulfate promotes insulin resistance associated with CKD. J. Am. Soc. Nephrol. 24, 88–99 (2013)
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  28. Leong S.C., Sirich T.L.: Indoxyl Sulfate-review of toxicity and therapeutic strategies. Toxins 8, E358 (2016)
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  30. Lin C.J., Wu V., Wu P.C., Wu, C.J.: Meta-Analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS One 10, e0132589 (2015)
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  31. Liu B., Luo F., Luo X., Duan S., Gong Z., Peng J.: Metabolic enzyme system and transport pathways in chronic kidney diseases. Curr. Drug. Metab. 19, 568–576 (2018)
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  32. McCaleb M.L., Izzo M.S., Lockwood D.H.: Characterization and partial purification of a factor from uremic human serum that induces insulin resistance. J. Clin. Invest. 75, 391–396 (1985)
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  33. Meijers B., Farré R., Dejongh S., Vicario M., Evenepoel P.: Intestinal barrier function in chronic kidney disease. Toxins, 10, doi: 10.3390/toxins10070298 (2018)
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  36. Moraes C., Borges N.A., Mafra D.: Resistant starch for modulation of gut microbiota: Promising adjuvant therapy for chronic kidney disease patients?. Eur. J. Nut. 55, 1813–1821 (2016)
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  39. Pan W., Kang, Y.: Gut microbiota and chronic kidney disease: implications for novel mechanistic insights and therapeutic strategies. Int. Urol. Nephrol. 50, 289–299 (2018)
    [CROSSREF]
  40. Pawlak, J., Derlacz R.A.: Mechanizm powstawania oporności na insulinę w tkankach obwodowych. Postępy Biochemii 57, 200–206 (2011)
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  42. 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 11, e0153893(2016)
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  43. Prokopienko A.J., Nolin T.D.: Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease. Expert Rev. Clin. Pharmacol. 11, 71–82 (2018)
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  44. Qin, J., Wang J. et al.: A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010)
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  47. Rigalleau V., Blanchetier V., Combe C., Guillot C., Deleris G., Aubertin J., Aparicio M., Gin H.: A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients. Am. J. Clin. Nutr. 65, 1512–1516 (1997)
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  48. Sabatino A., Regolisti G., Brusasco I., Cabassi A., Morabito S., Fiaccadori E.: Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrol. Dial. Transplant. 30, 924–933 (2015)
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  49. Salmean Y.A., Segal M.S., Langkamp-Henken B., Canales M.T., Zello G.A., Dahl W.J.: Foods with added fiber lower serum creatinine levels in patients with chronic kidney disease. J. Ren. Nutr. 23, e29–32 (2013)
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  50. Sato B., Murohara T. et al.: Relation of plasma indoxyl sulfate levels and estimated glomerular filtration rate to left ventricular diastolic dysfunction. Am. J. Cardiol. 111, 712–716 (2013)
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  51. Sircana A., De Michieli F., Parente R., Framarin L., Leone N., Berrutti M., Paschetta E., Bongiovanni D., Musso G.: Gut microbiota, hypertension and chronic kidney disease: recent advances. Pharmacol. Res. doi: 10.1016/j.phrs.2018.01.013 (2018)
  52. Soulage C.O., Koppe L., Fouque D.: Protein-bound uremic toxins... new targets to prevent insulin resistance and dysmetabolism in patients with chronic kidney disease. J. Ren. Nutr. 23, 464–466 (2013)
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  53. Spoto B., Pisano A., Zoccali C.: Insulin resistance in chronic kidney disease: a systematic review. Am. J. Physiol. Renal. Physiol. 311, 1087–1108 (2016)
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  54. Strzępa A., Szczepanik M.: Wpływ naturalnej flory jelitowej na odpowiedź immunologiczną. Postepy Hig. Med. Dosw. 67, 908–920 (2013)
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  55. Tojo R., Suarez A., Clemente M.G., de los Reyes-Gavilan C.G., Margolles A., Gueimonde M., Ruas-Madiedo P.: Intestinal microbiota in health and disease: Role of bifidobacteria in gut homeostasis. World J. Gastroenterol. 20, 15163–15176 (2014)
