Kidney–Gut Axis as Target for Chronic Kidney Disease: Comparison
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A well-balanced diet is integral for overall health, aiding in managing key risk factors for kidney damage like hypertension while supplying necessary precursors for metabolite production. Dietary choices directly influence the composition and metabolic patterns of the gut microbiota, showing promise as therapeutic tools for addressing various health conditions, including chronic kidney diseases (CKD). CKD pathogenesis involves a decline in the glomerular filtration rate and the retention of nitrogen waste, fostering gut dysbiosis and the excessive production of bacterial metabolites. These metabolites act as uremic toxins, contributing to inflammation, oxidative stress, and tissue remodeling in the kidneys. Dietary interventions hold significance in reducing oxidative stress and inflammation, potentially slowing CKD progression. Functional ingredients, nutrients, and nephroprotective phytoconstituents could modulate inflammatory pathways or impact the gut mucosa. The “gut–kidney axis” underscores the impact of gut microbes and their metabolites on health and disease, with dysbiosis serving as a triggering event in several diseases, including CKD. 

  • chronic kidney disease
  • gut microbiota
  • gut–kidney axis

1. Introduction

A well-balanced diet undoubtedly helps maintain overall health, while also aiding in the management and reduction of primary risk factors for kidney damage, such as diabetes and hypertension. It also serves as a primary supplier of the precursors necessary for metabolite production. In practice, dietary choices shape the composition of gut microbiota (GM), since the nutrients may directly influence the GM, impacting both its structure and the metabolic patterns of its microbial inhabitants, and thus emerge as promising therapeutic tools for addressing a variety of health conditions, including kidney diseases. A large and growing body of evidence solidifies the link between the Western diet intake, characterized by the excessive consumption of fatty and processed meats, saturated fats, salt, and sugars, and a simultaneous deficiency in fresh fruits and vegetables, with the onset of numerous diseases, including chronic kidney disease (CKD) [1]. As recently reviewed by Dobrek [2], a critical aspect of CKD pathogenesis also involves the interplay between the progressive decline in glomerular filtration rate (GFR) and the retention of nitrogen metabolic waste products. This dynamic interaction contributes to the emergence of gut dysbiosis and an excessive production of bacterial metabolites, such as phenols, indoles, and amines. As a result, it increases intestinal wall permeability, allowing these substances to enter the bloodstream, where they act as uremic toxins, perpetuating inflammation and enhancing oxidative stress in kidney tissues, ultimately playing a crucial role in tissue remodeling [2]. Therefore, dietary interventions seem to be of significant importance for patients with CKD, as they can help reduce oxidative stress and inflammation, thereby potentially slowing down the progression of CKD [3]. In this context, functional ingredients and nutrients like fiber, prebiotics, probiotics, synbiotics, and fatty acids, along with nephroprotective phytoconstituents, may play a pivotal role. They can either modulate pro- and anti-inflammatory pathways or exert their effects at the gut mucosal level.

