Salvadori M, Rosso G. Gut-kidney axis: Dysbiosis and renal disease. World J Nephrol 2026; 15(1): 115357 [DOI: 10.5527/wjn.v15.i1.115357]
Corresponding Author of This Article
Maurizio Salvadori, MD, Professor, Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Tuscany, Italy. maurizio.salvadori1@gmail.com
Research Domain of This Article
Urology & Nephrology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Co-first authors: Maurizio Salvadori and Giuseppina Rosso.
Author contributions: Salvadori M and Rosso G equally contributed to generating the manuscript; both authors wrote, controlled and approved the final version of the manuscript.
Conflict-of-interest statement: All authors declare that they have no conflict of interest to disclose.
Corresponding author: Maurizio Salvadori, MD, Professor, Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Tuscany, Italy. maurizio.salvadori1@gmail.com
Received: October 21, 2025 Revised: November 25, 2025 Accepted: January 14, 2026 Published online: March 25, 2026 Processing time: 144 Days and 10.1 Hours
Abstract
According United States renal data system the morbidity rate for chronic kidney disease (CKD) is 2.5 times than patients not affected by CKD and the mortality rate is 144.9 per 1000 persons-years. The gut microbiota is involved in uremic toxins (UTs) production. This fact was demonstrated by experiments in rats, which revealed better survival in CKD rats that were deprived of the gut microbiota. In men, UT levels are low in CKD patients without a colon. Diet may affect the gut microbiota through food additives such as prebiotics, probiotics and post biotics. Conservation processes and food processing may also affect the gut microbiota. Other factors are food quantity and composition. The gut microbiota may be the cause of UTs production and accumulation in the blood. Additionally, there is interplay among different organs such as liver, kidney and gut. Several theories have been formulated to justify the interplay between the metabolic dysfunctions. In particular, the increase of species such as Eggerthelia lenta, Fusobacterium nucleatum and Alistipes shahii leads to an increase of the aromatic amino acids degradation, and secondary bile acids and trimethyamine oxide biosynthesis in the intestine. This fact determines an increase of the levels of UT precursors such as indole, p-cresol, phenol, phenylacetaleyde, benzoic acid and trimethylamine. Recent studies document the following. The human microbiome project revealed that the gut microbiota may play an important role in both human health and diseases, including kidney disease. Recently, several studies have shown a strict correlation between the gut microbiota and CKD. Probiotics, prebiotics and synbiotics are possible therapies. Probiotics are living microorganisms that, consumed in adequate quantities, are beneficial for the patient, and act on the intestinal microbiome equilibrium. Lactobacilli and Bifidobacteria are common examples of probiotics. Prebiotics are generally fibers not absorbed by the gut, representing a selective nutrient for the microbiome already present in the gut, which favors their growth and activity. Inulin, fructo-oligosaccharides and other fibers are examples of prebiotics. The association and synergism between probiotics and prebiotics is symbiotic.
Core Tip: It has been recently established an axis among gut, liver and kidney. In conditions of gut microbiota modifications, otherwise called dysbiosis, this alteration can favor uremic toxins (UTs) in blood circulation and the progression of chronic kidney disease (CKD). The principal questions are which exactly is the cross talk between gut, liver and kidney, whether a specific microbiota is linked to CKD and in generating UTs, whether gut dysbiosis favors the progression of CKD. Finally, which are the possible therapeutical measures for such condition.
Citation: Salvadori M, Rosso G. Gut-kidney axis: Dysbiosis and renal disease. World J Nephrol 2026; 15(1): 115357
Chronic kidney disease (CKD) is a relevant public health issue. It is extremely common, being found in more than 843 million people. In addition, it is an increasingly cause of death, interestingly traditional cardiovascular risk factors because are associated with high levels of blood uremic toxins (UTs) related to CKD. The gut microbiota is involved in UTs production. This fact was demonstrated by experiments in rats, which revealed better survival in CKD rats that were deprived of the gut microbiota. In men, UT levels are low in CKD patients without a colon. UTs are metabolic products that accumulate in the body after renal failure. These UTs can be divided into small, water-soluble molecules (< 500 Dalton) such as urea and trimethylamine N-oxide (TMAO), middle molecules (> 500 Dalton) such as β2 microglobulin and protein-bound molecules, such as indoxyl sulfate (IS) and para cresyl sulfate (pCS)[1,2].
