Probiotic interventions in peritoneal dialysis: A review of underlying mechanisms and therapeutic potentials

Abstract

Peritoneal dialysis (PD) is a commonly used modality for kidney replacement therapy for patients with end-stage kidney disease (ESKD). PD offers many benefits, including home-based care, greater flexibility, and preservation of residual kidney function compared to in-center hemodialysis. Nonetheless, patients undergoing PD often face significant challenges, including systemic inflammation, PD-related peritonitis, metabolic disorders, and cardiovascular issues that can negatively affect their quality of life and treatment outcomes. Recent studies have demonstrated the crucial role of the gut microbiome in overall health and treatment results, supporting the hypothesis that probiotics may bring potential benefits to the general population of ESKD patients. However, specific data on probiotic use in PD patients are limited. This opinion review aims to summarize the current knowledge on the relationship between PD and the gut microbiome and offers a novel perspective by specifically exploring how probiotic interventions could improve the outcomes of PD treatment. The review also outlines some clinical data supporting the effectiveness of probiotics in patients undergoing PD and considers the difficulties and restrictions in their application. Based on the current knowledge gaps, this study seeks to explore future research directions and their implications for clinical practice.

Key Words: Peritoneal dialysis; Probiotics; Gut; Microbiota; Inflammation; Effectiveness; Treatment

Core Tip: One essential strategy for optimizing peritoneal dialysis (PD) outcomes may involve exploring probiotic interventions to modulate the intestinal microbiome. Recent research highlights altered gut microbiota in PD patients and their impact on inflammation, residual kidney function, and risks of peritonitis, technique failure, and cardiovascular disease. Probiotics could enhance intestinal defenses, regulate immune responses, and manage inflammation, potentially benefiting PD patients. Despite the limited data on probiotics for this patient cohort, exploring their use may represent a new approach to improving patients’ clinical outcomes and the sustainability of dialysis, with further research required to uncover their full potential and limitations.

INTRODUCTION

End-stage kidney disease (ESKD) is a growing global health burden affecting approximately two million individuals worldwide, with an incidence rate of 144 per million population per year[1,2]. The aging population, the increasing global incidence of diabetes mellitus, arterial hypertension, obesity, and the prolonged use of certain medications are key factors contributing to the rising prevalence of ESKD[3]. Despite recent advancements in the prevention and treatment of chronic kidney disease (CKD), the progression to ESKD remains a significant challenge, with mortality rates up to fivefold higher than the general population[1,2].

Timely and effective kidney replacement therapy (KRT) is crucial for ESKD patient survival. Among the available dialysis KRT options, peritoneal dialysis (PD) has emerged as a flexible and patient-centered approach[4,5]. PD offers several benefits, including the convenience of at-home treatment and the preservation of residual kidney function (RKF), which help address some of the limitations of in-center hemodialysis (HD), such as the frequent need for clinic visits and the associated disruption to daily life[4,6]. While effective, HD requires regular, often lengthy sessions at a healthcare facility, which can impact patients’ quality of life and restrict their daily activities[1]. However, PD also presents its own set of challenges, including maintaining the integrity of the peritoneal membrane, preventing PD-associated infections, and effectively managing systemic inflammation and uremic toxicity[4,6].

In recent years, there has been growing interest in exploring the effects of the gut microbiome on human health and disease, including CKD[7,8]. The gut microbiome, which comprises a diverse community of microorganisms inhabiting the digestive system, has been linked to various physiological processes relevant to CKD[9,10]. Examples include metabolic homeostasis, immune modulation, and the production and detoxification of uremic toxins. Dysbiosis, or the imbalance of this microbial community, has been associated with exacerbated systemic inflammation, increased cardiovascular risk, and heightened uremic toxicity in patients with CKD[9,11]. Moreover, variations in the gut microbiome and metabolome have been observed based on the causes and stages of CKD[9,11,12] and feature distinct peculiarities in patients undergoing PD[13,14].

Probiotics, defined as live microorganisms that confer health benefits to the host when administered in appropriate quantities, have emerged as a promising strategy for managing dysbiosis and its related complications in PD[11,15]. The therapeutic capacity of probiotics in this context is diverse because they target the complex relationship between the gut microbiome, systemic inflammation, and uremic toxin production[16,17]. Through the adjustment of the gut microbiota composition, probiotics may diminish the formation of gut-derived uremic toxins, such as indoxyl sulfate (IS) and p-cresol, alleviate systemic inflammation, and strengthen the gut barrier’s integrity[18-20]. Collectively, these mechanisms have the potential to enhance the general health and quality of life of PD patients. However, the scientific foundation for probiotic treatments in PD is constrained and characterized by a scarcity of randomized controlled trials and inconsistencies in research methodologies, probiotic strains utilized and their dosages, and treatment durations[9,15]. Moreover, the effects of probiotics on clinical outcomes, such as infection rates, cardiovascular disease (CVD), and mortality in PD patients, remain unclear, thus highlighting the need for further research[11,20].

