Introduction

Chronic kidney disease (CKD) is a major public health problem worldwide [1–3]. According to the Kidney Disease Outcomes Quality Initiative, CKD is divided into five stages. Stage 1 is defined by altered renal function (changed markers containing aberrant blood or urine tests or imaging analysis) with normal or raised glomerular filtration rate ≥ 90 mL/min per 1.73 m²; stage 2 is characterized by glomerular filtration rate 60–89 mL/min per 1.73 m² with evidence of kidney injury; stage 3 glomerular filtration rate 30–59 mL/min per 1.73 m²; stage 4 glomerular filtration rate 15–29 mL/min per 1.73 m²; stage 5 end-stage renal failure with glomerular filtration rate < 15 mL/min per 1.73 m² [4]. Renal fibrosis including tubulointerstitial fibrosis and glomerulosclerosis is the final outcome of CKD [5–7]. The progression of CKD indicates that patients who irreversibly reach end-stage renal disease (ESRD) require renal replacement therapies such as dialysis and transplantation [8–14]. CKD causes the progressive and irreversible nephron loss that leads to glomerular sclerosis, as well as progressive interstitial fibrosis and tubular injury, and ultimately further reductions in nephron numbers [15–17]. Irrespective of the initial etiology, tubular cell atrophy and interstitial fibrosis are cardinal pathological features of CKD. Renal fibrosis has a typical feature of excessive accumulation and deposition of extracellular matrix components [18]. In terms of underlying molecular mechanism, renal fibrosis is associated with the activated pathways, such as transforming growth factor-β/Smad, Wnt/β-catenin, inhibitory of kappa B (IκB)/nuclear factor kappa B (NF-κB), and Keap1/nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathways [19–23], as well as the activated cytokines, such as renin-angiotensin system and aryl hydrocarbon receptor [24–27] and the dysregulation of metabolites such as amino acids and lipids [28–30]. However, the underlying molecular characteristics of these pathological development and progression remain to be fully understood. In recent years, increasing evidence has indicated that the dysbiosis of gut microbiota is involved in CKD including immunoglobulin A (IgA) nephropathy, diabetic kidney disease (DKD), membranous nephropathy (MN), chronic renal failure (CRF) and ESRD patients [31–38]. Current review summarizes the dysbiosis of gut microbiota in patintestinal mucosal barrier, allowing live bacteria or their metabolitesients with CKD that reveals the human disease development and progression. This review also discusses therapeutic approaches for modulating microbial dysbiosis in patients to provide more specific concept-driven therapy strategy for CKD interventions.

Microbiome and gut microbiota

The human gut is extremely populated with microorganisms, dominantly anaerobic bacteria. This internalized ‘microbial organ’ is not encoded in the host genome. Currently, human microbiome is estimated to contain 10 times more cells and 100 times more genes than host, and includes a wide range of organisms, such as bacteria, fungi, protozoa, archaea and viruses. This ecosystem contains numerous native species that permanently colonize gastrointestinal tract, namely autochthonous and several other transient microorganisms, namely allochthonous species. Firmicutes (Gram-positive) and Bacteroidetes (Gram-negative) are the cardinal phyla in gut microbiota, accounting for roughly 60–80% and 20–40% of the total bacterial load. It is estimated that two microbial phyla take up 90% of the total microbiota. Additionally, Gram-positive bacteria, such as Actinobacteria, and Gram-negative bacteria, such as Verrucomicrobia, Proteobacteria, Cyanobacteria and Fusobacteria exist in relative less abundance in adult gastrointestinal tract [39]. Gut microbial community produces a natural defense barrier and influences physiology, immune function, metabolism and nutrition. A variety of clinical and experimental evidence has indicated that microbial environment has played a key role in health and disease, such as cancers, cardiovascular disease, obesity, diabetic mellitus, hypertension, CKD and non-alcoholic fatty liver disease [40–52].