The gut microbiota is involved in UTs production. This fact was demonstrated by experiments in rats, which revealed better survival in CKD rats that were deprived of the gut microbiota. In men, UT levels are low in CKD patients without a colon. In men affected by CKD, metabolites such as pCS and indole 3 acetic acid accumulate at extremely high concentrations and in a chronic manner[3]. There is a bidirectional relationship between gut dysbiosis and CKD as documented in Figure 1.
Figure 1 Bidirectional relationship between gut dysbiosis and chronic kidney disease.
CKD: Chronic kidney disease.
The main text will treat the following four points: (1) The existence of a CKD and its relationship with gut dysbiosis; (2) A specific microbiota involved in in CKD; (3) The Uremic toxins production and their role in progression of CKD; and (4) Therapeutic targets.
CROSS TALK BETWEEN GUT-DIET-KIDNEY
Diet may affect the gut microbiota through food additives such as prebiotics, probiotics and post biotics. Conservation processes and food processing may also affect the gut microbiota. Other factors are food quantity and composition. The gut microbiota may be the cause of UTs production and accumulation in the blood.
Several studies[4] have documented that gut microbiota and their metabolites exert their effects on several diseases through modulation of the T helper cell 17/T regulatory cell ratio.
High plasma levels of UTs may increase organ toxicity and might determine modifications in the gut microbiota composition and function, promoting an increase in UT-producing bacterial species and a decrease in the quantity of bacteria producing short-chain fatty acid (SCFA). This fact determines alteration of the intestinal barrier function as it provokes a disruption of the mucus layer and a decrease of the expression of tight junction proteins. This fact may cause leakage of bacterial derivatives such as lipopolysaccharide (LPS), which determines in addition to oxidative stress, both local and general inflammation. It is not exactly known how much UT precursors due to gut barrier disruption contributes to the increased levels of blood UTs[5].
Additionally, there is interplay among the liver, kidney and gut. Several theories have been formulates to explain this strict association between the metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD. These hypotheses include ectopic lipid accumulation, lipoglucotoxicity, altered glucose metabolism, oxidative stress, and endothelial dysfunction. All these dysfunctions are singularly associated with metabolic conditions such as obesity and type 2 diabetes. In addition, several pro inflammatory molecular pathways are associated with both MASLD and CKD. Gut dysbiosis induces the production of metabolites such as SCFAs, SBAs, and UT precursors, as those derived from aromatic amino acids (AAAs). The liver has a peculiar anatomical role in managing these metabolites as it is the first organ exposed to these gut-derived metabolites through the portal vein, plays a crucial role in their biotransformation into UTs. These toxins contribute to kidney fibrosis, impair renal filtration, and disrupt excretion. Some gut-derived metabolites also induce liver injury. In addition, harmful metabolites such as ammonia weaken the intestinal barrier, allowing bacterial products and endotoxins to enter the circulation, triggering immune activation and inflammation. This exacerbates damage to the kidney, liver and intestines. Moreover, through the biliary tract, the liver secretes primary bile acids and antimicrobial molecules into the gut, influencing both the microbiota composition and gut barrier integrity. This vicious cycle underpins the kidney-liver-gut axis[6].
A relevant paper on the impact of altered intestinal microbiota on CKD progression was published by Castillo-Rodriguez et al[7]. In particular, these authors examine the key UTs of bacterial origin that may promote CKD progression. Some of these toxins are protein bound, mainly albumin bound. These toxins are listed in Table 1[2,8-12]. Dissayabutra et al[13] characterized gut dysbiosis and intestinal barrier dysfunction in patients with MASLD and CKD. The study included 22 healthy controls and 180 patients were, including 90 patients with MASLD, 60 with CKD, and 30 with both diseases. The results of the study are reported in Table 2.