This opinion review aims to summarize the current knowledge on the complex relationship between PD and the gut microbiome and hypothesize how probiotic interventions could improve the outcomes of PD treatment. While probiotics have been studied in broader CKD populations, this study uniquely addresses the scarcity of data in patients undergoing PD. The review examines the fundamental mechanisms through which probiotic treatments could be advantageous for PD patients, focusing on their effects on the gut microbiota, uremic toxin production, inflammation, and cardiovascular risk. It also assesses the existing evidence from clinical trials, deliberates on the disputes and limitations of current studies, and proposes future research directions to establish the therapeutic potential of probiotics in managing PD patients.

PD AND THE GUT MICROBIOME

CKD and PD: Partners influencing the gut microbial ecosystem

CKD and PD play interconnected roles in altering the gut microbiota of patients. This contributes to profound changes in microbial composition and function, which can end up affecting patient health and outcomes. CKD initiates a cascade of changes within the gut microbiota-part of the broader gut–kidney axis-and reflects the bidirectional relationship between kidney function and the gut microbiome[9,21]. CKD progression features the accumulation of uremic toxins, changes in the body’s immune response, and alterations in the intestinal environment; all of these contribute to a shift in the gut microbiota[9,22,23]. Ultimately, it contributes to a decrease in microbial diversity, an increase in pathogenic bacteria, and a reduction in beneficial bacteria, often demonstrating an increase in the Firmicutes-to-Bacteroidetes ratio[10,22,24]. The Firmicutes-to-Bacteroidetes ratio is a key metric used to assess the composition of the gut microbiome, with normal values ranging from 0.1 to 10 or higher in healthy adults[25]. It has been associated with various health conditions, including CKD progression, and contributes to complications such as CVD, infections, and increased inflammation[11,26].

Another consequence of an altered gut microbiota is the production of uremic toxins, which exacerbate CKD progression. One significant consequence of this altered microbiota is the disruption of the intestinal epithelial barrier, a critical defense mechanism that prevents the translocation of harmful substances from the gut into the bloodstream[27-29]. The intestinal barrier dysfunction is compounded by uremic toxins, which not only degrade tight junction proteins essential for maintaining epithelial barrier integrity but also promote inflammation and oxidative stress, thereby accelerating CKD progression, CVD, and mortality[9,23,27,28].

PD therapy entails continuously infusing dialysis solution into the peritoneal cavity using the peritoneum as a natural semipermeable membrane to eliminate waste products and excess fluid from the bloodstream[30]. However, the prolonged exposure of a patient’s intestine to glucose-containing dialysis solutions and the increased intra-abdominal pressure associated with the PD solution can significantly affect the gut microbiota environment, potentially exacerbating the dysbiosis initiated by CKD[31,32]. Therefore, the choice of dialysis solution and its composition, tailored to each patient’s needs, can influence the gut microbiota profile[14]. This effect is exacerbated by underlying kidney diseases in which type 2 diabetes mellitus is the most prevalent[33,34]. Chronic hyperglycemia is well-known for its adverse effects on the kidneys and myocardium[35], often leading to atherogenic dyslipidemia[36], significant oss of RKF[37], and a high mortality rate in PD patients[34]. As a result, impaired kidney function, a hyperglycemic state, and dialysis characteristics hinder the efficient elimination of gut-derived byproducts, leading to the accumulation of uremic toxins in the gut[38–40]. When uremic toxins constantly build up, they can trigger changes in the gut microbiota structure, exacerbating intestinal barrier dysfunction, and causing systemic effects that contribute to inflammation, cardiovascular risk, infection, and other complications[14,31,40]. It has been demonstrated that long dialysis duration, high peritoneal glucose exposure, and loss of RKF are associated with gut microbiota alteration and reduced short-chain fatty acid (SCFA) production in PD patients[31]. In addition, comorbidities, the use of medications, dietary restrictions, and nutritional status can all influence the gut microbiota[10,41,42]. Recent data have shed light on the existence of a specific microbiome within the peritoneum of patients with ESKD, indicating that PD therapy may induce changes in this unique microbiome[43]. These findings suggest the possibility of PD-induced translocation of gut microbiota directly to the peritoneum, which has potential implications for the success and sustainability of PD treatment.