Gut microbiota in CKD patients

CRF and ESRD patients

CRF and ESRD belong to the advanced stages of CKD. CKD leads to the dysbiosis of gut microbiota that destroys intestinal mucosal barrier, allowing live bacteria or their metabolites to enter bloodstream. Leakage and translocation of their metabolites cross gut barrier to the circulation and trigger oxidative stress and inflammation that finally lead to local tissue and vascular dysfunction (Figure 1). Liu and his colleague [53] demonstrated a remarkable difference of gut microbiota between patients with CKD and healthy controls. After adjusting for confounders, lower Chao1 and Shannon indices were observed according to binary logistic regression predicted CKD prevalence. The increased relative abundances of Actinobacteria, Bifidobacterium, Alistipes and Bifidobacterium longum, activation of metabolic signaling pathways such as bacterial toxin and chloroalkane and its degradation might predict CKD [53]. Of note, the depletion of Bifidobacterium and Actinobacteria and decrease in chloroalkene and chloroalkane decomposition indicated high levels of free immunoglobulin light chains [53]. Chen and his colleague [54] demonstrated that Shannon entropy and Simpson indices showed no obvious difference in α-diversity between healthy controls and patients with stage 1–5 CKD. The weighted UniFrac or Bray–Curtis dissimilarity principal coordinate analysis showed that unique bacterial population aggregates were found in the faeces of patients with CKD at distinct stages compared with healthy group, which indicated the differences in composition rather than richness or numerical abundance between healthy controls and patients with CKD [54]. The relative abundance of Klebsiella pneumonia and the relative levels of S-adenosylhomocysteine in the faeces of patients with CKD were demonstrated to show a gradual increase with CKD severity [54]. Further results revealed increased Klebsiella pneumonia was positively correlated with increased S-adenosylhomocysteine in the faeces [54]. Moreover, Lv and his colleague [55] demonstrated that Enterobacteriaceae and Enterococcus showed high relative abundances in patients with CRF compared with healthy controls, while Lactobacillus, Bifidobacterium, Clostridium and Bacteroides showed lower relative abundances. Furthermore, Simpson index was decreased in patients with CRF compared with healthy controls, while Chao1 and Shannon indexes were increased in patients with CRF compared with healthy controls [55]. Flow cytometry analysis showed that the levels of CD3⁺, CD4⁺, CD8⁺ and CD4⁺/CD8⁺ were significantly decreased in patients with CRF compared with healthy controls, while the levels of CD14⁺, CD19⁺, and CD16⁺/CD56⁺ were significantly increased in patients with CRF compared with healthy controls [55]. Chao index was negatively correlated with levels of CD3⁺, CD4⁺ and CD8⁺ in patients with CRF. Chao index was positively correlated with levels of CD14⁺ and CD16⁺/CD56⁺ in patients with CRF [55]. These findings indicated that the dysbiosis of gut microbiota in CKD patients leads to the activation of inflammation and imbalance of immune function.

Display full size

Figure 1. 

Mechanisms involved in the relationship between gut microbial dysbiosis and CKD. CKD led to the dysbiosis of gut microbiota that destroys intestinal mucosal barrier, allowing live bacteria or their metabolites to enter the bloodstream. Leakage and translocation of their metabolites across gut barrier to the circulation can trigger oxidative stress and inflammation that finally leads to local tissue and vascular dysfunction

The latest study demonstrated that the marked alterations of the microbial diversity, taxonomic composition and functional potential of the microbiome were observed in the faecal samples of patients with ESRD compared with healthy controls [56]. Some increased gut microbial species in patients with ESRD were correlated with clinical indexes and encoded functions that were involved in toxin and secondary bile acids synthesis, which were associations between altered microbial functions and levels of metabolites in serum or faeces [56]. Treatment with microbiota from patients could blunt renal injury in the germ-free mice, while for antibiotic-treated rats it led to high levels of uraemic toxins in serum and exacerbated renal fibrosis compared with healthy controls [56]. Two species including Eggerthellalenta and Fusobacterium nucleatum could increase uraemic toxins production and promote renal damage in the adenine-induced CKD rats [56]. A probiotic Bifidobacterium animalis could reduce relative abundance of these species and decrease levels of toxins and disease severity in rats [56]. Taken together, the dysbiosis of gut microbiota has an important effect on patients with CRF or ESRD.

Gut microbiota-associated metabolites in patients with CKD

Metabolism regulation is one of three philological functions. The dysbiosis of gut microbiota leads to the disorder of metabolites. The latest study revealed that relative abundances of thirteen microbial species and levels of six serum metabolites were significantly changed across early to advanced stages of CKD patients [118]. Decreased relative abundance of Prevotella sp. 885 was related to urea excretion, while the levels of decreased caproic acid and increased p-cresyl sulfate were positively and negatively correlated with glomerular filtration rate, respectively [118]. Microbial genes related to secondary bile acid biosynthesis were enriched at the early stage, while pathway modules associated with lipopolysaccharide biosynthesis and lipid metabolism were enriched in microbiome at the advanced stage of CKD [118]. The results further showed identified biomarkers from metagenomics and metabolomics to discriminate cases of different severities from controls, among which Bacteroides eggerthii was of important value in early diagnosis of CKD patients [118]. Therefore, targeting the dysbiosis of gut microbiota could be considered as an alternative therapeutic strategy for CKD treatment (Figure 1).