Table 1 Main uremic toxins and their effect on the kidney.
Compound
Total plasma concentration in CKD
Lowest concentration active on cultured renal cells (μM)
Effects on cultured renal cells
Effects on kidneys in vivo
pCS
Median 50; maximum 500
100
Decreased viability, increased oxidative stress, increased inflammatory and profibrotic responses, decreased expression of nephroprotective factors
Progression of CKD, kidney fibrosis, promote epithelial-to-mesenchymal transition. Activate the renal-angiotensin system
pCG
Median 0.22; maximum 8
25
Decreased the function of proximal cell membrane transporters (MRP4)
The study on SCFA producing bacteria reveals an abundance of Bifidobacterium, Eubacterium, Coprococcus and Erysipelotrichaceae. These bacteria were greater in the healthy individuals than in the patient groups in the study. This is important because SCFAs are important gut metabolites that maintain gut barrier integrity and prevent endotoxins and bacterial translocation. SCFAs are central to maintaining gut health through multiple mechanisms, including reinforcing intestinal barrier function, exerting anti-inflammatory effects, regulating glucose and lipid metabolism, and influencing host immune responses[14].
In addition, in MASLD, Bifidobacterium has a protective effect against liver injury. Therefore, a decrease in the abundance of Bifidobacterium favors the progression of liver inflammation. Additionally, this study revealed that patients affected by both MASLD and CKD had fewer SCFA-producing bacteria, than healthy individuals did. A recent review[15] examined the opportunities, pitfalls and therapeutic potential in gut microbiome studies in CKD patients. The principal biotic intervention studies in patients with CKD are reported in Table 3[16-20].
Table 3 Biotic intervention studies in patients with chronic kidney disease.
Study design
Study duration (weeks)
CKD stage
n
Supplementation
Uremic toxin changes
Taxa changes post-intervention
RCT, SC, DBP
18
4, 5
37
9 bacterial strains across; Bifidobacterium, Lactobacillus and Streptococcus
The main conclusions of the authors were as follows: Because the kidney replacement therapies that are currently available are inadequate, new intervention methods are needed to reduce the levels of UTs. New techniques are needed to better understand the composition of the gut microbiome in CKD patients. Diet in patients with CKD strongly influences the microbiome composition. New methods to improve kidney function in patients with gut microbiome and UT production. Most of the studies were conducted on 16S ribosomal RNA. Only two studies have been conducted on the basis of more effective shotgun sequencing. Notably, investigations of microbial composition have long been performed using next- generation amplicon sequencing based on the16S ribosomal RNA gene[21]. However, such techniques have been superseded by shotgun sequencing; this technique provides high-resolution data and enables culture-independent evaluation of species and strain levels[22,23].
Considering all the above-described data, 4 principal questions should be addressed: Is there a specific gut microbiota associated with CKD? Is the gut microbiota involved in the overproduction of UTs? Is the gut microbiota involved in the progression of CKD? Is the gut microbiota an attractive therapeutic target in CKD?
IS THERE A SPECIFIC GUT MICROBIOTA ASSOCIATED WITH CKD?
In the previous chapter we discussed the role of gut and liver alterations in determining CKD and discussed that their altered microbiota may generate and aggravate CKD. It should be highlighted that several microbes have protective effects against renal fibrosis in CKD. This is the case of Bacteroides fragilis and Bacteroides ovatus as documented in several recent papers[24,25]. Indeed, Bacteroides fragilis is decreased in the feces of CKD mice. It seems that it acts via an increase of SGLT2. Similarly, Bacteroides ovatus is reduced in patients with CKD and it acts in two ways. By producing intestinal hypodeoxycholic acid. Also neohesperidin regulates the levels of Bacteroides ovatus and contributes to the mitigation of renal fibrosis.
