Role of Altered Intestinal Microbiota in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease

Denise Mafra; Julie C Lobo; Amanda F Barros; Laetitia Koppe; Nosratola D Vaziri; Denis Fouque


Future Microbiol. 2014;9(3):399-410. 

In This Article

Effects of Probiotics & Prebiotics in CKD

By modulating the composition of the intestinal microbiota, the use of probiotics could potentially minimize the deleterious effects of its imbalance, thereby improving the health of the gastrointestinal tract, strengthening the immune system, restoring the bioavailability of micronutrients, exerting antidiabetic actions, improving dyslipidemia and allergic disorders, and reducing the risk of certain cancers.[75]

The mechanism by which probiotics exert their favorable effects seems to include changes in intestinal pH, suppression of pathogens (through the production of antibacterial compounds, competitive exclusion of pathogens in receptor binding sites and competition for available nutrients), suppression of mutagenic and carcinogenic processes and protection of the intestinal barrier.[76,77]

Previous studies have demonstrated the immune modulatory and anti-inflammatory effects of probiotics, leading to a reduction in the influx of LPS into the systemic circulation, the attenuation of the TLR-4 mediated activation of NF-κB, the formation of proinflammatory cytokines, reductions in systolic blood pressure and fibrinogen levels, and interactions with immune cells, leading to improvements in intestinal integrity.[78,79] In addition, the use of probiotics may confer cardioprotective effects, including the prevention and attenuation of ischemic heart disease and the reduction of serum cholesterol.[80]

Regarding kidney disease, Simenhoff et al. were the first to administer lactobacillus to hemodialysis patients and to observe reductions in dimethylamine (DMA) and nitrosodimethylamine, which are toxins produced by the small intestine.[81] Other researchers have shown reductions in indoxyl sulfate, homocysteine and triglycerides levels with the oral supplementation of bifidobacteria in hemodialysis patients.[82,83] Ranganathan et al. also reported the prolongation of life, reduction in blood urea concentration and decreased progression of renal disease with 16 weeks of probiotic supplementation in uremic rats.[84] In a pilot study, the same group[85] found improvements in the symptoms and quality of life in patients with stages III and IV CKD who received 6 months of supplementation with probiotics.

Notably, the driving force behind changes in the intestinal microbiome is the uremic milieu. Consequently, the introduction of probiotics may be ineffective or less effective, as their survival may be hampered by the uremic environment of the gut into which they are introduced.

Another strategy for modulating the intestinal microbiota is the use of prebiotics, such as oligofructose inulin polymers, fructooligosaccharides, galactooligosaccharides and other oligosaccharides. Prebiotics have proven effective in improving glycemic control and plasma lipid profiles. The mechanisms of action of prebiotics are complex, and several hypotheses have been proposed in the literature, including: soluble fibers may reduce the digestion of macronutrients by delaying gastric emptying and/or intestinal transit time; improve the secretion of GLP-1; increase the production of SFAs; modulate the composition of colonic microbiota, reducing LPS and increasing the contents of gut bifidobacteria.[86]

Several studies have shown reductions in urinary p-cresyl sulfate and indoxyl sulfate levels with the use of prebiotics, such as oligo-fructose, in healthy subjects, as well as in hemodialysis patients.[59,87] Moreover, in CKD mice, treatment with prebiotics has been shown to reduce the production of p-cresol and to improve insulin resistance and dyslipidemia. Finally, we have observed reductions in the blood urea level with the administration of a prebiotic diet for 3 months in CKD mice [Koppe L, Unpublished Data]. The effect of prebiotics on other intestinal metabolites in CKD is currently unknown, and studies on the efficacy of prebiotics in preventing CKD-associated metabolic disturbances in humans are lacking (Figure 2). Nakabayashi et al. used supplemental symbiotics (probiotic combined with prebiotic) for two weeks and observed significant reductions in p-cresyl sulfate levels and the normalization of bowel habits in hemodialysis patients.[88] Furthermore, AST-120, an oral adsorbent capable of binding solutes and preventing their intestinal absorption represents a type of therapy able to reduce the levels of indoxyl sulfate.[89] In addition, a recent study demonstrated that supplementation with AST 120 appears to improve intestinal barrier, inflammation and oxidative stress of CKD.[90]

Figure 2.

The possible effects of pre/probiotics on intestinal metabolites in chronic kidney disease patients. CKD leads to an intestinal microbiota imbalance and patients accumulate the toxins produced by intestinal bacteria (IS, PCS, amines, ammonia and TMAO) in plasma. These compounds interact negatively with biological functions, resulting in pathological impact such as increased oxidative stress and inflammation, increasing the cardiovascular risk. The use of pre- or pro-biotics can modulate the intestinal microbiota minimizing the deleterious effects caused by its imbalance and thereby promotes improved health of the gastrointestinal tract (A), reducing plasma levels of intestinal toxins (B), reducing oxidative stress and inflammation (C), and attenuating cardiovascular risk in CKD patients (D).
CKD: Chronic kidney disease; IS: Indoxyl sulfate; LPS: Lipopolysaccharides; PCS: p-cresyl sulfate; TMAO: Trimethylamine-N-oxide.

More recently, fecal microbiota transplantation has been suggested as an new approach to restore the dysbiosed microbiota. However, experience with this technique is limited and requires careful consideration.[91,92] In addition, the development of genetically modified probiotics may be beneficial; for example, clinical benefit was observed with genetically modified L. lactis treatment to deliver IL-10 from intestinal mucosa in Crohn's disease patients. Although engineering probiotics is promising, their safety must be further validated.[93]