In sum, PD therapy exacerbates CKD-initiated dysbiosis, contributing to intestinal barrier dysfunction, systemic inflammation, and adverse clinical outcomes. PD can lead to a distinct gut microbiota profile that is influenced not only by the dialysis modality but also by individualized dialysis prescriptions and the patient’s unique clinical characteristics. The subsequent sections explore the current understanding of the unique characteristics of gut microbiota and metabolites in PD patients, emphasizing their clinical relevance.

Variations in gut microbiota composition in PD

Studies investigating specific alterations in the gut microbiota among patients undergoing PD are not as abundant and exhibit more variability than those focusing on the broader population of patients with CKD[44]. For example, the overwhelming majority of studies have reported a significant decrease in both the alpha and beta diversity of the gut microbiota in PD patients compared with healthy controls. Metrics, such as the Shannon, Chao1, and ACE indices, which are used to assess alpha diversity and account for both richness and evenness of species, have been found to be significantly reduced in PD patients in multiple studies[14,31,44,45]. In addition, metrics of beta diversity, such as Bray–Curtis dissimilarity or UniFrac distances, quantify the differences in microbial composition between samples and indicate distinct microbial community structures in PD patients compared with healthy controls[13,44,46]. However, some reports have shown no significant differences in alpha and beta diversity indices between PD patients and healthy controls. Teixeira et al[47] found no significant differences in the Shannon, Chao1, and ACE indices between PD patients and age-matched household contacts. Similarly, another study reported no significant differences in alpha diversity between PD patients and controls[48].

Comparisons with pre-dialysis and HD patients also revealed variations in the differences in gut microbiota composition between these groups. Some studies have reported greater reductions in alpha diversity indices and more pronounced shifts in the abundance of certain microbial taxa in PD patients compared with non-dialysis ESKD and HD patients[13,46,49]. However, other studies have found no significant differences in alpha diversity or overall gut microbiota composition between PD and HD patients[45,50]. Despite these inconsistencies, all studies revealed significant alterations in the gut microbiota composition at the taxonomic levels of phylum, class, order, family, genus, and species in PD patients compared with both healthy controls and HD patients. The most often reported and, therefore, evidenced changes include the following[14,44-47,50]: Phylum level: Decreased abundance of Firmicutes; increased abundance of Proteobacteria and Fusobacteria and variable changes in Bacteroidetes, with some studies reporting a decrease and others finding no significant difference. Class level: Decreased abundance of Clostridia and increased abundance of Gammaproteobacteria. Order level: Decreased abundance of Clostridiales and increased abundance of Enterobacteriales. Family level: Decreased abundance of Lactobacillaceae, Lachnospiraceae, Ruminococcaceae, and Bifidobacteriaceae and increased abundance of Enterobacteriaceae, Pseudomonadaceae, and Enterococcaceae. Genus level: Decreased abundance of Faecalibacterium, Roseburia, Bifidobacterium, and Prevotella and increased abundance of Escherichia, Shigella, Pseudomonas, and Enterococcus. Species level: Decreased abundance of Faecalibacterium prausnitzii and increased abundance of Escherichia coli (E. coli).

Despite some discrepancies across studies, significant alterations in the gut microbiota composition at various taxonomic levels are evident in PD patients. These changes can be summarized as a significant decrease in beneficial and butyrate-producing bacteria (Faecalibacterium prausnitzii, Roseburia spp., Bifidobacterium, and Lactobacillus) and an increase in potentially harmful bacteria, including taxa capable of producing urease, indole, and p-cresol, such as Escherichia within genera and Enterobacteriaceae and Enterococcaceae at the family level, which are predominant in patients undergoing PD.

Gut microbial metabolome in PD

Beyond compositional changes, the metabolic activities of the gut microbiota, collectively called the microbial metabolome, undergo substantial alterations in patients treated with PD[14,44,45]. The altered metabolic landscape encompasses changes in various key metabolites, including SCFAs, trimethylamine N-oxide (TMAO), IS, and p-cresol[14,31,44]. These alterations are intricately linked to shifts in the composition of the gut microbiota and exert profound effects on the peritoneal membrane function and patients’ prognosis[13,14,31,51]. For example, the decreased abundance of beneficial bacteria, such as Faecalibacterium, Roseburia, and Bifidobacterium, may lead to reduced SCFA production, which may contribute to the increased systemic inflammation and cardiovascular risk observed in PD patients[14,31]. Conversely, an increase in the abundance of potentially pathogenic bacteria, such as Escherichia, Shigella, and Enterococcus, may be associated with a higher risk of peritonitis and other infections in PD patients[32]. Gut dysbiosis is not the sole determinant of metabolite alterations in CKD patients in general and in those undergoing PD in particular; several factors exert influence on the changes and are collectively referred to as the gut–kidney axis[21,39]. Reduced kidney clearance and the resulting uremic environment, dietary restrictions aimed at managing CKD, decreased colonic fermentation and absorption, and the intricacies of the dialysis process all play pivotal roles in altering metabolite levels[21,39].