This is the most recent information concerning gut microbiota composition in CKD. Overall, there is a modification of biodiversity with a reduction in richness. There are increases in bacteria from the Enterococcaceae/Desulfovibrionaceae families and decreases in the abundances of bacteria from Prevotellaceae and Lactobacillaceae. The principal data come from the studies of Zhao et al[26] as shown in Tables 4 and 5. In the Table 4 Zhao et al[26] report the characteristics of intestinal microbiota in patients with CKD compared to healthy controls. Zhao et al[26] reviewed twenty-five studies with a total of 1436 CKD patients and 918 healthy controls. The studies with more enrolled patients are reported in Table 5[27-29]. These data revealed increased abundances of Proteobacteria and Fusobacteria, the genera Escherichia_Shigella, Desulfovibrio and Streptococcus, and lower abundances of Roseburia, Faecalibacterium, Pyramidobacter, Prevotellaceae_UCG-001, and lower Prevotella_9 in CKD patients. There are several limitations in the interpretation of these studies. Indeed, 68% of the studies are Chinese, and information on dietetics is limited. These studies focus more on microbiota composition than on function and the populations are heterogeneous, and long-term follow-up is not performed. Shotgun sequencing was performed in only two studies, in the other studies 16S ribosomal RNA was performed. Half of the studies were conducted on dialysis patients.
Table 4 Characteristics of intestinal microbiota of patients with chronic kidney disease.
Species
Genus
Family
Order
Class
Phylum
Alteration of taxa
Escherichia coli
Escherichia Shigella, Desulfobrio and Streptococcus
Enterococcaceae and Fusobecteriaceae
Enterobacteriales and Coriobacteriales
Bacteoidia Gammaprotobacteria, Fusobacteria and Actinobacteria
Proteobacteria and Fusobacteria
More abundant
66.6% studies showed lower richness compared to healthy controls. 90.9% studies showed distinct bacterial composition from healthy controls
Roseburia, Faecalibacterium, Pyramidobacter, Prevotellaceae and Prevotella 9
Prevotellaceae, Lachnospiraceae and Lactobacillaceae
Clostridiales, Burkolderiales and Verrucomicrobiales
IS THE GUT MICROBIOTA INVOLVED IN GENERATING UREMIC TOXINS?
Several studies have reported that the modification of the gut microbiota generates UTs and, in this way, may aggravate the patient conditions. This condition has been described by several studies[27-35] followed by other studies[36-40].
Wang et al[27] firstly reported that an aberrant gut microbiota alters the host metabolic pathways, so favoring renal failure in humans and rodents, principally through the generation of UTs. In this study, the fecal and serum metabolomes of patients with end stage renal disease (ESRD) were strictly related and were characterized by the increased levels of UTs and SBAs.
In addition, the increased levels of UTs and SBAs in patients with ESRD has been found to be associated with gut microbiome-mediated AAAs degradation and microbial SBA biosynthesis.
Finally, the transplantation of microbiota from subjects with ESRD, increased the levels of serum UTs and favored the increase of renal fibrosis in renal injured germ-free mice and antibiotic-treated rats.
In particular, the increase of species such as Eggerthelia lenta, Fusobacterium nucleatum and Alistipes shahii leads to AAAs degradation, and SBA and TMAO biosynthesis in the gut, resulting in increased precursors of UTs such as indole, p-cresol, phenol, phenylacetaleyde, benzoic acid and TMA. The latter through the portal vein and the liver are definitively transformed into UTs in the circulation as IS, pCS, phenyl sulfate, phenylacetylglutamune, hippuric acid, and TMAO. This fact is reinforced by the enrichment of Ruminococcus_M322, Clostridium perfrigens, Coprococcus sp ART55/1 and Eggerthella lenta. Both pathways also led to the increases in the circulation of conjugated bile acids (taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenonodeoxycholic acid, taurodeoxycholic acid, glycodeoxycholic acid). Moreover, the reduction of species such as Faecalibacterium prausnizii, Roseburia and Prevotella leads to a decreased gut microbial SCFAs biosynthesis. The main consequences are increased cardiovascular disease, abnormal lipid metabolism and systemic inflammation.
