The Influence of the Gut Microbiota and the Gut-Peritoneal Axis on Peritoneal Dialysis: A Literature Review

Abstract

The gut microbiota corresponds to the entirety of the microbial flora present in the various sections of the intestine. It is altered in end-stage renal disease on peritoneal dialysis and may play a role in peritoneal physiology and possibly in the prognosis of peritoneal dialysis. Furthermore, until recently, the peritoneal cavity was considered a sterile environment. New studies challenge this dogma and identify a microbiome within this cavity in patients undergoing peritoneal dialysis and those with chronic kidney disease, even in the absence of a cavity breach. This review article aims to summarize the existing literature on the potential impact of the gut microbiota and the gut-peritoneal axis on the prognosis of peritoneal dialysis.

Introduction

The gut microbiota represents the entirety of the microbial flora present in various sections of the intestine. The microbiome refers to the collective genetic material associated with this microbiota [1]. The gut microbiota plays a critical role in several physiological functions, including metabolic functions, vitamin synthesis (B and K groups), maintenance of the immune system, and modulation of the autonomic nervous system[2][3][4]. Additionally, through the production of short-chain fatty acids, it contributes to colonocyte survival, regulation of gene expression, intestinal gluconeogenesis (via a cAMP-dependent mechanism), and appetite regulation [5][6]. Healthy gut microbiota also provides defense against pathogenic species through direct mechanisms (competition for resources, modification of partial oxygen pressure, production of toxins or antibiotics, detoxification of antibiotics) and indirect mechanisms (via host immune system stimulation) [5]. The gut microbiota interacts with the host’s autonomic nervous system and also plays a role in intestinal motility [7].

Peritoneal dialysis (PD) is an extracorporeal purification technique that uses the peritoneal cavity and peritoneal membrane as a filter to eliminate uremic toxins, regulate ions, and manage fluid balance. This technique requires the placement of a catheter to access the peritoneal cavity for exchange procedures. PD may be complicated by infections at the catheter exit site, subcutaneous tunnel infections, and peritonitis [8][9][10]. Other non-infectious complications are also encountered, such as peritoneal membrane dysfunction characterized by insufficient ultrafiltration [11]. The pathophysiology and susceptibility factors for these complications remain only partially understood.

The gut microbiota is altered in chronic kidney disease (CKD) and end-stage renal disease, particularly in patients undergoing PD [12][13][14].

This article aims to review the existing literature on the gut microbiota in patients undergoing peritoneal dialysis and the potential associations between alterations in the gut microbiota and certain infectious and non-infectious complications of PD.

Literature Review

1. General Overview of the Gut Microbiota

The gut microbiota encompasses the entire microbial flora present in the different sections of the intestine. It is composed of 3.8 x10¹³ microorganisms in a 70 kg adult male, corresponding to a total mass of 200 g. The concentration of microorganisms is not uniform throughout the digestive tract, with an anterograde increasing gradient from the stomach to the colon [15][16].

Defining a healthy gut microbiota in adults is challenging due to inter-individual variability. The Human Microbiome Project Consortium studied the composition of the microbiota in 242 disease-free individuals and demonstrated that, unlike highly variable microbial taxa, the metabolic pathways carried by the microbiota are stable over time and across individuals. Therefore, characterizing a healthy microbiota should focus on the functional capacities of the microbiota rather than its taxonomic composition [2][17].

2. Composition of the Microbiota

Normal Microbiota

The identification of species colonizing the gut microbiota has undergone significant advancements over the past decades with the advent of molecular biology-based technologies [18]. Rajilić-Stojanović et al. described, based on ribosomal RNA sequences, a phylogenetic framework of 1,057 species (92 Eukaryotes, 8 Archaea, and 957 Bacteria) cultured from the human gut microbiota. It was found that the phyla Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria are the most abundant and diverse. However, there are other bacterial phyla of varying abundance, such as Verrucomicrobia, Lentisphaerae, Synergistetes, Planctomycetes, Tenericutes, and the Deinococcus-Thermus group.

In addition to bacteria, fungi are also present (the mycobiota, primarily composed of Candida, Saccharomyces, Malassezia, and Cladosporium), as well as archaea, viruses, and phages [19].