Several studies have demonstrated that the dysbiosis of gut microbiota was associated with the dysregulation of metabolites in patients with IgA nephropathy. Wu et al. [119] demonstrated that Enterococcus and Streptococcus showed high relative abundances in patients with IgA nephropathy, whereas Bacteroidetes and Bacteroides showed low relative abundances, which led to dysregulated metabolites, especially free amino acid, polyunsaturated fatty acids, and oligopeptides, and activated phenylalanine metabolism. PE (17:0), trimethoprim, bilirubin, stearamide, phenylalanine and cis-9,10-epoxystearic acid were associated with metabolic pathway and networks in gut and serum. Of note, 5-hydroxyeicosatetraenoic acid and 5-hydroxy-6E,8Z,11Z-eicosatrienoic acid were related to glomerulosclerosis classification [119]. The latest study demonstrated that the levels of intestinal fatty acids, mostly unsaturated fatty acids, were significantly decreased in patients with IgA nephropathy [120]. Disorders of linoleic acid, arachidonic acid, anti-/pro-inflammatory fatty acid metabolites, and intestinal aryl hydrocarbon receptor signaling deficiency might indicate intestinal mucosal barrier injury in patients with IgA nephropathy [120]. Moreover, high levels of galactose deficient IgA1, interleukin-22 and tumour necrosis factor α while lower level of 3-indolepropionic acid were related to kynurenine metabolic pathway from tryptophan metabolism, indicating tryptophan metabolites including 3-indolepropionic acid, kynurenine and indoleacrylic acid had synergistic effects on modulating immuno-inflammatory responses in patients with IgA nephropathy [120]. In addition, Chai and his colleague [121] demonstrated that α-diversity and β-diversity were remarkably different between patients with IgA nephropathy and healthy controls, which were accompanied by decreased levels of caproic acid, acetic acid, propionic acid, butyric acid and isobutyric acid in faeces of patients with IgA nephropathy compared to healthy controls. Further, the relative concentrations of butyric acid and isobutyric acid in faeces were negatively correlated with urea acid concentrations, while faecal butyric acid concentrations were negatively correlated with blood urea nitrogen concentrations; faecal caproic acid concentrations exhibited negative correlation with 24 h proteinuria concentrations [121]. Acetic acid concentrations in faeces were positively associated with Clostridiales and Eubacterium_coprostanoligenes. Butyric acid concentrations in faeces were positively associated with the relative abundance of Alistipes. Their relative abundances were significantly reduced in patients with IgA nephropathy compared with healthy controls [121].

A number of evidence has showed the dysregulation of metabolites in CKD patients. Several studies have indicated that the dysregulation of metabolites was involved in the dysbiosis of gut microbiota in patients with DKD. Zhang and his colleague [122] demonstrated that eleven bacteria and 239 serum metabolites were found between DKD patients with ESRD and DKD patients without ESRD. Serum 192 metabolites that were related to eleven bacteria were high enriched in six metabolic pathways. Of note, tryptophan and phenylalanine metabolic pathways were related to the progression of DKD. Hippuric acid, 3-phenyllactic acid, dihydro-3-coumaric acid and 3-hydroxy-cinnamate in the phenylalanine metabolic pathway and indole-3-acetic acid in the tryptophan metabolic pathway were positively correlated with the progression of DKD, while tryptophan presented a negative correlation with the progression of DKD [122]. The relative abundances of norank Peptococcaceae and Abiotrophia were positively correlated with enhancing renal function and hippuric acid [122]. The relative abundances of Lachnospiraceae_NC2004_group were negatively correlated with improving renal function as well as 3-phenyllactic acid and indole-3-acetic acid in serum [122].

Summary and perspectives

The dysbiosis of gut microbiota plays an important role in the pathogenesis of CKD, which significantly affects the number, composition and functions of gut microbiota in patients with CKD. Proteins and nitrogenous endogenous compounds are metabolized by gut microbiota, producing the metabolites especially harmful microbial metabolites uremic toxins such as trimethylamine-N-oxide, indoxyl sulfate and p-cresyl sulfate in patients with CKD. The levels of these metabolites correlate with disease progression. Increased uremia toxins leaked into the bloodstream through the intestinal epithelial cell barrier damage that triggered endotoxemia and mediated systemic or local inflammation, which aggravated declining renal function in patients with CKD (Figure 1). The complex interaction between gut microbiota, intestinal epithelial cell barrier, bloodstream microbial-derived metabolites and kidney tissues might orchestrate subclinical changes in the pathogenesis of CKD and contribute to CKD progression. A number of clinical trials have indicated that targeting gut microbiota regulation via intervention approaches, such as prebiotics, probiotics and synbiotics supplementation as well as dietary guidance could ameliorate CKD and inhibit progressive renal fibrosis. Further studies should be conducted by systems biology including metagenomics-based gut microbiota analysis to identify gut microbiota community, metabolic signaling pathways and microbial genes, metabolomics-based blood metabolite identification and illumination of metabolite-mediated underlying molecular mechanism in host organs. Therefore, the modulation of gut microbiota could be considered as a promising therapy in complement to traditional drugs and dialysis treatment for patients with CKD. However, the investigation should be performed for identifying gut microbiota at the early disease stages to provide references for dietary intervention for CKD patients. These future studies may provide a clue for disease etiology, metabolic pathways and alternative treatment for CKD.