The study by Laiola et al[34] is of particular interest. The Laiola et al’s study[34] analyzed the gut microbiome of 240 non-dialysis patients with CKD. In this study, shotgun metagenomics was used with follow-up data from 103 patients after 3 years, and they were compared with those of healthy volunteers. First, gut microbiomes of patients with CKD at baseline were compared with those of healthy controls to identify a CKD-specific gut microbiome signature and species associated with CKD. Second, differences in the gut microbiome between patients with moderate and severe CKD, categorized by an estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m2 were analyzed. A multiomics integrative analyse was performed to identify which biomarkers were related both to disease severity and CKD progression. Third, changes in the microbiome over time were examined by comparing data from T0 and T1, and the results were used to assess the impact of diet on the gut microbiome composition. Finally, the causal relationships between the gut microbiota, UT production and kidney function deterioration in CKD patients were explored.
In patients with CKD, enrichment of species from the Enterocloster and Hungatella genera and a tendency to harbor more UT-producing species have been reported among patients with CKD.
Consistent with the findings of previous studies[2,27], patients with severe CKD had higher UT levels and a different serum UT characterisation than those with moderate CKD. Correlation analysis between the quantities of metagenomic species pangenomes (MSPs) that differed between CKD levels and serum UT concentrations. The relative abundances of severe CKD-related MSPs, such as Desulfovibrio fairfeldensis msp_0295, Lachnoclostridium pacaense msp_0772 and Intestimimonas massiliensis msp_1012, were correlated with indole-derived and phenol-derived UT, as previously reported[27].
Multiomics was conducted to analyze the gut microbiome, UT producers, biochemical parameters and diet to identify biomarkers that can be used to determine CKD severity. Overall, 57 biomarkers were found, highlighting the relationship among diet, gut microbiome modifications, UT accumulation and CKD severity. The authors performed fecal microbiota transplantation using stool samples from rats with CKD and healthy rats into antibiotic-treated CKD model mice. Overall, these studies documented that the altered gut microbiome of patients with non-dialysis CKD may favor a further deterioration of kidney function and may be associated with enhanced production of UTs.
IS THE GUT MICROBIOME INVOLVED IN THE PROGRESSION OF CKD?
Several previously cited studies have reported that gut dysbiosis may be involved in the CKD progression. Zhao et al[26] performed a state-of-art review, and reported that specific alterations in the gut microbiota may aggravate kidney inflammation worsening the eGFR over time. In a different study, Wang et al[27], reported that an aberrant gut microbiota altered the host metabolic pathways and affected renal failure in humans and rodents. In addition, a study by Ramezani et al[41] documented the role of the gut microbiome in uremia and a study by Wahlström et al[42] documented intestinal interrelationship between bile acids and the microbiota and their interference on host metabolism. In addition, a study by Laiola et al[34] explored the causal relationship among the gut microbiota, UTs production and kidney function deterioration in CKD patients.
Recent studies document the following. The human microbiome project (HMP) revealed that the gut microbiota plays a crucial role in human health and diseases, including kidney disease[43,44]. Recently, several studies are documenting a strict correlation between the gut microbiota and CKD[45,46].
In a very recent study, Xi et al[47], evaluated the correlation between the gut microbiota and renal function in CKD patients. They reported that the abundances of Acidobacteria, Blautia and Candidatus-Salibacter significantly increased in CKD patients.
In a very recent study by Liu et al[48], the authors reported that a reduction of Akkermansia, UCG_005, Lachnospiraceae, Monoglobus and Eubacgterium in the gut lumen was associated with an increase in levels of fecal metabolites l-aspartic acid, normatanephrine, vanillymandelic, 5,6 dihydroxyndole, L-phenylalanine and urovanic acid, which are associated with CKD progression, oxidative stress and mitophagy (Figure 2).
Figure 2 Axis between gut and kidney mediated by microbiotas and their products.
