Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD

Eikan Mishima, Shinji Fukuda, Hisato Shima, Akiyoshi Hirayama, Yasutoshi Akiyama, Yoichi Takeuchi, Noriko N. Fukuda, Takehiro Suzuki, Chitose Suzuki, Akinori Yuri, Koichi Kikuchi, Yoshihisa Tomioka, Sadayoshi Ito, Tomoyoshi Soga, Takaaki Abe

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79 Citations (Scopus)

Abstract

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) onCKD. Oral administration of lubiprostone (500 mg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresismass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.

Original languageEnglish
Pages (from-to)1787-1794
Number of pages8
JournalJournal of the American Society of Nephrology
Volume26
Issue number8
DOIs
Publication statusPublished - 2015 Aug 1

ASJC Scopus subject areas

  • Nephrology

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    Mishima, E., Fukuda, S., Shima, H., Hirayama, A., Akiyama, Y., Takeuchi, Y., Fukuda, N. N., Suzuki, T., Suzuki, C., Yuri, A., Kikuchi, K., Tomioka, Y., Ito, S., Soga, T., & Abe, T. (2015). Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD. Journal of the American Society of Nephrology, 26(8), 1787-1794. https://doi.org/10.1681/ASN.2014060530