Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is characterized by gut dysbiosis with a decrease in short-chain fatty acid (SCFA)-producing bacteria. Levels of protein-bound uremic toxins (PBUTs) and post-translational modifications (PTMs) of albumin increase with CKD, both risk factors for cardiovascular morbidity and mortality. The relationship between fecal metabolites and plasma concentrations of PBUTs in different stages of CKD (n = 103) was explored. Estimated GFR tends to correlate with fecal butyric acid (BA) concentrations (rs = 0.212; p = 0.032), which, in its turn, correlates with the abundance of SCFA-producing bacteria. Specific SCFAs correlate with concentrations of PBUT precursors in feces. Fecal levels of p-cresol correlate with its derived plasma UTs (p-cresyl sulfate: rs = 0.342, p < 0.001; p-cresyl glucuronide: rs = 0.268, p = 0.006), whereas an association was found between fecal and plasma levels of indole acetic acid (rs = 0.306; p = 0.002). Finally, the albumin symmetry factor correlates positively with eGFR (rs = 0.274; p = 0.005). The decreased abundance of SCFA-producing gut bacteria in parallel with the fecal concentration of BA and indole could compromise the intestinal barrier function in CKD. It is currently not known if this contributes to increased plasma levels of PBUTs, potentially playing a role in the PTMs of albumin. Further evaluation of SCFA-producing bacteria and SCFAs as potential targets to restore both gut dysbiosis and uremia is needed.

Traditional Chinese Medicine: An Exogenous Regulator of Crosstalk between the Gut Microbial Ecosystem and CKD

“…At present, an increasing number of studies have focused on the interplay among SCFAs, intestinal barrier, and CKD [ 66 , 67 ]. Significantly decreased SCFA concentrations were observed in CKD patients compared to healthy controls [ 68 ]. Recent evidence suggested that concentrations of SCFAs, especially acetate and butyrate, are almost completely suppressed in patients and animal models with CKD [ 69 , 70 ].…”

The Urinary Microbiome; Axis Crosstalk and Short-Chain Fatty Acid

“…In a study comparing fecal SCFA according to CKD grade, the concentration of butyrate is decreased significantly as renal function deteriorates. Although change in concentrations of acetate and propionate acetate did not show a significant difference, they showed a decreasing trend [ 13 ]. In addition, decreases of SCFA-producing strains, Butyricicoccus spp., Faecalibacterium prausnitzii, and Roseburia spp., were identified.…”

“…In addition, decreases of SCFA-producing strains, Butyricicoccus spp., Faecalibacterium prausnitzii, and Roseburia spp., were identified. These decreases were associated with a decrease of each SCFA in CKD patients [ 13 ]. The pathogenic interconnection between gut microbiota and kidney disease is referred to as the gut–kidney axis.…”

“…Recent studies on more axes in connection with various diseases have been presented [ 10 , 11 , 12 , 13 ]. In these interactions, inflammasomes, multiprotein oligomers that can initiate inflammatory responses and metabolites of the microbiome such as short-chain fatty acids (SCFA), play an important role.…”

Yishen Qingli Heluo Granule Ameliorates Renal Dysfunction in 5/6 Nephrectomized Rats by Targeting Gut Microbiota and Intestinal Barrier Integrity

“…An emerging evidence indicated that the concentrations of SCFAs, especially acetic acid and butyric acid, were almost completely suppressed in humans and animal models with CKD ( Jiang et al, 2016 ; Mishima et al, 2017 ). In addition, an increasing body of evidence demonstrated the reduction of SCFAs could compromise the renal function ( Steenbeke et al, 2021 ). Conversely, supplementation of SCFAs, particularly butyric acid, could promote barrier function and control microbial translocation, and ultimately protect the kidney from injury ( Wang et al, 2019 ).…”