SCFAs, such as acetate, propionate, and butyrate, are important metabolites produced by the fermentation of dietary fibers by gut bacteria[52,53] and are vital in the maintenance of gut barrier integrity, modulating immune responses, and providing energy to colonocytes[53]. Beyond their role in gut health, SCFAs are also involved in regulating blood pressure, body weight, insulin sensitivity, glucose homeostasis, and cholesterol synthesis[52,54], all of which are adversely affected in patients undergoing PD. Despite the recognized importance of SCFAs in health and disease, research focusing on these metabolites in PD patients is scarce. A recent report by Li et al[14] stands out as one of the few that has documented significant reductions in SCFAs and SCFA derivatives, such as methyl butanoic and methyl propanoic acid, in the feces of PD patients. The findings indicate that fecal levels of acetic acid, butyric acid, valeric acid, and caproic acid were lower in PD patients than in healthy individuals, with a particularly significant decrease observed in butyric acid content[14]. There was also a positive correlation between the relative abundance of Faecalibacterium and Bacteroides vulgatus and the fecal levels of butyric acid. Conversely, the relative abundance of Blautia showed a negative correlation with the fecal level of valeric acid[14]. Despite the widespread discussion on the general benefits of SCFAs in CKD and their potential relevance for PD patients, it is unclear what benefits they lead to as far as the population is concerned. The plausible benefits for PD patients may include a reduction of oxidative stress and systemic inflammation, which may contribute to the preservation of RKF and improved CVD outcomes[52,53,55].

TMAO is a metabolite produced by gut microbes from dietary nutrients, such as choline, betaine, and carnitine, which are found in high amounts in animal products, such as red meat, eggs, and fish[56]. This process involves the breakdown of dietary choline and L-carnitine by gut bacteria into trimethylamine, which is then converted into TMAO in the liver[57,58]. The current findings have not established a clear association between serum TMAO levels and specific gut microbiota in the PD population[44]. However, based on current knowledge of TMAO metabolism, genera such as Clostridium asparagiforme, Clostridium hathewayi, Clostridium sporogenes, Edwardsiella tarda, Escherichia fergusonii, and Proteus penneri have been identified as contributors to the production of trimethylamine and TMAO in the general population[59]. These findings may also be relevant for PD patients, as there is an observed increase in the abundance of these bacteria. Although the gut microbiota plays a crucial role in TMAO production, its serum levels primarily depend on kidney function[60,61]. As a result, TMAO levels are consistently elevated in PD patients[14,44]. These heightened TMAO levels in patients undergoing PD have been linked to increased peritoneal inflammation and a heightened risk of peritonitis[62]. In addition, elevated TMAO levels have been associated with a greater risk of CVD and all-cause mortality in this patient population[56,58,63]. However, the precise mechanisms through which TMAO contributes to these complications remain incompletely understood and represent an active area of ongoing research.

IS and p-cresol, particularly in its sulfate form known as p-cresyl sulfate (PCS), are protein-bound uremic toxins produced by the gut microbiota during the fermentation of proteins[64]. Specifically, IS is generated from the metabolism of tryptophan, while PCS is produced from the metabolism of tyrosine and phenylalanine[64]. The production of these toxins is influenced by the composition of the gut microbiota, with specific bacterial species responsible for their generation from amino acid precursors[23,65]. For example, several bacterial strains, including those from the genera Escherichia, Clostridium, and Peptostreptococcus, have been identified as capable of producing indole and p-cresol[23,65]. In patients undergoing PD, there is a notable abundance of bacteria producing indole and p-cresol, while the elimination of these toxins is hindered, resulting in their accumulation in the body[39,64]. However, the direct association between the abundance of indole- and p-cresol-producing bacteria and the serum levels of the corresponding uremic toxins in PD patients is not straightforward. Some studies have reported significant expansions of indole-producing bacteria, such as E. coli, in patients with ESKD, along with upregulation of bacterial tryptophan metabolism pathways, leading to increased serum concentrations of IS and PCS[66]. Other reports have highlighted that, while there was an expansion of bacteria possessing enzymes for producing indole and p-cresol in PD patients, the direct correlation between these bacteria and the serum levels of the toxins was not explicitly established[14,44]. For example, Bao et al[44] showed that the degree of microbiota disorder in PD patients was more closely related to PCS than to IS and TMAO, suggesting that various factors, such as RKF, individual patient- and dialysis-related characteristics, dietary intake, and the efficacy of PD in removing these toxins, could influence IS and PCS serum levels[67]. Nonetheless, elevated serum concentrations of IS and PCS are strongly linked to adverse clinical outcomes in PD patients, including RKF decline, high peritoneal transport status, reduced dialysis adequacy, and heightened markers of oxidative stress and proinflammatory cytokines, ultimately leading to a higher incidence of PD-associated peritonitis, PD failure events, and an increased risk of CVD events[44,67,68].

