Uremic Toxin-Producing Gut Microbiota in Rats with Chronic Kidney Disease

Abstract

Background: In patients with chronic kidney disease (CKD), many metabolites of gut microbiota retain in the body as uremic toxins (UTs). However, the kinds of bacteria producing UTs are rarely discussed. Methods: We analyzed UT production and the composition of gut microbiota in CKD rats and cecectomized rats. AST-120, a spherical carbon adsorbent, was administrated to evaluate how the precursors of UT affect gut microbiota. Serum and urine levels of UTs were quantified by liquid chromatography/electrospray ionization-tandem mass spectrometry. Gut microbiota were analyzed using 454-pyrosequencing of the 16S rRNA gene. Operational taxonomic unit (OTU) clustering and UniFrac analysis were performed to compare gut microbiota among the groups. Results: Serum and urine levels of indoxyl sulfate and phenyl sulfate were higher in CKD versus control rats (p < 0.05). AST-120 administration decreased UT production (p < 0.01) and changed overall gut microbiota composition in CKD rats. UT urinary excretion and gut microbiota composition changed in cecectomized rats, with the relative abundance of Clostridia- and Bacteroidia-affiliated species being significantly reduced (p < 0.01). We identified candidate indole- and phenol-producing intestinal microbiota, 3 Clostridia, and 2 Bacteroidia. These OTUs have a tryptophanase/tyrosine phenol-lyase gene in the closest sequenced genome out of the OTUs declined following cecectomy. Conclusion: Our data suggest that UT production is correlated with a subset of indigenous gut microbiota. However, UT may be induced by other non-symbiotic microbiota that are influenced by factors other than microbiota populations. The relationship between specific microbiota and UTs in patients requires further clarification.

Characteristics of Colon-Derived Uremic Solutes

“…Many more colonderived solutes have been identified in rats and mice in which suppression of microbial solute production is easier to accomplish. Studies in these species have identified at least 27 colon-derived solutes which are normally excreted in the urine and/or accumulate in the plasma when kidney function is reduced (Supplemental Table 5) (1,(22)(23)(24)(25)(26)(27)(28).…”

Gut microbiota and inflammation in chronic kidney disease and their roles in the development of cardiovascular disease

“…The gut microbiota manipulates the processes leading to CKD through inflammatory [25], endocrine [20], and neurologic pathways [90]; a healthy gut microbiota protects the CKD, whereas gut dysbiosis contributes to the development of CKD [2]. In fact, CKD is associated with alterations in the gut microbiota; species producing uremic toxins, such as Enterobacteriaceae, Clostridiaceae, Pseudomonadaceae, and Bacteroidiaceae, are increased, whereas beneficial species, such as Lactobacillaceae, Bifidobacteriaceae, and Prevotellaceae, are decreased [101][102][103][104]. Consistently, fecal transplantation from CKD patients to antibiotic-treated mice results in an increase in the plasma TMAO levels [29].…”

Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

“…Testing the isolated effect of the loss of kidney function on microbiome composition is only possible in experimental models. In several studies exploring the effects of surgically induced CKD in rats, total richness was reduced in CKD and the microbial community was differentially structured [6,8]. Andersen et al performed a similar analysis in collagen type IV α3-deficient mice with Alport syndrome-related progressive CKD.…”