Gut Microbiota in Chronic Kidney Disease

Alterations in gut microbiota composition (dysbiosis) are well documented in CKD and end-stage renal disease, with findings including increased levels of Alphaproteobacteria, Streptococcaceae, Streptococcus, Blautia, and Bacilli, and decreased levels of Prevotellaceae, Prevotella, Firmicutes, and Roseburia [20][21][22]. With moderate evidence, an increase in Klebsiella and Escherichia-Shigella has also been observed [23][24][25].

Gut Microbiota in PD

Dysbiosis is also reported in patients on PD. Stadlbauer V. et al. compared the gut microbiota of 15 hemodialysis (HD) patients, 15 peritoneal dialysis patients, and 21 controls [14]. They observed a decrease in potentially beneficial species and an increase in potentially pathogenic ones in both HD and PD patients compared to controls, with more pronounced changes in HD patients. This taxonomic alteration is associated with changes in metagenomic functionality. For example, the reduction of Roseburia intestinalis [14][26], a bacterial genus associated with numerous health benefits [27], may contribute to decreased butyrate synthesis in the intestines [14].

Consistent with findings from CKD studies, PD patients also exhibit reduced levels of Firmicutes and Actinobacteria, particularly Bifidobacteriaceae sp. and Lactobacillaceae sp., alongside an overrepresentation of Enterobacteriaceae sp. [12][13][14].

Li J. et al. demonstrated that gut microbiota diversity in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) is reduced compared to non-dialyzed CKD patients and healthy controls [28]. Interestingly, they found that intestinal microbial environments were more favorable in patients on CAPD for a longer duration (60 months vs. 24-36 months), suggesting a capacity for self-regulation and microbiota adaptation over time under stable conditions. The relationship between residual renal function and protection against intestinal dysbiosis may partially be explained by a less aggressive peritoneal dialysis strategy [29].

Several studies indicate that Helicobacter pylori infection is less frequent in dialysis patients compared to those with preserved renal function [30][31]. Furthermore, CAPD patients reportedly have lower infection rates compared to HD patients [30]. A meta-analysis showed an inverse correlation between dialysis duration (both HD and CAPD) and Helicobacter pylori infection, despite limited data specifically comparing PD to HD [32]. The causes for this reduction remain unclear but may involve the unfavorable uremic conditions for infection development.

Several factors have been implicated in intestinal dysbiosis in PD patients [33], including a phosphorus- and potassium-restricted diet that reduces fiber and symbiotic intake, uremic toxins such as urea that alter gut flora composition [34], medications like potassium binders, and finally, the PD technique itself [28].

Peritoneal dialysis has several unique features related to gut microbiota that distinguish it from other of end-stage renal disease treatment modalities. These include intraperitoneal hyperglycemia and elevated intra-abdominal pressure, which promote specific microbiota changes such as increased Enterobacteriaceae. Additionally, preservation of residual diuresis partially mitigates the deleterious effects of dysbiosis. Finally, the progressive adaptation of gut microbiota in long-term PD patients highlights a unique adjustment mechanism in this technique. These specificities strengthen the hypothesis of a close interaction between gut microbiota and peritoneal physiology in PD.

3. Association with PD Complications

3.1. Non-infectious Complications

Microbiota and Peritoneal Fibrosis

Peritoneal sclerosis is a severe complication associated with ultrafiltration failure and solute transport abnormalities. It is characterized by morphological alterations of the peritoneal membrane, including interstitial fibrosis and hyalinizing vasculopathy [35]. This condition has long been attributed to the lack of biocompatibility of the dialysis solution on the peritoneal membrane, involving factors such as high osmolarity, low pH, high glucose concentrations, advanced glycation end-products (AGEs), and glucose degradation products. These agents trigger degenerative damage to the tissue components of the peritoneal membrane and induce abnormal biological responses [36].

However, recent evidence suggests that factors independent of PD, such as uremia, may play a significant role in the pathogenesis of peritoneal sclerosis even before the initiation of PD [37]. These findings broaden our understanding of peritoneal sclerosis, suggesting that this complication could result from multiple mechanisms involving both PD-related factors and pre-existing conditions.