CKD: Chronic kidney disease.
This fact is further exacerbated in the case of the development of a uremic enterocolitis such as shown in Figure 3. All the cited studies document the impact of gut dysbiosis on the CKD progression. However, which bacteria contribute to CKD progression remain unknown. Gut dysbiosis increases the production of some UTs species. These, in turn, cause structural modifications of the intestine consisting principally of a decreased number of tight junctions and a reduction in the mucus layer. This has been documented in CKD rats with 5/6 nephrectomy[49]. Andersen et al[50] reported increased intestinal permeability of the colon 26 cells. They reported that intestinal dysbiosis, barrier dysfunction and bacterial translocation are strictly related with CKD systemic inflammation. Turner[51] previously documented the intestinal mucosal barrier function in health and disease. The increased intestinal permeability induced by differently sized polyethylene glycols has been documented in two studies by Magnusson et al[52,53]. Vaziri has been the author of several studies and reported that CKD causes disruption of gastric and small intestinal epithelial tight junctions[54-58].
Figure 3 Development mechanisms of uremic enterocolitis and its systemic consequences.
CKD: Chronic kidney disease; TMA: Trimethylamine; CV: Cardiovascular.
IS THE GUT MICROBIOTA AN ATTRACTIVE THERAPEUTIC TARGET IN CKD?
A premise should be done before treating the possible therapeutic strategies in CKD. Inflammation and gut dysbiosis are important drivers of CKD[59]. Indeed CKD is associated with inflammation; other factors include cellular senescence, depletion of SCFAs and gut barrier dysfunction. Wide evidences indicate that local inflammation play pivotal roles in the pathogenesis and progression of CKD and dysbiosis of gut microbiota. CKD is often associated with intestinal inflammation and oxidative stress, which lead to rapid systemic translocation of bacterial derived UTs, including indoxyl sulfate, phenyl sulfate and indole-3-acetic acid with the consequent aggravation of renal fibrosis[60].
Several strategies may act at different levels. We may act at the generation level, avoiding gut protein fermentation by taking antibiotics, and leveraging sodium glucose transporter (SGLT2) receptors, by consuming a low protein plant-based diet and by taking pro/pre/sinbiotics. Indeed, in a very recent study[61] in SGLT2i-treated CKD patients a survey of metabolomic profiles revealed a reduction of two uremic solutes, indoxyl sulfate and pCS, and several short-chain fatty acids (formic, acetic, propionic, valeric, and 2-methylbutanoic acid).
Diet is important. The gut should be considered as an excretory organ in CKD management. Maintaining regular bowel movements to aid toxin excretion is essential. In kidney failure, the gut becomes a primary production site and a secondary excretion route for various UTs (e.g., indoles, phenols, TMAO). Constipation or fecal retention prolongs the contact time of these toxins with the intestinal mucosa, increasing their absorption into the bloodstream and exacerbating the uremic burden and systemic inflammation. Therefore, alleviating constipation and maintaining normal intestinal transit time should be considered a crucial aspect of non-pharmacological management in CKD. Many bacterial strains and dietary fibers improve gut motility, increase stool bulk and water content, thereby achieving the dual benefit of detoxification and laxation; Lactiplantibacillus plantarum SK 151 is a typical example of such bacterial strains[62]. We may act in blood circulation directly towards UTs. Finally, we may favor the clearance of UTs either by preserving residual renal function or by dialysis absorption.
Cedillo-Flores et al[63] performed a systematic review and a network meta-analysis on the impact of gut microbiome modulation on UT reduction in CKD patients. The main studies reporting gut microbiota modulation are shown in Table 6[64-67]. All these results are promising. Indeed, several studies indicate that the modification of the composition of patients’ gut microbiota may induce a decrease in pCS and IS. However, these findings are not sufficient, highlighting the need for more randomized clinical trials with larger sample sizes. Voroneanu et al[68] also performed a systematic review on treatments for the gut microbiota in CKD. The results of their study are reported in Table 7[69-74] and later by[75-78]. Accordingly, the correct selection of probiotics/prebiotics/synbiotics is crucial for their effectiveness in CKD.