Overall, one of the most crucial factors influencing the clinical outcomes of PD patients is the gut microbiome. A decrease in beneficial bacteria and an increase in harmful strains are associated with negative clinical consequences, such as increased inflammation, peritonitis risk, CVD events, and mortality. Dysbiosis influences the production of key metabolites, such as SCFAs, TMAO, IS, and PCS, further affecting patient health. Although ongoing research seeks to elucidate the exact mechanisms behind these alterations, understanding the interplay between gut microbiota, metabolites, and clinical outcomes is essential for improving PD patient care. Characterizing these changes can guide targeted interventions, such as probiotic interventions, aimed at restoring microbial balance and enhancing outcomes in PD patients.

PROBIOTICS: MECHANISMS OF ACTION AND THERAPEUTIC POTENTIAL IN PD

Probiotic supplements have gained significant prominence in clinical practice and have shown promise for improving patient outcomes[15,69]. Coined by Werner Kollath in 1953, the term “probiotic” originated from the Latin “pro” and the Greek “βιο”, which means “for life”. Kollath’s definition underscores probiotics as active organisms with essential functions beneficial to various aspects of health[70]. The International Scientific Association for Probiotics and Prebiotics defines probiotics as “live microorganisms that, when consumed in adequate amounts, provide health benefits to the host organism”[71]. A wide array of bacterial strains from genera such as Bifidobacterium, Lactococcus, Pediococcus, Enterococcus, Streptococcus, Propionibacterium, and Bacillus are considered potential probiotic candidates[69,72]. Among the commonly used probiotic microorganisms are Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. However, it is essential to note that the health benefits attributed to probiotics depend on the specific strain rather than simply the species or genus[72].

Probiotics exert their beneficial effects through various mechanisms, primarily involving modulation of the gut microbiota, production of antimicrobial substances, reinforcement of the intestinal barrier, and modulation of the immune response (Figure 1).

Figure 1 Key mechanisms of probiotic activity. Probiotics exert their effects through several mechanisms to promote gut health. (1) Modulation of gut microbiota: Probiotics colonize the gut epithelium and promote the growth of beneficial bacteria while inhibiting harmful pathogens through competitive exclusion and the production of short-chain fatty acids and antimicrobial substances (bacteriocin); (2) Enhancement of gut barrier function: Probiotics tighten tight junctions between intestinal epithelial cells and stimulate mucin production, reducing gut permeability and protecting against harmful substances; and (3) Immunomodulation: Probiotics interact with immune cells, particularly dendritic cells (DCs) and macrophages, through pattern recognition receptors, such as TLRs. This interaction leads to reduced lipopolysaccharide (LPS) production, inhibition of the nuclear factor-kappa B inflammatory pathway, decreased proinflammatory cytokine production, and enhanced secretion of anti-inflammatory cytokines. Probiotics also increase the levels of immunoglobulin (Ig) A-secreting plasma cells, promoting the secretion of secretory IgA into the gut lumen, which helps prevent bacterial invasion. SCFA: Short-chain fatty acid; DC: Dendritic cell; LPS: Lipopolysaccharide; NF-Κb: Nuclear factor-kappa B; IgA: Immunoglobulin A; IL-10: Interleukin-10; TGF-β: Transforming growth factor-β; Th: T helper cells; Treg: Tegulatory T cells. Created in BioRender.com (Supplementary material).

The primary action of probiotics is the modulation of the gut microbiota, in which they exert influence by altering their composition and function[15,69,73]. Probiotics facilitate the growth of beneficial bacteria while impeding the proliferation of harmful pathogens. This modulation occurs primarily through two mechanisms: Competitive exclusion and the production of antimicrobial substances[15,69,73]. Competitive exclusion involves several steps. First, probiotics colonize the gut epithelium, hindering the attachment of pathogenic bacteria to the intestinal lining. Subsequently, they compete with pathogenic microorganisms for essential nutrients, depriving them of the energy required for growth and replication within the gut environment[17,69,73]. In addition, probiotics produce various antimicrobial substances, including mucus, bacteriocins, hydrogen peroxide, organic acids, and SCFAs. These metabolites exhibit inhibitory effects on pathogenic organisms, further suppressing their proliferation and promoting gut health[69,73,74].

