Written by Milica Maksimovic
Reviewed by Griet Glorieux
The gut microbiota has received a lot of attention recently with data showing its contributory role to the pathogenesis of a variety of diseases, including hypertension and chronic kidney disease (CKD). The microbiota communicates with multiple organs through its metabolism-dependent pathways . Because of the metabolic effects, the microbiota can be considered as an endogenous organ.
Under healthy conditions, the gut epithelial layer forms a barrier between mucosa and submucosa preventing translocation of pathogenic gut microorganisms across the epithelium . The gut mucosa is the most dynamic reservoir of the microbiota that is constantly influenced and modified by factors including diet, toxins, pathogens and drugs. Immune cells residing inside lymph nodes monitor the intestinal environment and maintain gut homeostasis. The enteric nervous system, which is composed of numerous nerve plexuses, perceives mechanical and chemical changes within the gut and communicates with the autonomic nervous system. Enterohormones, metabolites, immune cells and cytokines derived from this complex mucosal and submucosal network have systemic impacts on other organs as they are taken up in circulation and can affect the cardiovascular system, bone marrow, brain and the kidneys. Several transporters proteins that regulate endogenous metabolite flow from the gut, to liver and at the side of the kidney where they are involved in excretion of waste products (the gut-liver-kidney axis) have been characterised .
The microbiome, is an important source of uremic toxins such as p-cresyl sulfate (pCS) and indoxyl sulfate (IxS), which are products of proteolytic fermentation of aromatic amino acids tyrosine and phenylalanine, and tryptophan, respectively . Next to the more favorable, saccharolytic fermentation, which generates short-chain fatty acids (SCFA). pCS and IxS are well known to impact almost every cell type of the cardiovascular (CV) system and are believed to increase CV and overall mortality in CKD patients [5,6]. Because of their binding to albumin, these toxins are not easily removed by dialysis as only free fraction (not bound to albumin) is cleared.
The increased intestinal concentration of urea and ammonia associated with the progression of CKD leads to microbial dysbiosis and overgrowth of pathobionts . This subsequently promotes the loss of the intestinal barrier integrityallowing translocation of endotoxin and bacterial degradation products to the systemic circulation triggering pro-inflammatory responses, which could further accelerate the progression of CKD and development of CV disease. Changes in the composition of gut microbiota in end-stage kidney disease has been demonstrated for the first time in 2012 [8, 9]. In paediatric patients, the type of renal-replacement therapy may have an effect on the microbiota composition as well . In fact, associations between intestinal microbiota and levels of uremic toxinsare observed already in early kidney disease .
More recently the association between intestinal microbiota and the levels of pCS and IS was studied in 18 haemodialysis patients. When faecal samples of patients with highest pCS and lowest IS were compared to the samples with lowest pCS and highest IS serum concentrations in this cohort, their microbial composition differed significantly. More specifically, the Enterococcus taxa were found to be more abundant in the former, whereas Bacteriodes in the latter group . In CKD patients in various stages of disease. The levels of aromatic amino acids and toxin precursors (pC and I) in colon did not differ between CKD stages, neither did theurinary toxin ratios to creatinine, suggesting that there is no increased generation of these toxins as CKD progresses. The increased plasma levels of pCS and IxS are thus mainly result of the reduced elimination due to impaired kidney function (Gryp et al, abstract FO079). Even though renal disease can profoundly affect the colonic microenvironment and has been associated with a distinct colonic microbial composition and function, other factors, such as dietary or other kidney-related factors are suggested to have an important impact as well .
Potential interventions in CKD include measures to decrease availability or generation of toxin precursors and/or prevent their absorption (Figure 1). It should be kept in mind that the uremic toxins are not necessarily detrimental at the site of their generation. Indol, in fact, has a beneficial role e.g. in establishing an intact epithelial barrier in vivo in colon itself . Therefore, it might be important to interfere differentially with intestinal generation of these toxins, and it has been demonstrated to be possible to modulate generation rates of pCS independent fromIS [15,16].