2. The Kidney–Gut Axis: A Potential Connection between Gut Dysbiosis and CKD

The kidney plays a critical role in maintaining plasma osmolarity by intricately regulating water, solute, and electrolyte levels in the bloodstream. Beyond this, they also maintain an acid-base balance, produce essential hormones, and participate in specific metabolic functions. Of notable significance, the kidneys are indispensable in excreting nitrogenous waste products, including urea, creatinine, and ammonia ions. Consequently, any substantial alterations in renal function lead to the accumulation of these waste products within the body [6][4]. It should be emphasized that the kidneys’ ability to perform their functions is predominantly determined during fetal development. Throughout this phase, the formation of nephrons occurs, and the final number that is established before birth becomes the lifelong kidney endowment. A literature analysis reveals considerable variability in the number of nephrons, observed in both humans [7][5] and various animals, such as mice [8][6], rats [9][7], pigs [10][8], and sheep [11][9]. Recent findings strongly indicate that the gut microbiota (GM) have emerged as a key player in CKD pathogenesis, and the interaction between GM and CKD is reciprocal. CKD can influence the composition of the gut microbiota, leading to gut dysbiosis. Conversely, dysbiosis in CKD patients may elevate uremic toxin levels, thereby contributing to the progression of CKD [18,19,20][10][11][12]. Microorganisms, including bacteria, yeasts, and viruses, residing within the gastrointestinal tract, collectively referred to as the GM, play a crucial role in maintaining the overall balance and well-being of the host, although they can also act as a potential source of disease [21][13].  From the moment of birth, the establishment of the microbiome is an extremely dynamic process, characterized by continuous changes in its composition, which are greatly influenced by a wide range of external factors, especially during the early stages of life. Elements like the delivery method, dietary preferences, hygiene practices, and medication use, particularly antibiotics, all play a significant role in shaping the final composition and diversity of the gut microbiota [23][14]. During the first 2–3 years of human life, the gut microbiome starts to develop, eventually stabilizing into a configuration that closely resembles the typical microbial taxonomy found in adults [24][15]. This intestinal microbial species exert a remarkable influence on the absorption, metabolism, and storage of nutrients [4][16]. Most importantly, GM also play a critical role in facilitating the fermentation of a diverse array of compounds, especially those that that are resistant to digestion by human enzymes. This results in the generation of a diverse array of metabolites that can affect host cells, tissues, and organs [26][17]. Gut-microbiota-derived products encompass both intermediates and the end products of bacterial metabolic processes, and their ultimate composition in the gut is greatly influenced by the dietary intake of specific nutrients. The microbial fermentation of complex non-digestible dietary carbohydrates primarily occurs in the cecum and proximal regions of the colon. The large intestines also serve as a site for the fermentation of dietary proteins that escaped digestion in the upper regions of the gastrointestinal tract. Residual proteins and peptides are subjected to hydrolysis, breaking down into amino acids through the action of extracellular proteases and peptidases produced by intestinal microorganisms [27][18]. It should be emphasized that the non-digestible carbohydrate fermentation is much more favorable as it results in the production of short-chain fatty acids (SCFAs) and gases such as carbon dioxide, hydrogen, methane, and hydrogen sulfide [28,29][19][20]. SCFAs, particularly acetate, propionate, and butyrate, are recognized for their crucial roles in regulating the energy metabolism, preserving the integrity and functionality of the gut barrier, inhibiting inflammation and oxidative stress, and modulating the immune response (Figure 1) [30,31][21][22].
Metabolites 14 00078 g001
Figure 1. Effects of short-chain fatty acids on the body. SCFAs are the end products of the bacterial fermentation of complex polysaccharides. SCFAs are straight-chain saturated fatty acids, including acetate, propionate, and butyrate. SCFAs are involved in regulating energy metabolism, inhibiting inflammation and oxidative stress, and regulating the immune response.
On the other hand, undigested dietary proteins represent a significant source of nitrogen, urea, and other protein fermentation products in the colon. When there is inadequate dietary carbohydrate intake, a significant amount of α-amino nitrogen is generated from the microbial fermentation of aromatic amino acids such as tyrosine, phenylalanine, and tryptophan [32][23]. The alpha-amino nitrogen is subsequently metabolized in colonocytes and the liver to form so-called protein-bound uremic toxins such as p-cresyl sulfate (PCS), indoxyl sulfate (IS), indole acetic acid (IAA), kynurenate, phenyl sulfate, and uric acid. In patients with chronic kidney disease, the reduced renal excretion of PCS, IS, and IAA leads to an increased accumulation of these metabolites in the blood, and also in the intestinal epithelium [33][24]. The enhanced transfer of these gut-derived uremic toxins into the bloodstream can significantly elevate cardiovascular morbidity and mortality. This is due to their well-documented role in promoting vascular calcification through a variety of mechanisms, including the apoptosis of vascular smooth muscle cells, impairment of endothelial cell function, induction of oxidative stress, and interaction with the local renin-angiotensin–aldosterone system (Figure 2) [34][25].
Metabolites 14 00078 g002
Figure 2. An inadequate diet contributes to the development of a dysbiotic intestinal microbiota. Intestinal dysbiosis leads to the increased production of potentially toxic metabolites such as indoxyl sulfate and p-cresyl sulfate, and increased permeability and damage to the intestinal barrier. Damage to the intestinal barrier results in increased host exposure to uremic toxins and endotoxins. The accumulation of uremic toxins in the body contributes to increased oxidative stress and inflammation, resulting in the development of chronic kidney disease (CKD).