The improvement of gut barrier function by probiotics is primarily achieved through the tightening of tight junctions and the promotion of mucin production[69,73,75]. Probiotics have the capability to enhance the expression of proteins that constitute tight junctions between intestinal epithelial cells, thereby reducing gut permeability and preventing the passage of harmful substances. Probiotics stimulate the production of mucins, which become the primary component of the mucus layer, protecting the gut lining from irritants and pathogens[15,69,73].

Probiotics exert their immunomodulatory effects through interactions with key cellular components of the immune system, particularly dendritic cells (DCs) and macrophages[69,73]. Pattern recognition receptors, such as the toll-like receptors, which communicate with adaptive immune cells (e.g., regulatory T cells and B cells), facilitate the interaction. Ultimately, this interaction leads to a decrease in lipopolysaccharide (LPS) production, resulting in decreased macrophage activation and the inhibition of the nuclear factor-kappa B (NF-κB) signaling cascade[73,76]. The process is important in dampening the innate immune response by inhibiting the NF-κB inflammatory pathway and reducing proinflammatory cytokine production, consequently mitigating inflammation[15,76]. Moreover, by signaling to DCs, probiotics stimulate the secretion of anti-inflammatory cytokines, helping control and reduce inflammation[69,73,76]. Probiotics also contribute to enhancing the immune barrier of the gut by increasing the levels of immunoglobulin (Ig) A-secreting plasma cells within the lamina propria. This elevation in IgA-secreting cells promotes the transcytosis of secretory IgA across the epithelial cell layer, resulting in its secretion into the luminal mucus layer. The presence of secretory IgA in the mucus layer is vital for preventing and limiting the bacterial penetration of host tissues, thereby serving a protective role against pathogenic invasion[73,76].

The recognized mechanisms of action of probiotics have spurred their widespread use in treating numerous diseases, including CKD. Probiotics, particularly strains from the Lactobacillus and Bifidobacterium genera, have been shown to modulate the gut microbiota, leading to a reduction in the levels of LPS, proinflammatory cytokines, and uremic toxins and an increase in SCFAs[15,77]. This modulation not only helps to reduce the toxin load but also potentially delays the progression of kidney failure[19,74,77]. Recently, there has been a surge in research examining the mechanisms and potential benefits of probiotic supplementation in CKD. Several recent experimental and clinical studies involving CKD or HD cohorts are presented below, alongside the only preclinical study that has investigated the therapeutic potential of a probiotic in the context of PD.

Wang et al[78] evaluated whether probiotic administration could slow declining kidney function in CKD patients and used an experimental mouse model on clinical patients to assess the effects of probiotics on renal health. The findings indicated that after a six-month intervention with probiotics, there was a significant decrease in the glomerular filtration rate (GFR) decline and the serum levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, and IL-18. Moreover, there were changes in stool forms toward normal with probiotic treatment, suggesting an improvement in gastrointestinal symptoms and a potential modulation of the gut microbiota[78]. In a recent meta-analysis comprising 18 randomized controlled trials, Chen et al[79] reaffirmed the findings by demonstrating that probiotic supplementation led to significant reductions in serum creatinine, blood urea nitrogen (BUN), and uric acid levels among patients with CKD. Probiotics also effectively decreased the serum levels of C-reactive protein (CRP) and enhanced the GFR rate; these are indicators of improved kidney function. This can be interpreted to mean that probiotics may offer a beneficial approach toward managing CKD by enhancing kidney function and alleviating inflammation[79].

The ProLowCKD trial recently demonstrated that a probiotic-supplemented low-protein diet in patients with non-dialysis ESKD could lead to significant reductions in BUN, total cholesterol, and triglycerides after two months on a low-protein diet[80]. Patients were randomized to receive either probiotics or a placebo for an additional three months. According to the reported findings, the placebo group showed increased serum values of total cholesterol, low-density lipoprotein cholesterol, and lipoprotein-associated phospholipase A2, whereas these parameters did not increase in the probiotic group, suggesting a potential benefit of probiotics in managing dyslipidemia in CKD patients[80]. Although direct evidence of cardiovascular improvements in CKD due to probiotics is lacking, there is promising data from Tang et al’s study[81]. Specifically, probiotics with Lactobacillus strains improved post-myocardial infarction cardiac function in mice, likely through the mechanism of increasing the SCFA levels[81]. This observation suggests a possible pathway through which probiotics could exert beneficial effects on the cardiovascular system, even in the context of CKD.

