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: 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
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 26 Issue 8 Pg. 1787-94 (Aug 2015) ISSN: 1533-3450 [Electronic] United States
• PMID: 25525179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Society of Nephrology.

Chemical References

• Chloride Channel Agonists
• Lubiprostone
• Alprostadil
• Adenine

Topics

• Adenine
• Alprostadil (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Chloride Channel Agonists (pharmacology, therapeutic use)
• Disease Progression
• Drug Evaluation, Preclinical
• Gastrointestinal Tract (drug effects, microbiology)
• Kidney Failure, Chronic (chemically induced, prevention & control)
• Lubiprostone
• Male
• Mice, Inbred C57BL
• Microbiota (drug effects)
• Random Allocation
• Uremia (prevention & control)