Eman Wehedy
Ibrahim F. Shatat
Souhaila Al Khodor- 1College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
- 2Research Department, Sidra Medicine, Doha, Qatar
- 3Nephrology Department, Sidra Medicine, Doha, Qatar
Chronic kidney disease (CKD) is an increasing global health burden. Current treatments for CKD include therapeutics to target factors that contribute to CKD progression, including renin–angiotensin–aldosterone system inhibitors, and drugs to control blood pressure and proteinuria control. Recently, associations between chronic disease processes and the human microbiota and its metabolites have been demonstrated. Dysbiosis—a change in the microbial diversity—has been observed in patients with CKD. The relationship between CKD and dysbiosis is bidirectional; gut-derived metabolites and toxins affect the progression of CKD, and the uremic milieu affects the microbiota. The accumulation of microbial metabolites and toxins is linked to the loss of kidney functions and increased mortality risk, yet renoprotective metabolites such as short-chain fatty acids and bile acids help restore kidney functions and increase the survival rate in CKD patients. Specific dietary interventions to alter the gut microbiome could improve clinical outcomes in patients with CKD. Low-protein and high-fiber diets increase the abundance of bacteria that produce short-chain fatty acids and anti-inflammatory bacteria. Fluctuations in the urinary microbiome are linked to increased susceptibility to infection and antibiotic resistance. In this review, we describe the potential role of the gut, urinary and blood microbiome in CKD pathophysiology and assess the feasibility of modulating the gut microbiota as a therapeutic tool for treating CKD.
Introduction
Chronic kidney disease (CKD) is a growing healthcare burden affecting about 13.4% of the population worldwide (1). In the last few decades, the number of CKD patients has steadily increased (2). In adults, hypertension and diabetes are the leading causes of CKD, while congenital anomalies of the kidney and urogenital track account for the majority of CKD etiologies in children. Factors that contribute to the progression of CKD include activation of the renin–angiotensin–aldosterone system, proteinuria, a state of chronic inflammation and repetitive acute kidney injury (3–7). CKD is associated with the development of severe health conditions like cardiovascular diseases, neurological complications, adverse pregnancy outcomes, and hyperkalemia (8–12). In children, CKD affects neurocognitive abilities, school performance, growth, quality of life and the cost of medical care (6, 13–15).
Current treatments for CKD include renin–angiotensin–aldosterone system inhibitors and drugs to control blood pressure and proteinuria. An increasing number of studies suggest that the composition of the microbiome has a key role in maintaining health. The human microbiome is the collection of all microbial DNA in the human body, which is distributed in various body parts as; skin, gastrointestinal, urinary tract, respiratory tract, and oral cavity (16). These microbes play crucial roles in the digestion and metabolic processes, stimulation and regulation of the immune response, production of vitamins, and protection against pathogens (17, 18). This microbial community is in a symbiotic relation with the host in the healthy states (19). Dysbiosis refers to a disruption of the microbial balance, and this phenomenon is associated with various diseases and pathological conditions including CKD (20, 21).
The major part of the human microbiome is centralized in the gut (22). The gut microbiota harbors 10-fold more microbial cells than human cells, which regulates nutrient metabolism and produces various metabolites that affect the kidney, heart, vascular system, and liver (23). There is a bi-directional relationship between dysbiosis and the pathogenesis of CKD (20, 24–26). We summarized this relationship in Figure 1. It is well-established that an increase in levels of harmful metabolites including trimethylamine N-oxide (TAMO), indoxyl sulfate, and p-cresyl sulfate are associated with renal fibrosis, endothelial dysfunction, a decline in the estimated glomerular filtration rate (eGFR), cardiovascular complications, and increased mortality and morbidity in CKD (27–30). Moreover, the serum levels of 5-methoxytryptophan and indoxyl sulfate correlate positively with CKD progression (31). On the other hand, renoprotective metabolites including short-chain fatty acids prevent the progression of CKD by suppressing the disruption of the epithelial barrier and regulating the anti-inflammatory response (25, 32). The level of indole propionic acid, derived from the gut flora, negatively correlates with p-cresyl sulfate and indoxyl sulfate concentrations in CKD patients (33).
