Effects of the oral adsorbent AST-120 on fecal p-cresol and indole levels and on the gut microbiota composition

https://doi.org/10.1016/j.bbrc.2020.02.141Get rights and content

Highlights

  • AST-120 profoundly reduced the amount of fecal p-cresol in mice with renal failure.

  • Renal failure and AST-120 treatment significantly changed gut microbiota.

  • AST-120 reduced the abundance of microbes involved in p-cresol production.

  • AST-120 increased the abundance of microbes involved in tryptophan-indole synthesis pathway.

Abstract

In chronic kidney disease, elevated levels of circulating uremic toxins are associated with a variety of symptoms and organ dysfunction. Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are microbiota-derived metabolites and representative uremic toxins. We have previously shown that the oral adsorbent AST-120 profoundly reduced pCS compared to IS in adenine-induced renal failure in mice. However, the mechanisms of the different attenuation effects of AST-120 between IS and pCS are unclear. To clarify the difference of AST-120 on IS and pCS, we investigated the levels of fecal indole and p-cresol, the respective precursors of IS and pCS, and examined the influence on the gut microbiota. Although fecal indole was detected in all groups analyzed, fecal p-cresol was not detected in AST-120 treatment groups. In genus level, a total of 23 organisms were significantly changed by renal failure or AST-120 treatment. Especially, AST-120 reduced the abundance of Erysipelotrichaceae uncultured and Clostridium sensu stricto 1, which have a gene involved in p-cresol production. Our findings suggest that, in addition to the adsorption of the uremic toxin precursors, AST-120 affects the abundance of some gut microbiota in normal and renal failure conditions, thereby explaining the different attenuation effects on IS and pCS.

Introduction

Chronic kidney disease (CKD) is defined by reduced renal function and evidence of kidney damage for at least 3 months. As renal clearance is reduced in CKD, the progression of CKD leads to the accumulation of uremic toxins in the circulation and tissues [1,2]. Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are representative uremic toxins that have various harmful effects [[3], [4], [5]]. We have previously described the accumulation of IS and pCS in 15 organs in mice with adenine-induced renal failure (RF) [6]. The accumulated uremic toxins are related to a variety of symptoms and organ dysfunctions in CKD, such as renal damage, cardiovascular damage, mineral and bone disorder (MBD), and muscle wasting [[6], [7], [8], [9], [10], [11], [12], [13]]. In the kidney, IS induces interstitial fibrosis, cellular senescence, kidney fibrosis, matrix expansion, and oxidative stress [7,11,12]. From animal models, it has been demonstrated that high serum IS levels are associated with increased oxidative stress and cardiac/renal fibrosis [7]. In addition, it has been suggested that uremic toxins cause a deterioration of bone mineral properties, and disturbance in bone elasticity due to changes in bone material properties has been reported in CKD animals [8,9]. Recently, we indicated that IS induces metabolic alteration in muscle cells and leads to muscle loss in CKD animals. Furthermore, we have demonstrated that plasma IS levels have a significant inverse association with skeletal muscle mass in CKD patients [14].

AST-120 is an orally administrated intestinal sorbent consisting of porous carbon particles 0.2–0.4 mm in diameter. It has been approved for clinical use in CKD patients for prolonging the time to initiation of hemodialysis and improvement of uremic symptoms in Japan and Asia [15,16]. It adsorbs low-molecular-weight compounds containing indole and p-cresol, which are precursors of IS and pCS, respectively, in the intestine. In CKD animals, exercise capacity and mitochondrial biogenesis of skeletal muscle were improved by the administration of AST-120 [17]. In addition, administration of AST-120 in CKD-animals improved CKD-induced bone abnormalities as blood IS levels decreased [9]. In our previous study, we measured the plasma IS and pCS levels in four groups of mice: control (Cont), control mice treated with AST-120 (Cont + AST), RF mice (RF), and RF mice treated with AST-120 (RF + AST) [6]. Both plasma IS and pCS levels were significantly increased in RF mice. While plasma pCS levels were significantly lowered by AST-120, plasma IS levels were not significantly lowered. Furthermore, plasma pCS was not detected in Cont + AST mice. AST-120 profoundly reduced pCS compared to IS in our previous study [6]. The reason of this difference is unclear.

The adsorption of substances by AST-120 depends on the molecular size and polarity of the substances [18]. Thus, AST-120 can equivalently adsorb indole and p-cresol. Similarly, AST-120 can equivalently adsorb tryptophan and tyrosine, which are precursors of indole and p-cresol, respectively. IS and pCS are microbiota-derived uremic toxins, whose production is governed by the gut microbiota metabolism [19]. Thus, we hypothesized that AST-120 may influence the composition of the microbiota and subsequently influence the amounts of IS and pCS.

This study assessed the effects of AST-120 on the gut microbiota and the precursor of uremic toxins. To do this, we evaluated the composition of the gut microbiota of RF and AST-120-treated mice using metagenomic analysis.

Section snippets

Animals

All animal experiments were approved by the Animal Committee of Tohoku University School of Medicine (2016PhA-019). Experimental protocols and animal care were performed according to the guidelines for the care and use of animals established by Tohoku University. Male, 8- to 9-week-old C57BL/6JJcl mice were purchased from CLEA Japan, Inc. (Tokyo, Japan). The mice were randomized to the Cont and RF groups. Cont group mice were fed a normal diet (Oriental Yeast, Tokyo, Japan) for 7 weeks. RF

Fecal indole and p-cresol

We measured the content of the fecal indole and p-cresol precursors of IS and pCS, respectively, in the four groups of mice using gas chromatography-mass spectrometry (GC-MS) (Fig. 1). Fecal indole tended to be increased in the Cont + AST group compared to the Cont and RF groups of mice (p = 0.06). In the RF + AST group, fecal indole was significantly increased compared to the Cont (p < 0.05) and RF group (p < 0.05). In addition, fecal indole of RF + AST group tended to be increased compared to

Discussion

In our previous study, plasma IS and pCS of RF group were significantly increased (28.1 ± 6.4 mg/mL and 14.0 ± 6.5 mg/mL, respectively) compared to those of Cont group (1.6 ± 0.7 mg/mL and 1.2 ± 0.9 mg/mL, respectively), and AST-120 treatment reduced plasma levels of IS and pCS (21.7 ± 6.4 mg/mL and 0.047 ± 0.018 mg/mL, respectively) [6]. AST-120 profoundly reduced plasma pCS compared to IS. In the present study, we examined the levels of fecal indole and p-cresol and the influence of AST-120

Acknowledgments

We acknowledge the technical assistance of the staff at the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences. We thank Yoshiko Kawana for the technical support. We would like to thank Editage (www.editage.jp) for English language editing. We acknowledge the Tohoku University Center for Gender Equality Promotion (TUMUG)

References (22)

  • S. Yamamoto et al.

    Uremic toxicity and bone in CKD

    J. Nephrol.

    (2017)
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