3. Nutritional Strategies Focusing on the Gut Microbiota as a Novel Treatment for Counteracting CKD Progression

As recently reviewed by Naber and Purohitet [47][26], CKD is closely associated with several clinically important complications, including hypertension, hyperkalemia, hyperphosphatemia, and metabolic acidosis; however, these risks can be reduced, and the disease’s progression slowed, through the diligent monitoring of protein, phosphorus, potassium, sodium, and calcium levels in the diet, potentially alleviating the progressive loss of renal function symptoms. Given the close bidirectional association between gut microbiota and CKD progression, it is also crucial to emphasize the significance of gut-derived uremic toxins in this process. These toxins impact the intestinal, renal, and cardiovascular systems and are challenging to eliminate through standard dialysis methods. Therefore, they warrant special attention in the context of CKD treatment. The modulation of GM with an emphasis on increasing saccharolytic bacteria over proteolytic bacteria through the use of prebiotics, probiotics, and synbiotics could represent an especially promising potential therapeutic avenue.
Probiotics are living, non-pathogenic microorganisms that, when consumed in sufficient quantities, can inhabit the intestines and exert a positive influence on the gut microbiota by promoting the growth of beneficial bacteria [48][27]. These microorganisms can encompass a diverse range, including bacteria, yeast, and molds. Among them, the most commonly used probiotics include Bifidobacteria, Lactobacillus, Propionibacteria, Bacillus, Akkermansia muciniphila, and Saccharomyces [49][28]. Lactobacillus- and Bifidobacterium-based probiotics play a crucial role in altering gut pH, countering pathogens by generating antimicrobial compounds, and competing for binding sites with pathogens, as well as for available nutrients and growth factors, triggering immunomodulatory cells and producing enzymes like lactase, as well as essential vitamins such as B1, B4, B6, and B12 [50][29]. These probiotic strains also have the potential to restore the mucosal barrier of the gut and generate short-chain fatty acids through cross-feeding interactions, thereby promoting the growth of other colonic bacterial species. This process may help mitigate uremic toxicity, lower pro-inflammatory markers, and slow the progression of chronic kidney disease [51,52][30][31].
On the other hand, prebiotics could provide an alternative to probiotics due to their well-documented, comprehensive, health-promoting effects, which may aid in mitigating chronic kidney failure [75][32]. The concept of prebiotics was initially introduced in 1995 by Gibson and Robefroid [76][33]. These authors defined prebiotics as dietary components that remain undigested in the upper gastrointestinal tract and have a beneficial influence on the host organism by selectively stimulating the growth and/or activity of bacterial populations in the colon [76][33]. In subsequent years (2004–2007), thanks to the simultaneous collection of data from both animals and humans, the concept of prebiotics expanded and was redefined as natural plant-derived ingredients that confer health benefits to the host by modulating the growth and activity of gut microbiota [77,78][34][35]. The current definition of prebiotics was introduced in 2016 during a meeting of the International Scientific Society for Probiotics and Prebiotics (ISAPP). The expert panel ultimately identified prebiotics as substrates that are selectively utilized by microorganisms, thus promoting improvements in host health [79][36]. 
As reviewed by Zirker [90][37], various types of prebiotic carbohydrates can be utilized in patients with CKD. These include inulin-type fructans (ITFs), which are divided into three subcategories: long-chain (inulin), medium-chain (oligofructose or fructooligosaccharides), and short-chain fructose monomers (short-chain fructooligosaccharides). Additionally, there are other prebiotic carbohydrates, like mannan oligosaccharides (MOS), xylooligosaccharides (XOS), galactooligosaccharides (GOS), raffinose oligosaccharide (RFO), isomaltooligosaccharide (IMO), and other non-starch polysaccharides (NSP), such as β-glucans, arabinoxylans, and pectins. Indeed, both dietary sources and prebiotic supplements are readily available to CKD patients [90][37]. Prebiotics naturally exist in various plant-based foods, including wheat bran, soy, raw potatoes, raw oats, unrefined wheat, wholegrain barley, onions, beans, green bananas, asparagus, and chicory [75,91][32][38]. They play a crucial role in CKD prevention by fostering the growth of health-promoting bacteria, such as Bifidobacterium and Lactobacillus. This, in turn, reduces the production of uremic substances originating in the colon while increasing the production of short-chain fatty acids [46][39]. For individuals with end-stage kidney disease who adhere to protein-restricted diets, prebiotics emerge as a crucial dietary supplement. They contribute to the elevation of short-chain fatty acids, positively influencing the metabolites produced by the gut bacteria and concurrently reducing systemic inflammation [52][31]. However, similar to probiotics, there is currently no established daily recommended dosage of dietary prebiotics for CKD patients. 
Synbiotics are probiotic supplements combined with prebiotics, which have attracted significant interest in the context of chronic kidney disease therapy due to the potentially synergistic effects of their individual components. However, the results obtained so far are inconclusive, and further research is necessary to confirm the efficacy of synbiotics as a therapy for chronic kidney disease [88][40]. For instance, a meta-analysis conducted by Yu et al. [52][31] assessed the effectiveness of dietary supplementation with probiotics, prebiotics, and synbiotics in individuals undergoing dialysis for end-stage renal disease. The findings revealed that prebiotics were particularly effective in reducing the plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as in lowering plasma levels of indoxyl sulfate (IS), malondialdehyde (MDA), and blood urea nitrogen (BUN). On the other hand, synbiotics demonstrated greater efficacy in lowering plasma levels of C-reactive protein (CRP) and endotoxins, including protein-bound uremic toxins. 
Medicinal plants have been used for centuries, with many modern drugs originating from natural products that were initially utilized in traditional medicine [94][41]. The demand for herbal remedies is increasing in both developing and developed countries due to their affordability and minimal side effects. Phytochemicals and medicinal plants are gaining significance in healthcare due to their natural origin and safety [95][42]. Plants and their extracts can be used as dietary supplements, herbal medicines, or as part of a healthy diet [96][43]. They contain organic compounds that exert specific physiological actions, including phenols, saponins, glycosides, flavonoids, alkaloids, tannins, steroids, and terpenoids [97][44]. Phytochemicals influence the gut microbiome by promoting the growth of probiotics and limiting the development of pathogens. Phytochemicals are distributed in various plant tissues, cell walls, and subcellular compartments, exhibiting diverse biological activities. These include antioxidant, chemopreventive, neuroprotective, cardioprotective, and immunomodulatory properties, as supported by research [98][45].