Figure 1. The relationship between the gut microbiome and chronic kidney disease (CKD) is bi-directional. In one direction, the gut microbiota affect the kidney; the emerging role of gut microbiota in (A) The healthy gut, (B) The leaky gut due to microbial dysbiosis and disruption of the mucosal layer, (C) Release of pro-inflammatory factors in the bloodstream and initiation of the inflammatory cascade, accumulation of uremic toxins, (D) A decline in the estimated glomerular filtration rate (eGFR), the elevation of the albumin creatinine ratio (ACR) and loss of the endocrine functions of the kidney. In the other direction, CKD drives dysbiosis in the gut (indicated by the dotted arrows) and initiates an inflammatory cascade.
The composition of the gut microbiota can be altered by therapeutic dietary interventions and intake of probiotics, and so dietary interventions and probiotics intake can be used to improve CKD outcomes (27, 34). A very low-protein diet decreases plasma levels of indoxyl sulfate, and p-cresyl sulfate and increases the diversity of both butyrate-forming bacteria such as Coprococcus and Roseburia, and the levels of anti-inflammatory bacteria like Blautia and Faecalibacterium (27). A high-fiber diet improves kidney function by lowering the harmful uremic metabolite levels and decreasing microbial diversity (35). Conversely, a high-fat diet increases the plasma level of gut microbiota-derived TAMO metabolites in a mouse model (36).
While the gut is the main repertoire of microbes and the most studied site to date, urine and blood also harbor different types of microbes and microbial signatures in both healthy and disease conditions (22, 37, 38). Several studies have examined the role of gut-derived metabolites in CKD, but little is known about the role of the composition of the urinary and blood microbiomes in the progression of CKD (20, 28, 39).
Our manuscript will focus on the relationship between the human microbiome and its products in the CKD pathophysiology and modulating the gut microbiota as a therapeutic strategy for CKD treatment.
Pathophysiology of CKD
A medical literature search was conducted using PubMed for articles published until May 24th, 2021. The initial search was done using the general search terms: “microbiome,” “chronic kidney disease,” and “metabolites.” Only articles published in English were included. The search resulted in a total of 143 articles. After excluding review articles, we focused on 57 studies summarized in Tables 1, 2, 3, we classified the studies based on the CKD model into clinical studies, animal studies, and dietary interventions studies. References of the included articles were also reviewed for additional relevant articles.
Table 1. Role of gut microbiota and microbial related metabolites in the pathogenesis of CKD (Clinical studies).
Table 2. Role of gut microbiota and microbial related metabolites in the pathogenesis of CKD (Animal models studies).
Table 3. Effect of dietary intervention on CKD outcomes.
To sum up three studies were included in the clinical (Table 1) and animal (Table 2) studies, and one study was included in Tables 1, 3 as different CKD models have been used in these four studies. In the tables, we focused on the techniques used to assess gut microbiota and microbial related metabolites not all the techniques used in each study. Of note, gut microbiota and its related metabolites have a significant role in CKD progression and are associated with different circumstances. The exact mechanism of the gut-kidney axis is not clearly identified and both mechanisms of the role of gut microbiota in CKD (causative or consequence) are applicable. Furthermore, dietary intervention studies using animal models showed a change in the disease outcomes, but in humans did not show a big difference. This may be due to most of the participants were in a late CKD stage (ESRD or CKD on hemodialysis) in which most kidney functions are compromised.