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  56. Tsai M.L., Hsieh I.C., Hung C.C., Chen C.C.: Serum free indoxyl sulfate associated with in-stent restenosis after coronary artery stentings. Cardiovasc. Toxicol. 15, 52–60 (2015)
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  57. Turnbaugh P.J., Ley R.E., Mahowald M.A., Magrini V., Mardis E.R., Gordon J.I.: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)
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  58. 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. 36, 438–443 (2012)
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FIGURES & TABLES

REFERENCES

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  31. Liu B., Luo F., Luo X., Duan S., Gong Z., Peng J.: Metabolic enzyme system and transport pathways in chronic kidney diseases. Curr. Drug. Metab. 19, 568–576 (2018)
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  32. McCaleb M.L., Izzo M.S., Lockwood D.H.: Characterization and partial purification of a factor from uremic human serum that induces insulin resistance. J. Clin. Invest. 75, 391–396 (1985)
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  33. Meijers B., Farré R., Dejongh S., Vicario M., Evenepoel P.: Intestinal barrier function in chronic kidney disease. Toxins, 10, doi: 10.3390/toxins10070298 (2018)
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  34. Meropol S.B., Edwards A.: Development of the infant intestinal microbiome: a bird’s eye view of a complex process. Birth Defects Res. C Embryo. Today 105, 228–239 (2015)
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  35. Mishima E., Abe T. et al.: Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model. Am. J. Physiol. Renal Physiol. 315, F824–833 (2018)
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  36. Moraes C., Borges N.A., Mafra D.: Resistant starch for modulation of gut microbiota: Promising adjuvant therapy for chronic kidney disease patients?. Eur. J. Nut. 55, 1813–1821 (2016)
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  39. Pan W., Kang, Y.: Gut microbiota and chronic kidney disease: implications for novel mechanistic insights and therapeutic strategies. Int. Urol. Nephrol. 50, 289–299 (2018)
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  48. Sabatino A., Regolisti G., Brusasco I., Cabassi A., Morabito S., Fiaccadori E.: Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrol. Dial. Transplant. 30, 924–933 (2015)
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  49. Salmean Y.A., Segal M.S., Langkamp-Henken B., Canales M.T., Zello G.A., Dahl W.J.: Foods with added fiber lower serum creatinine levels in patients with chronic kidney disease. J. Ren. Nutr. 23, e29–32 (2013)
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  50. Sato B., Murohara T. et al.: Relation of plasma indoxyl sulfate levels and estimated glomerular filtration rate to left ventricular diastolic dysfunction. Am. J. Cardiol. 111, 712–716 (2013)
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  51. Sircana A., De Michieli F., Parente R., Framarin L., Leone N., Berrutti M., Paschetta E., Bongiovanni D., Musso G.: Gut microbiota, hypertension and chronic kidney disease: recent advances. Pharmacol. Res. doi: 10.1016/j.phrs.2018.01.013 (2018)
  52. Soulage C.O., Koppe L., Fouque D.: Protein-bound uremic toxins... new targets to prevent insulin resistance and dysmetabolism in patients with chronic kidney disease. J. Ren. Nutr. 23, 464–466 (2013)
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  53. Spoto B., Pisano A., Zoccali C.: Insulin resistance in chronic kidney disease: a systematic review. Am. J. Physiol. Renal. Physiol. 311, 1087–1108 (2016)
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  54. Strzępa A., Szczepanik M.: Wpływ naturalnej flory jelitowej na odpowiedź immunologiczną. Postepy Hig. Med. Dosw. 67, 908–920 (2013)
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  55. Tojo R., Suarez A., Clemente M.G., de los Reyes-Gavilan C.G., Margolles A., Gueimonde M., Ruas-Madiedo P.: Intestinal microbiota in health and disease: Role of bifidobacteria in gut homeostasis. World J. Gastroenterol. 20, 15163–15176 (2014)
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  56. Tsai M.L., Hsieh I.C., Hung C.C., Chen C.C.: Serum free indoxyl sulfate associated with in-stent restenosis after coronary artery stentings. Cardiovasc. Toxicol. 15, 52–60 (2015)
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  57. Turnbaugh P.J., Ley R.E., Mahowald M.A., Magrini V., Mardis E.R., Gordon J.I.: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)
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