An emerging area of interest is the role of gut microbiota in the progression of PD-related complications. A prospective cohort study demonstrated that reduced gut microbiota diversity is associated with an increased risk of technique failure in PD patients. This association persists even after adjusting for various risk factors, including age, coronary artery disease history, diabetes, statin use, and levels of albumin, phosphorus, NT-proBNP, and glucose. Patients with lower gut microbiota diversity had significantly poorer PD technique survival compared to those with more diverse microbiota (HR, 2.038; 95% CI, 1.057–3.929; p = 0.034) [38].

Guo et al.’s study revealed a significant enrichment of Escherichia-Shigella in PD patients with reduced gut microbiota diversity compared to those with greater microbial diversity. This bacterial genus, known to include opportunistic pro-inflammatory pathogens in the intestinal tract, has been associated with elevated levels of both systemic and local pro-inflammatory cytokines [39][40]. Additionally, Escherichia-Shigella increases intestinal permeability by elevating luminal lipopolysaccharide (LPS) levels, facilitating the translocation of pathogens and harmful metabolites into systemic circulation, thereby contributing to systemic inflammation [41][42]. In PD patients, this chronic inflammation—both local and systemic—can stimulate peritoneal angiogenesis and fibrosis, exacerbating ultrafiltration failure, increasing cardiovascular event risks, and leading to discontinuation of PD therapy or even death[43][44].

The interplay between reduced microbial diversity and poor PD technique survival may, therefore, be partly explained by alterations in gut microbiota. Chronic inflammatory responses induced by the relative expansion of Escherichia-Shigella seem to play a key role in the association between gut dysbiosis and PD technique failure.

Gut dysbiosis, defined as a disruption of the normal gut microbiota composition, is increasingly recognized as a key factor in the pathogenesis of various chronic diseases, including obesity [45], insulin resistance, diabetes [46], and CKD [13]. In the context of PD, low microbial diversity has also been correlated with metabolic imbalances, such as increased triglycerides and decreased HDL-C, both of which are established cardiovascular risk factors [47][48].

Additionally, Enterobacteriaceae have been implicated in the production of uremic toxins, such as indole and p-cresol, whose elevated levels can exacerbate various diseases by inducing oxidative stress and increasing pro-inflammatory cytokine production[49][50]. Residual renal function (RRF) may play a protective role by eliminating these toxins, suggesting a potential interaction between RRF and protection against gut dysbiosis in PD patients.

Gut dysbiosis is thus a potentially important mechanism in the onset and progression of numerous diseases, including renal, metabolic, and inflammatory conditions. In PD patients, enrichment of uremic toxin-producing bacteria and depletion of short-chain fatty acid-producing bacteria can disrupt the intestinal barrier, leading to the translocation of microorganisms and their toxins into the bloodstream, thereby exacerbating peritoneal complications[51][52].

Although studies on PD patients are limited, research on hemodialysis patients has shown that altered gut microbiota is a major source of uremic toxins not cleared by the kidneys [53]. Consequently, it is plausible that the gut microbiota in PD patients is also a significant source of toxic metabolites, thereby contributing to fibrosis in organs, including the heart, kidneys, and peritoneum [35].

The accumulation of bacterial structural components, their metabolites, and uremic toxins significantly impacts fibrosis development, suggesting that uremia is a globally pro-fibrotic condition [54][55]. This condition may activate various signaling pathways promoting epithelial-to-mesenchymal transition and extracellular matrix production by mesenchymal cells [55][56][57].

In summary, gut dysbiosis associated with CKD and PD creates a vicious cycle where chronic inflammation—both intraperitoneal and systemic—and the adverse effects of glucose-based solutions contribute to peritoneal fibrosis. This complex interaction between gut microbiota and PD underscores the importance of microbiota-targeted strategies to prevent or mitigate PD-related complications [53].

Effects of Dysbiosis on Cognition

PD is a home-based treatment requiring self-management and operation by patients. Consequently, cognitive function is particularly important in PD patients, as any impairment could lead to adverse events [58]. In elderly patients with cognitive disorders, the loss of executive or memory functions may result in errors in PD management, increasing the risk of PD-associated peritonitis [59]. Additionally, cognitive impairment is an independent predictor of mortality and survival in PD patients [60]. Recently, growing evidence has demonstrated a strong link between gut dysbiosis and the onset and progression of nervous system disorders, with the underlying mechanism potentially involving the «microbiota-gut-brain axis» [61]. This association has been reported in various conditions, including end-stage CKD [62]and in HD patients [63]. Very recently, this link was also confirmed in PD patients [64], suggesting a negative impact of gut dysbiosis on the progression of cognitive impairment in peritoneal dialysis patients.