CKD encompasses a spectrum of pathophysiologic processes associated with abnormal kidney function and a progressive decline in the glomerular filtration rate (GFR) (29). The underlying etiology varies by age, presence of co-morbid conditions, repeated occurrences of acute kidney injury and level of proteinuria (5, 6). The decline in kidney function and micro-structural changes are considered chronic when they last more than 3 months (85). Irrespective of the underlying etiology (which is considered the initiating mechanism), hyperfiltration and hypertrophy of the remaining nephrons, tubulointerstitial fibrosis, activation of the renin–angiotensin–aldosterone system, and disruption of endothelial barriers disruption are common and lead to a reduction in the renal excretion efficacy and decline in the eGFR (3, 86). The eGFR is used to grade disease severity in CKD patients, a higher grade is associated with a lower filtration rate and more advanced disease (85). The transition from one grade to the next grade is usually accompanied by a loss in the endocrine function of the kidney (86). In particular, CKD patients suffering from cardiovascular events show deterioration in renal functions and severe inflammation (87). Infiltration of immune cells in the tubulointerstitial space and accumulation of immune-derived components contribute to CKD progression (88). A key goal of CKD therapies is to prevent patients progressing to the next stage of the disease.
Microbial Dysbiosis in CKD
The dominant bacterial phyla in the gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria (89). The interplay between bacteria present in the gut (and their metabolites) and kidney function is occasionally referred to as the gut–kidney axis (90). Recent studies indicate that aberrant gut microbiota has a key role in the pathophysiology of CKD with severe CKD outcomes (24, 61). Bifidobacterium and Lactobacilli are negatively correlated with CKD progression and long-term survival (27, 34, 39). A study of 223 patients with end-stage renal disease revealed that Eggerthella lenta, Fusobacterium nucleatum, and Alistipes shahii are positively correlated with increased levels of secondary bile acids and uremic toxins in CKD patients compared with the control group (39). In this study, the authors showed that the presence of Faecalibacterium prausnitzii, Roseburia, and Prevotella (which produce short-chain fatty acids) was negatively correlated with disease progression and uremic toxin accumulation (39). Another study of 92 patients with CKD reported an increased abundance of Paraprevotella, Pseudobutyrivibrio, and Collinsella stercoris in the CKD cohort; this finding led the authors to suggest that this signature can be used to discriminate between patients with CKD (even those in the early stages of the disease) and healthy individuals (20).
Dysbiosis in the gut has an emerging role in many inflammatory-related diseases and is thought to contribute to the inflammatory component of both acute and chronic kidney disease (91, 92). Microbial alterations in the gut affects the permeability of the intestinal mucosal barrier and releases pro-inflammatory factors and endotoxins in the bloodstream, which initiate the inflammatory cascade (93).
Another mechanism by which gut dysbiosis may contribute to CKD progression is via the role of gut dysbiosis in endothelial dysfunction, the vasoconstrictor response, and the subsequent development of hypertension; a well-known risk factor for CKD (94, 95). Mice fed a high-salt diet had aberrant microbiota compared with mice fed a normal diet; these changes were associated with activation of T-lymphocytes and an elevation in blood pressure (96). A lower abundance of Lactobacillus species in the gut is associated with the development of hypertension and kidney diseases (97). Changes in the gut microbiota could be the starting point for CKD progression through a series of immune response modifications, blood pressure alterations, metabolic changes, and prolonged inflammation.
Microbial Metabolites in CKD
In general, microbial metabolites associated with CKD are classified into two groups; harmful and renoprotective metabolites. This bi-direction relationship of microbial-derived metabolites is illustrated in Figure 2. Several human and animal studies have demonstrated the deleterious effects of TAMO on the kidney, manifested as kidney interstitial fibrosis, eGFR decline, endothelial dysfunction, and an increased risk of cardiovascular disease risk (34, 36, 47, 81). The increased risk of mortality and morbidity in patients with CKD has been attributed to the accumulation of indoxyl sulfate and p-cresyl sulfate (27, 28, 33, 39). These toxins bind with high affinity to plasma proteins, which mitigates their removal through the dialysis membrane (28). TAMO, indoxyl sulfate, and p-cresyl sulfate are involved in SMAD signaling, tryptophan metabolism, and tyrosine pathways, respectively (20, 46, 54).