Finally, emerging research highlights the potential of specific probiotic strains, such as Lactobacillus casei Zhang, in ameliorating peritoneal fibrosis in experimental mice[82]. This probiotic was found to correct gut dysbiosis, suppress macrophage-related inflammation through the butyrate/PPAR-γ/NF-κB pathway, and enrich beneficial bacteria-producing SCFAs in PD effluents[82]. These findings underscore the intricate interplay between gut health, immune response, and the peritoneal environment in PD patients, thus offering a promising therapeutic avenue for managing peritoneal fibrosis through the modulation of gut microbiota and its metabolic products.

The knowledge gained from experimental research and studies in the general population of CKD patients offers valuable insights that can be applied to patients undergoing PD. As the pathophysiological mechanisms and common issues, such as gut dysbiosis and systemic inflammation, overlap, it is plausible that the beneficial effects observed with probiotic intervention in CKD could potentially be applicable to patients undergoing PD. However, the unique challenges encountered by PD patients, such as infection risk and peritoneal fibrosis, emphasize the necessity of innovative therapeutic approaches. Probiotics, with their capacity to modulate gut microbiota, strengthen gut barrier function, reduce uremic toxins, and alleviate inflammation, present a promising avenue for enhancing the health and treatment outcomes of PD patients. Figure 2 illustrates the potential probiotic benefits in PD, offering a clear and concise overview of how probiotics could positively affect patients undergoing PD.

Figure 2 Potential probiotic benefits in peritoneal dialysis. Created in BioRender.com (Supplementary material).

CLINICAL EVIDENCE ON PROBIOTIC INTERVENTIONS IN PD

Despite the promising potential of probiotics in CKD and HD populations, the specific evidence base for PD patients is notably sparse. To date, only a handful of studies, including two randomized clinical trials and one case-series study, have directly investigated the effects of probiotics on PD patients.

Pan et al[20] conducted a randomized clinical trial to assess the effects of probiotic supplementation on gut microbiota composition and overall health outcomes in PD patients. The study aimed to determine whether probiotics could alleviate systemic inflammation and improve the nutritional status of PD patients by modulating the gut microbiota. Prescribing a probiotic containing Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus at a dose of 10⁹ colony-forming units (CFU) for two months in 98 PD patients, the authors observed a significant decrease in serum CRP and IL-6 and an increase in serum albumin, upper arm circumference, and triceps skinfold thickness. These changes partially improved malnutrition and the quality of life of patients. The study also indicated a positive shift in gut microbiota composition, characterized by an increase in beneficial bacterial strains and a decrease in uremic toxins. However, the need for further research was highlighted, particularly to conclusively determine the long-term benefits of probiotic supplementation in this patient population[20].

Wang et al[83] investigated the potential of probiotics to lower the incidence of PD-related peritonitis. This randomized clinical trial examined the effects of a specific probiotic formulation (consisting of 10⁹ CFU each of Bifobacterium bifidum A218, Bifidobacterium catenulatum A302, Bifidobacterium longum A101, and Lactobacillus plantarum A87) administered for three months on the frequency of peritonitis episodes among 39 PD patients over one year. The results indicated a decrease in the rate of peritonitis episodes among patients receiving probiotic supplementation compared with the control group, thus suggesting a potential role for probiotics in bolstering the peritoneal defense mechanism against infections. Other observations included a massive decline in endotoxin and pro-inflammatory cytokines (TNF-α and IL-6) serum levels and an increase in the serum levels of IL-10. Furthermore, RKF was preserved[83].

A case-series study investigated the use of probiotics in addressing recurrent peritonitis in 14 PD patients[84]. Probiotics, specifically E. coli Nissle, were prescribed at a dosage of 100 mg twice daily alongside standard peritonitis management for 2–3 weeks. Notably, there were no instances of peritonitis recurrence during the 18-month follow-up period. Although the study’s design restricts the ability to draw definitive conclusions, it offers valuable insights into the potential of probiotics as a preventive measure against PD-related peritonitis. All the studies indicated that administering probiotics to patients undergoing PD was safe and well tolerated.