Low protein diet increased Akkermanmsiaceae and Bacterpoidaceae and decreased Christensenellaceae Clostridiaceae, and Pasteurellaceae Lactobascillaceae levels
The question is what the differences are among probiotics, prebiotics and synbiotics. Probiotics are living microorganisms that, consumed in adequate quantities, are beneficial for the patient, and act on the intestinal microbiome equilibrium. Lactobacilli and Bifidobacteria are common examples of probiotics. Prebiotics are generally fibers not absorbed by the gut, representing a selective nutrient for the microbiome already present in the gut, which favors their growth and activity. Inulin, fructo-oligosaccharides and other fibers are examples of prebiotics. The association and synergism between probiotics and prebiotics is symbiotic.
In a mini review, Koppe et al[79] reviewed probiotics. Probiotics are live microorganisms that can survive in the gastrointestinal tract restoring the intestinal flora balance. Their beneficial effects include enhancing the gut barrier by increasing mucus integrity, epithelial tight junctions, and epithelial survival[80,81]. Other effects include antimicrobial effects through a reduction in local pH, antimicrobial peptide production, and defensing, all of which mitigate the increase of pathobionts. Probiotics can stimulate the production of secretory immunoglobulin A, providing additional protection from the luminal microbiota. Other probiotic actions include anti-inflammatory effects and improved immune tolerance. Symbionts and probiotics have an interaction with the dendritic cells and macrophages through toll-like receptors, which provide signal to adaptive immune cells as regulatory T cells and B cells. A decrease in LPS production reduces the activation of macrophages and the nuclear factor-kappa B cascade. Additionally, there is competition for nutrient and bile acid metabolism. The reduction in pathobionts limits the production of gut-derived UTs. The presence of probiotics increases bile salt hydrolase activity, which decreases the abundance of tauro-beta-muricholic acid and SCFA production.
However, probiotics can have different effects on the gastrointestinal tract. On the one hand, probiotics can limit LPS production and increase the epithelial barrier, thus reducing inflammation. On the other hand, CKD is associated with the diffusion of a large quantity of urea in the gastrointestinal tract. Subsequent hydrolysis of urea by urease expressed by some probiotics and pathobionts may result in the formation of large quantities of NH3 and NH4OH and an increase in pH, which may affect the growth of commensal bacteria and promote the proliferation of aerobic bacteria. Therefore, the damage to the epithelial tight junction barrier caused by ammonia/ammonium hydroxide and the increase in LPS flow may promote the activation of the nuclear factor-kappa B pathway and inflammation.
Some human studies on the use of probiotics in CKD patients are listed in Table 8[82-87]. Other therapies are also possible, especially for the future. Several of these treatments are still operating in preclinical models, but look to be promising for the future. For example, oral agents that inhibit CUDC/D enzymes reduce circulating TMAO levels. A pan-tyryptophanase inhibitor blocks the formation of indole in the mouse gut and reduces indoxyl-sulfate levels in serum. Healthy diets, such as dietary approaches to stop hypertension lower the risk of developing CKD. Diets rich in methionine and cysteine inactivate microbial enzymes that generate UTs, but the patient’s compliance with such diets is often poor.
Table 8 Human studies reporting the use of probiotics in chronic kidney disease.
Additional studies are needed to examine the gut microrganisms and the targeted strategies[88]. We have already mentioned the role of tryptophane, an AAA. Therefore, tryptophan metabolism in gut, as an actionable actor, exhibited a therapeutic perspective, through either molecule targeting in a specific pathway or utilizing microorganisms manipulating tryptophan metabolism[89]. A particular condition is that of patients with ESRD and treated by peritoneal dialysis (PD). A recent review outlines the effectiveness of probiotics in patients undergoing PD[90].