Figure 2. The bidirectional role of gut-derived metabolites in the pathophysiology of CKD; (A) Beneficial bacteria produce renoprotective metabolites that inhibit kidney damage, (B) Unfavorable bacteria produce harmful metabolites which promote kidney damage and CKD progression. Trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), p-cresyl sulfate (PSC), short-chain fatty acids (SCFAs), bile acids (Bas), and Indole derivatives (IDs).
A wide array of uremic toxins and other microbial metabolites accumulate in biological samples of patients with CKD, including those in common biological samples such as plasma, stool, and urine, but also volatile metabolites in exhaled breath and gases collected from fecal cultures. For example, accumulation of gaseous metabolites including isoprene, aldehyde, dimethyldisulfide, dimethyltrisulfide, and thioesters occurs in patients with CKD (65).
Dietary Interventions and CKD
Microbial dysbiosis and accumulation of gut-derived metabolites have been reported in CKD patients (20, 29, 53). Randomized controlled clinical trials in patients with CKD indicate that changes in the composition of the gut microbiota after treatment with prebiotics and probiotics improved disease outcomes and reduced uremic toxin levels (98–100). Patients with a high abundance of Bifidobacterium and Lactobacillus had lower serum levels of uremic toxins, a reduced inflammatory milieu, and improved renal function (98, 101).
The consumption of food items rich in choline and L-claritin—which are precursors of TAMO—such as egg yolk, kidney, liver, meat and milk, correlates with a high accumulation of uremic toxin and a decline in the glomerular filtration rate (102). A prospective, crossover clinical trial randomized 60 patients with CKD to different dietary interventions; the group on the very low-protein diet had an increase in the gut abundance of Actinobacteria and a decrease in the inflammatory Proteobacteria compared with the group on a regular diet (27).
Prebiotics are non-digestible dietary components such as dietary fiber and digestion-resistant starch. They are present in cereals, fruits, milk, honey, and vegetables or can be given as a dietary supplement (103). Fermentation of prebiotics beneficially modifies gut bacteria by increasing the abundance of Bifidobacterium spp and lactobacillus and reducing the levels of Bacteroides, Clostridia, and Enterobacteria (104). In patients with CKD, dietary fiber intake decreases the levels of circulating pro-inflammatory cytokines, slows the decline in eGFR, lowers the plasma levels of uremic toxins, and minimizes CKD-related cardiovascular risk (105, 106). Esgalhado and colleagues studied the effect of digestion-resistant starch supplementation (16 g/day) in patients with CKD; they observed a reduction in the plasma levels of uremic toxins (indoxyl sulfate, and p-cresyl sulfate), interleukin (IL)-6, and thiobarbituric acid-reactive substances (107). These results are consistent with another study of 32 patients with CKD randomized into two groups; the group that received lactulose syrup for 8 weeks had a greater abundance Bifidobacterium and Lactobacillus in the gut microbiome and decreased serum creatinine levels (108). While these studies demonstrated that probiotics and prebiotics have a beneficial effect on CKD, other studies have shown no significant changes in circulating gut-derived metabolites or changes in CKD outcomes (34, 84). It is important to point out that existing studies are heterogeneous; they used different dietary supplements, had varying durations of intervention, and administered to patients with other comorbidities, patients with varying kidney disease severity and varying underlying etiology. This heterogeneity makes it extremely difficult to draw conclusions from these studies. That being said, superior results may be obtained from the study of dietary interventions in children as other cofounding factors are minimal.
Overall, these studies imply that nutrition therapy has the potential to modulate the microbiome composition and its metabolites, and consequently ameliorate CKD complications and the rate of CKD progression. However, further well-designed, prospective studies are needed to definitively demonstrate the benefit of nutrition therapy on CKD.