4. Conclusions

In conclusion, the intricate relationship between the gut microbiota and overall health, particularly its impact on chronic kidney disease, underscores the importance of understanding and modulating this complex ecosystem. The gut microbiota’s crucial functions extend beyond nutrient absorption, metabolism, and storage to include the fermentation of non-digestible dietary carbohydrates, yielding short-chain fatty acids that play pivotal roles in energy metabolism, gut barrier integrity, inflammation inhibition, and immune response modulation. However, the delicate balance of the gut microbiota can be disrupted, especially in CKD, leading to the accumulation of uremic toxins, such as indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide. These toxins contribute to cardiovascular morbidity and mortality, primarily through mechanisms like vascular calcification, inflammation, and oxidative stress. The dysbiosis observed in CKD, characterized by an imbalance between proteolytic and saccharolytic bacteria, results in enhanced intestinal permeability, systemic inflammation, and impaired tight junctions.
Novel therapeutic approaches focus on manipulating the gut–kidney axis through interventions targeting the gut microbiota. Probiotics, prebiotics, and synbiotics emerge as potential strategies. Probiotics, comprising beneficial microorganisms like Lactobacillus and Bifidobacterium, can positively influence the gut microbiota, but the optimal dosage and strain selection remain uncertain. Prebiotics, including dietary fibers and non-carbohydrate compounds, promote the growth of beneficial bacteria, potentially mitigating uremic toxicity and inflammation. Synbiotics, combining probiotics and prebiotics, present a synergistic approach with promising but inconclusive results in CKD therapy.
In the quest to unravel the complexities of the gut–kidney axis, ongoing research will undoubtedly seek to identify optimal interventions, including dietary modifications and supplementation, to foster a healthy gut microbiota and mitigate the progression of chronic kidney disease. The multifaceted interactions within the gut microbiome and their consequences underscore the need for personalized and targeted therapeutic approaches tailored to the diverse landscape of individual microbiomes and CKD stages.

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