Nutritional Status and Gut Microbiota

Malnutrition is a common complication among dialysis patients, both in HD and PD. It results from a complex mechanism involving multiple factors, including patient-related ones such as loss of residual renal function, intestinal dysfunction [65], and inadequate nutritional intake [66], as well as PD-related factors, such as the inefficiency of dialysis, protein loss with PD effluent, and chronic microinflammation [67]. Malnutrition is also a key factor affecting the quality of life and prognosis of patients [68]. Malnourished PD patients experience higher hospitalization rates, longer hospital stays, and significantly increased risks of peritonitis and mortality [69]. Therefore, malnutrition in these patients deserves heightened attention in clinical practice. Recent studies point to a possible imbalance in the gut microbiota of malnourished PD patients [70].

3.2. Infectious Complications

Recent studies reveal the presence of microbiomes in body sites previously considered sterile, such as the peritoneum [13]. As previously mentioned, gut dysbiosis can disrupt the intestinal barrier in PD patients, favoring «atopobiosis,» defined as the translocation of enteric organisms or bacterial toxins into the peritoneal cavity through the intestinal epithelial barrier. This mechanism may represent an underestimated cause of peritonitis in PD patients. The detection of bacterial DNA in PD effluent supports the hypothesis of atopobiosis in PD patients[71][72]. Thus, the gut microbiome may represent a novel pathway for PD-associated infections, warranting further research. Nevertheless, to date, no study has definitively attributed PD-associated peritonitis to dysbiosis.

4. Therapeutic Perspectives – The Role of Gut Microbiota Modulation

Numerous factors can potentially influence the gut microbiota of PD patients, including antibiotic use, rural or urban environment, diet, physical activity, alcohol, and tobacco. Genetics appears to play a minor role in gut microbiota composition [73][74].

Physical exercise has been associated with an improvement in gut bacterial profiles[75][76]. In an interventional study of insulin-resistant subjects [77], regular physical activity was associated with reduced endotoxemia via decreased markers of intestinal inflammation, as well as changes in gut microbiota favoring protective bacterial genera (reduced Firmicutes/Bacteroidetes ratio, reduced Clostridium and Blautia, and increased Bacteroidetes genera).

In numerous studies, the role of diet in modulating gut microbiota and its metabolic capacities has been extensively documented .[76][78] [79][80][81][82][83][84][85]

Probiotics represent another promising intervention for positively modulating the gut microbiota of CKD patients. In the specific context of PD, Wang I-K et al. demonstrated in a double-blind, randomized controlled trial that administering probiotics over six months to PD patients (21 in the probiotic group and 18 in the placebo group) significantly reduced blood levels of several inflammatory markers (TNF-α, IL-5, IL-6) and endotoxins, significantly increased IL-10 (anti-inflammatory), and preserved residual renal function [86].

Conclusions and Recommendations

Gut dysbiosis is well-documented in PD, but the literature lacks studies evaluating the clinical implications of dysbiosis in this context. Dysbiosis appears to be associated with reduced PD technique survival and may represent a risk factor for infectious complications through the phenomenon of atopobiosis.

The gut microbiota and the gut-peritoneal axis could thus represent a promising research avenue in PD, with potential clinical implications for preventing both infectious and non-infectious complications.

Currently, professional societies do not recommend modulating the gut microbiota in PD patients.. However, the literature suggests a potential beneficial effect of such interventions. The clinical impact of each taxonomic modification of the microbiota remains to be fully investigated.

Authors’ Contributions

Maxime Taghavi and Lucas Jacobs designed the project. Lucas Jacobs, Laura Mannie-Corbisier, and Maxime Taghavi jointly drafted the manuscript, while Maxime Taghavi and Joëlle Nortier supervised the writing of the article.

Ethical Considerations

Not applicable.

Funding

The authors received no funding for this work.

Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.

ORCID

Lucas Jacobs: https://orcid.org/0000-0001-8148-0349

Laura Mannie-Corbisier: https://orcid.org/0009-0009-8521-342X

Maxime Taghavi : https://orcid.org/0000-0003-1442-9716

Joëlle Nortier : https://orcid.org/0000-0003-3609-8217

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