Role of the Urinary and Blood Microbiomes in CKD
Most of the attention in the microbiome field is on the gut microbiota and its metabolites; however, the urinary microbiome is receiving more attention. Until recently, urine was considered a sterile fluid that was only rendered unsterile because of infection (109, 110). But the development of next-generation sequencing techniques enabled studies showing that the urinary tract of healthy individuals is dominated by different kinds of microbes, and the distribution pattern of these microbes affects the health of urinary tract health (110, 111). Fluctuation in the urinary microbiome occurs in urinary tract infections and is involved in antibiotic resistance (109, 112). The urinary microbiome undergoes changes after kidney transplantation, and these modifications thought to be responsible for allograft dysfunction and increased susceptibility to infection (113, 114). In addition, the diversity in microbes in the urinary tract of patients with CKD is associated with the eGFR value (115).
The circulatory microbiome in healthy individuals contains diverse bacterial taxa, and the dominated phylum is Proteobacteria (38). Gut-derived endotoxins circulating in the bloodstream were shown to alter the blood microbiome (93). A study investigating the correlation between blood metabolome and α-diversity of gut microbiota on 399 participants indicated that gut-derived metabolites like p-cresyl and TAMO reflect the Shannon diversity of gut bacteria and could be a biomarker reflecting the gut health (116). A case-controlled study using 16S rRNA target sequencing of blood samples showed that compared with control groups, patients with CKD had a higher diversity of Enterobacteriaceae and Pseudomonadaceae, which was also correlated with lower eGFR (117). Hence, we see the gut microbiota has an ultimate effect on CKD outcomes through different routes.
Conclusion
Microbial dysbiosis plays an important role in the pathogenesis of various diseases. In this review, we summarized and reviewed the literature examining the dual role of the gut microbiome and its metabolic products in the pathophysiology and progression of CKD. We described how gut dysbiosis can initiate the inflammatory process and cause leaking of gut-derived metabolites into the bloodstream. It is well-established that TAMO, indoxyl sulfate, and p-cresyl sulfate and other harmful microbial metabolites accumulate in patients with CKD, and levels of these metabolites correlate with disease progression. Lower levels of bifidobacterium, lactobacillus, and bile acid composition are linked to adverse outcomes in patients with CKD. Our analysis of the literature suggests that the complex interaction between the gut, urinary tract and blood microbiota and associated metabolites may orchestrate subclinical changes in the pathogenesis of CKD and contribute to disease. Modulating the gut microbiota using dietary interventions could improve the clinical outcomes of patients with CKD. Our recommendations are i. conducting omics-based studies like metagenomics and metatranscriptomics to identify the gut microbiota community, metabolic pathways, and microbial genes associated with CKD. ii. screening gut microbiota at different disease stages, especially at the early disease stages. iii. performing dietary intervention studies for CKD patients in the early stages. iv. assessment of urinary and blood microbiome studies for CKD patients. These directions may give a clue about the disease etiology, metabolic pathways and potential treatment for CKD.
Author Contributions
EW wrote the first draft. IS and SA reviewed and finalized the content of the manuscript. All authors read and approved the final version.
Funding
This work is funded by Sidra Medicine Internal Research Fund 2019 (No. SDR 200055).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
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Keywords: chronic kidney disease, gut microbiota, urinary microbiome, dysbiosis, uremic toxins, renoprotective, diet therapy
Citation: Wehedy E, Shatat IF and Al Khodor S (2022) The Human Microbiome in Chronic Kidney Disease: A Double-Edged Sword. Front. Med. 8:790783. doi: 10.3389/fmed.2021.790783
Received: 07 October 2021; Accepted: 20 December 2021;
Published: 17 January 2022.
Edited by:
Dong Zhou, University of Connecticut, United StatesReviewed by:
Yanjiao Zhou, UCONN Health, United StatesYue Tu, Nanjing University of Chinese Medicine, China
Minggang Wei, The First Affiliated Hospital of Soochow University, China
Copyright © 2022 Wehedy, Shatat and Al Khodor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Souhaila Al Khodor, salkhodor@sidra.org