In conclusion, we can state the following: Empirical selection of prebiotic and probiotic strains is crucial for symbiotic formulation; probiotics containing urease enzymes may exacerbate ammonia production; a uremic gut environment can impact probiotic survival and benefits; the compatibility between probiotics and prebiotics is essential for symbiotic effectiveness, as gut microbiota interactions vary with different prebiotics. Probiotics should have fiber-hydrolyzing enzymes; should not have tyrosinase, tryptophanase or urease; and should have a pH resistance profile. All these points are also highlighted by Beau et al[91], who also highlight examples of intelligent biotic selection and produce a rigorous flow chart for the selection of a symbiotic to improve dysbiosis and the production of UTs.
CONCLUSION
CKD is a major public health issue. It is extremely common, interesting more than 843 million people. In addition it is an increasingly cause of death, in particular due to traditional cardiovascular risk factors. In the case of CKD, this is due to the high levels of blood UTs related to CKD. Such elevated level of UTs is due to the reduced elimination rate by the kidney, but also to an increased production by the gut microbiota in condition of dysbiosis. Indeed, there is a link between gut and kidney: The so-called gut kidney axis. This often involves also the liver. In condition of gut dysbiosis there is increase in bacteria from the Enterococcaceae/Desulfo vibrio naceae families and a decrease in the abundance of bacteria from Prevotellaceae and Lactobacillaceae. Several studies reported that the modification of the gut microbiota generates UTs and the blood levels also increase for the reduction of eGFR. The HMP documented that the gut duysbiosis is corretated with kidney disease and the progression of CKD. Traditional treatments are based on the use of probiotics, prebiotics and their combination called synbiotics, but new treatments are to date available and shed new lights for future researches and treatments. The efficacy of a low-protein diet has been well documented by the study of Marzocco et al[92], who reported both a decrease in IS and a decrease in gut modules involved in the production of UTs and amino acid metabolites such as tryptophan.
An important study on the efficacy of a low-protein, high-plant diet was conducted by Lobel et al[93]. The authors reported that a high-plant and low-protein diet decreases the production of UTs species. Additionally, the authors reported that a high-diversity plant-based diet alters the gut microbiome, plasma metabolome and improves diet quality and symptoms in adults with CKD 3-4. Maintaining regular bowel movements to aid toxin excretion is essential. Some bacterial strains and dietary fibers improve gut motility. In a different study, the authors documented the relevance of the type of amino acid in the diet. In mice with CKD, a diet high in sulfur- containing amino acids induced a posttranslational modification of microbial proteins that induced the progression of CKD. On the other hand, there was an increase in tryptophan with subsequent degradation to indole, pyruvate and ammonia. In a different study, Hsu et al[61] documented the effects of SGLT2 inhibitors on modulating protein-bound UTs and the gut microbiota in pre-dialysis CKD patients. Finally, is fecal microbiota transplantation ever appropriate in the treatment of CKD? The study by Benech and Koppe[94] reveals preclinical data suggesting that fecal transplantation could effectively promote a beneficial microbiome in CKD patients.
We may conclude the following: The gut microbiota is a key factor in CKD progression through enrichment in species that produce gut-derived UTs. Promising targeted therapeutic strategies that may be taken as an “a take home message on treatment” include the following: Prebiotics/probiotics administration: Promising but require targeted and innovative approaches; fecal microbiota transplantation requires further validation; diet: Targeting amino acid intake, plant-based diets, and UPS modulation; medications (e.g. SGLT2 inhibitors and others) should be further explored.
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[PubMed] [DOI]
Scientific quality: Grade B, Grade B, Grade B, Grade C
Novelty: Grade A, Grade B, Grade B, Grade D
Creativity or innovation: Grade A, Grade B, Grade B, Grade D
Scientific significance: Grade A, Grade B, Grade B, Grade D
P-Reviewer: Deng Z, PhD, Associate Chief Physician, China; Wang XM, MD, PhD, Professor, China; Zhao YY, MD, PhD, Dean, Professor, China S-Editor: Liu JH L-Editor: A P-Editor: Wang CH
