Probiotics are the focus of a thorough investigation as a natural biotreatment due to their various health-promoting effects and inherent ability to fight specific diseases including chronic kidney disease (CKD). Indeed, intestinal microbiota has recently emerged as an important player in the progression and complications of CKD. Because many of the multifactorial physiological functions of probiotics are highly strain specific, preselection of appropriate probiotic strains based on their expression of functional biomarkers is critical. The interest in developing new research initiatives on probiotics in CKD have increased over the last decade with the goal of fully exploring their therapeutic potentials.
The efficacy of probiotics to decrease uremic toxin production and to improve renal function has been investigated in in vitro models and in various animal and human CKD studies. However to date, the quality of intervention trials investigating this novel CKD therapy is still lacking. This review outlines potential mechanisms of action and efficacy of probiotics as a new CKD management tool, with a particular emphasis on uremic toxin production and inflammation.
Chronic kidney disease (CKD) is emerging as a major risk factor of cardiovascular disease (CVD). Uremic illness is considered to be due to the accumulation of organic waste products, so-called uremic retention solutes (URSs) that are normally cleared by the kidneys. URS such as phenols and indoles are generated along the gastrointestinal tract (GIT), where the gut microbiota has a significant role in their production1 and have been shown to have deleterious effects on the cardiovascular system.
A number of treatments targeting URS have been proposed, such as reducing substrates (dietary protein restriction), decreasing absorption (oral adsorbents such as AST-120), increasing clearance by renal replacement therapies (long and/or more efficient dialysis, absorbent membranes, kidney transplantation), and modulating cellular pathways (organic anion transporters and antioxidants).2 Unfortunately, most of these treatments display inherent disadvantages (side effects, high cost, unavailability in patients with moderate CKD) and remain limited to experimental studies.
PROBIOTICS AND HEALTH
Definition
The term probiotic is often misused, which has led to the marketing of products that exploit this term. In 2014, the International Scientific Association for Probiotics and Prebiotics established a consensus statement clarifying the scope of and the appropriate use for the term ‘probiotic’.13 The consensus definition is that probiotics are natural or genetically modified microorganisms expressing specific exogenous enzymes that are able to survive stomach acid and bile, to increase the colon concentration of symbiotons, and confer a health benefit.
Probiotics and mucosal effects
Even though the mechanisms regulating epithelial responses to probiotics are complex and poorly understood, the presumed first target of probiotic action is the intestinal epithelial cell through enhancement of epithelial integrity. Some strains may block pathogen entry into the epithelial cell by providing a physical barrier, referred to as colonization resistance, and competition for a limited niche, thereby excluding a site for replication by pathogens. For example, Lactobacillus helveticus possesses hydrophobic cell surface properties and therefore is able to nonspecifically bind to intestinal cells. In addition, most probiotics create a mucus barrier by increasing mucin synthesis and secretion from goblet cells.
Probiotics may enhance cell survival and decrease apoptosis during various intestinal assaults. In fact, soluble factors secreted by Lactobacillus rhamnosus were found to activate protein kinase B in a phosphatidylinositol-3′-kinase-dependent manner and prevent cytokine-induced apoptosis in human and mouse intestinal cells. Lactobacillus rhamnosus is able to produce soluble proteins (p40 and p75), which protect the intestinal barrier from hydrogen peroxide–induced insult. Other probiotics maintain intestinal integrity by increasing the intercellular apical epithelial tight junction via the upregulation of zonula occludens-1 expression or by preventing epithelial tight junction protein redistribution. The protective effects of probiotics on intestinal function have been confirmed in in vivo studies using Citrobacter rodentium infection in a mouse model of bacterial-induced infectious colitis.19 This observation should be considered in clinical studies in CKD patients who frequently present with a chronic inflammation of the GIT and where probiotics could enhance the mucosal barrier function.
Probiotics and antimicrobial effects
Several studies have confirmed that probiotics might reduce digestive infection.3 This is of particular interest as CKD patients are at higher risk of Clostridium difficile infection. Indeed, some probiotic strains have been shown to produce elaborated antibacterial compounds referred to as bacteriocins or antimicrobial peptide. Antimicrobial peptides may act as colonizing peptides, facilitating the competition of a probiotic with the resident microbiota, as killing peptides eliminating pathogens, or serve as signaling peptides for other bacteria or the immune system. Along the same line, lactic acid-producing Lactobacilli exert antimicrobial effects by reducing the local pH in the gut lumen. Lactobacillis salivarus produces an in vivo bacteriocin that has been shown to significantly protect mice against infection with the invasive foodborne pathogen Listeria monocytogenes. Finally, Lactobacillus fermentum stimulates human β-defensin mRNA expression and protein secretion in the intestine.
Other probiotics could influence gene expression of microbial pathogens and thereby reduce their hostility. For instance, Lactobacillus acidophilus may interfere with the virulence gene expression of enterohemorrhagic Escherichia coli O157:H7. Probiotics could prevent the binding of enteric pathogens to mucosal surfaces by obscuring the receptor-binding sites, thus preventing pathogens from invading the host and allowing for an increased clearance of the pathogen from the GIT.
Probiotics, immunity, and inflammation
By decreasing the presence of pathobionts, probiotics have proven that it is possible to enhance both innate and adaptive arms of the host immune system.26 For instance, some probiotic strains have the ability to promote the differentiation of B cells and increase the production of secretory IgA. Polymeric IgA sticks to the mucus layer overlying the gut epithelium and binds to pathogenic microorganisms, thereby reducing their ability to gain access to the endothelial cells.
Other probiotic strains stimulate the innate immune system by signaling to dendritic cells, which then travel to mesenteric lymph nodes where they induce regulatory T cells (FoxP3+) and the production of anti-inflammatory cytokines (interleukin-10 and transforming growth factor-β). For example, Saccharomyces boulardii was shown to reduce intestinal inflammation through modulation of the T-cell response and reduced trafficking of Th1 cells, which resulted in a reduction of the proinflammatory cytokine interferon-γ. The relative serum cytokine profiles have been reported to predict the ability of the probiotic strains to have an impact on disease outcome.
Probiotics can also modulate the activation of the proinflammatory nuclear factor-κB to slow down the deleterious LPS flow and decrease interleukin-8 secretion, which is a potent neutrophil chemoattractant to sites of intestinal injury.26 However, there are also reports that some strains of probiotics are able to activate nuclear factor-κB and increase levels of the proinflammatory cytokine directly or through the increase of ammonia and ammonium hydroxide (NH3/NH4OH) production. These discrepancies serve to further emphasize the strain-specific effects of probiotics on the host.
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