title: Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD.
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) on CKD. Oral administration of lubiprostone (500 µg/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 electrophoresis-mass 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.
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;
authors.forename: Eikan
authors.initials: E
authors.lastname: Mishima
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Hisato
authors.initials: H
authors.lastname: Shima
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan;
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hirayama
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan;
authors.forename: Noriko N
authors.initials: NN
authors.lastname: Fukuda
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Chitose
authors.initials: C
authors.lastname: Suzuki
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan; and.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yuri
authors.affiliation: Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan; and.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tomioka
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan;
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine and Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan takaabe@med.tohoku.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
mesh_terms: D000225:Adenine; D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D065101:Chloride Channel Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000382:microbiology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000517:prevention & control*; D000068238:Lubiprostone; D008297:Male; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects*; D011897:Random Allocation; D014511:Uremia / Q000517:prevention & control
chemical_list: D065101:Chloride Channel Agonists; D000068238:Lubiprostone; D000527:Alprostadil; D000225:Adenine
keywords: CKD; gastrointestinal medications; intestine; uremia