This intestinal microbial species exert a remarkable influence on the absorption, metabolism, and storage of nutrients
[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
[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
[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
[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)
[21][22].
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
[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
[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)
[25].
3. Nutritional Strategies Focusing on the Gut Microbiota as a Novel Treatment for Counteracting CKD Progression
As recently reviewed by Naber and Purohitet
[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
[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 [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
[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
[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
[32]. The concept of prebiotics was initially introduced in 1995 by Gibson and Robefroid
[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
[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
[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
[36].
As reviewed by Zirker
[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
[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
[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
[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
[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
[40]. For instance, a meta-analysis conducted by Yu et al.
[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
[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
[42]. Plants and their extracts can be used as dietary supplements, herbal medicines, or as part of a healthy diet
[43]. They contain organic compounds that exert specific physiological actions, including phenols, saponins, glycosides, flavonoids, alkaloids, tannins, steroids, and terpenoids
[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
[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.