The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development

Abstract

It is well-established that uremic toxins are positively correlated with the risk of developing chronic kidney disease and cardiovascular disease. In addition, emerging data suggest that gut bacteria exert an influence over both the production of uremic toxins and the development of chronic kidney disease. As such, modifying the gut microbiota may have the potential as a treatment for chronic kidney disease. This is supported by data that suggest that rescuing microbiota dysbiosis may: reduce uremic toxin production; prevent toxins and pathogens from crossing the intestinal barrier; and, reduce gastrointestinal tract transit time allowing nutrients to reach the microbiota in the distal portion of the gastrointestinal tract. Despite emerging literature, the gut-kidney axis has yet to be fully explored. A special focus should be placed on examining clinically translatable strategies that might encourage improvements to the microbiome, thereby potentially reducing the risk of the development of chronic kidney disease. This review aims to present an overview of literature linking changes to the gastrointestinal tract with microbiota dysbiosis and the development and progression of chronic kidney disease.

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options

“…Although the study failed to demonstrate a signiicant change in total serum IS levels (−2 mmol/L, 95% CI −5 to 1 mmol/L, p = 0.12), the change in serum PCS levels did reach a level of statistical signiicance, with a 13% reduction in the treatment group (−14 mmol/L, 95% CI −27 to −2 mmol/L, p = 0.03). Furthermore, after excluding the 10 participants who had received antibiotic therapy during the trial, which is known to afect the balance of bacterial species in the gut [8,42], the changes in serum levels with synbiotic therapy for both total IS (−5 mmol/L, 95% CI −8 to −1 mmol/L, p = 0.03) and PCS (−25 mmol/L, 95% CI −38 to −12 mmol/L, p = 0.001) were signiicant. The changes in free IS and PCS levels were also signiicant amongst antibiotic-free completers.…”

“…Gut dysbiosis may in turn lead to the production of various toxins and metabolites that contribute to uraemic toxicity, cardiovascular disease and progressive kidney scarring and failure [4][5][6]. The central role of the gut microbiome in kidney health therefore makes it an appealing therapeutic target in patients with CKD [7,8].…”

“…IS is produced by tryptophan metabolism facilitated by Escherichia coli and Clostridium sporogenes, while PCS is generated by break down of tyrosine and phenylalanine by intestinal anaerobes, such as Clostridium diicile, Faecalibacterium prausnizii, Subdoligranulum and selected strains within the Biidobacterium and Lactobacillus genus [8]. IS and PCS are both solely produced by the gut microbiota [9][10][11][12] and accumulate in the serum of patients with CKD due to both increased intestinal production and reduced glomerular iltration and proximal tubular secretion [12][13][14].…”

“…Gut dysbiosis may in turn lead to the production of various toxins and metabolites that contribute to uraemic toxicity, cardiovascular disease and progressive kidney scarring and failure [4][5][6]. The central role of the gut microbiome in kidney health therefore makes it an appealing therapeutic target in patients with CKD [7,8].Two key nephrovascular toxins produced by proteolytic bacterial fermentation in the gut are indoxyl sulphate (IS) and p-cresyl sulphate (PCS). IS is produced by tryptophan metabolism facilitated by Escherichia coli and Clostridium sporogenes, while PCS is generated by break down of tyrosine and phenylalanine by intestinal anaerobes, such as Clostridium diicile, Faecalibacterium prausnizii, Subdoligranulum and selected strains within the Biidobacterium and Lactobacillus genus [8].…”

“…The central role of the gut microbiome in kidney health therefore makes it an appealing therapeutic target in patients with CKD [7,8].…”