CHALLENGES AND LIMITATIONS IN PROBIOTIC APPLICATION IN PD

To fully harness the massive potential of probiotics in PD, it is imperative to address the various challenges and limitations, most of which stem from the inherent properties of probiotics and the clinical landscape of PD patients. There is also an aspect of regulatory and quality control concerns in which the varying classifications of probiotics across countries, ranging from dietary supplements to therapeutic agents, result in disparities in quality control measures, manufacturing standards, and labeling accuracy. Such discrepancies can compromise the reliability and uniformity of probiotic products[15]. In addition, probiotics comprise diverse strains, each possessing unique properties and mechanisms of action[69,71,72]. Identifying the most effective strains for addressing PD-related complications is challenging due to the strain-specific nature of probiotic effects. Extensive research is necessary to match specific probiotic strains with the desired health outcomes in PD patients. Furthermore, establishing the appropriate dosage and treatment duration for probiotics in PD remains uncertain, with considerable variations observed across studies[15]. Empirical evidence predominantly guides the selection of probiotic strains, contributing to discrepancies in the research findings. Intervention durations are typically 2-32 weeks, while probiotic dosages exhibit wide variability, spanning 10⁹ to 2.0 × 10¹² CFU, thus lacking a standardized dosing protocol[15,85]. While longer durations of probiotic use (e.g., 24-32 weeks) generally seem to provide more pronounced benefits than shorter periods (e.g., two weeks), there is currently insufficient evidence to conclusively determine whether extended treatment offers significantly greater advantages over shorter durations[15,79,83]. The absence of consensus on optimal probiotic strains, dosages, and treatment durations complicates their clinical application, with potential risks of suboptimal outcomes or adverse effects stemming from over- or underdosing.

Safety is the primary concern for the immunocompromised status of PD patients. Although probiotics are generally deemed safe, there is a possibility of elevating the risk of infections or exacerbating immune dysregulation similar to that reported in instances of PD-related peritonitis associated with Lactobacillus gasseri[86]. Consequently, meticulous monitoring and the selection of probiotic strains with established safety profiles are imperative. Moreover, PD patients frequently receive multiple medications, heightening the likelihood of interactions with probiotic supplements. Probiotics can influence the pharmacokinetics of some drugs, which can lead to either better efficacy or even worse toxicity. Again, factors such as genetic predisposition, dietary habits, and existing gut microbiota composition can affect the effectiveness of probiotic supplementation. Consequently, they can lead to inconsistent outcomes across diverse patient populations. The diverse challenges highlight the need for a comprehensive assessment and tailored approaches, particularly to maximize the therapeutic benefits of probiotics in PD patients.

A better understanding of the challenges and limitations linked to probiotic use in PD patients is needed to determine the right interventions. Some notable gaps in the current knowledge can be addressed with high-quality, randomized controlled trials, which may provide more insights into the effectiveness, optimal strains and dosages, safety profiles, and potential complications of probiotics in PD patients[15,20,85]. In future studies, establishing standardized guidelines for probiotic use in PD patients can help ensure their safe and effective application in clinical practice.

CONCLUSION

Current clinical evidence on probiotic interventions in patients undergoing PD is promising, particularly in improving patient outcomes. Studies have already demonstrated the potential of PD in promoting the growth of beneficial bacterial strains while reducing the abundance of harmful microbes and uremic toxins, which then contribute to a healthier gut microbiota profile. Most importantly, probiotics could help reduce peritonitis rates, preserve RKF, modulate inflammation, improve nutritional status, and enhance the health-related quality of life in PD patients through the manipulation of the gut microbiome. However, despite these positive outcomes, there is limited evidence of probiotic interventions in PD. To better understand the interaction between probiotics and the gut microbiome in PD patients, more clinical trials are needed. These studies should focus on specific probiotic strains, their effects on microbial diversity, metabolite production, and immune function within the gut. Future research should involve large-scale trials with organized follow-ups to explore the interplay between probiotics and the gut microbiome. Investigating the impact of probiotics on the unique microbiome composition in the peritoneal cavity and the functioning of the peritoneal membrane could provide valuable insights. In addition, integrating clinical measures with studies on the effects of probiotics can help develop personalized therapeutic approaches, improving both microbial and clinical outcomes.

Nevertheless, the potential risks of probiotics must be considered, such as infections in immunocompromised individuals, negative interactions with medications, and the adverse effects of changes in the gut microbiome. To mitigate these risks, it is crucial to select well-researched probiotic strains with proven safety profiles and adhere to proper guidelines for strain-specific dosing and monitoring. Furthermore, cardiovascular morbidity and mortality rates are significantly higher in PD patients than in the general population[87,88]. A more thorough assessment of probiotics’ effects on cardiovascular outcomes is needed, with future clinical trials evaluating surrogate markers of cardiovascular health, such as blood pressure, lipid profiles, arterial stiffness, and cardiac function, for better insights into the cardioprotective effects of probiotics among PD patients. Moreover, longitudinal studies assessing major cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, are warranted to determine the long-term cardiovascular benefits of probiotic interventions in PD patients. Finally, future research should go beyond conventional clinical endpoints and include a holistic assessment of patient-centered outcomes. Studies could focus on conventional clinical markers alongside other patient-reported outcomes, such as quality of life, symptom burden, and treatment satisfaction.