Case Control Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2017; 23(47): 8355-8366
Published online Dec 21, 2017. doi: 10.3748/wjg.v23.i47.8355
Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity
Kosuke Kaji, Hiroaki Takaya, Soichiro Saikawa, Masanori Furukawa, Shinya Sato, Hideto Kawaratani, Mitsuteru Kitade, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Akira Mitoro, Hitoshi Yoshiji
Kosuke Kaji, Hiroaki Takaya, Soichiro Saikawa, Masanori Furukawa, Shinya Sato, Hideto Kawaratani, Mitsuteru Kitade, Kei Moriya, Tadashi Namisaki, Takemi Akahane, Akira Mitoro, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
Author contributions: Kaji K collected and analyzed the data, and drafted the manuscript; Takaya H also collected and analyzed the data; Saikawa S, Furukawa M, Sato S, Kawaratani H, Kitade M, Moriya K, Namisaki T, Akahane T and Mitoro A offered the technical or material support; Yoshiji H designed and supervised the study; all authors have read and approved the final version to be published.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Nara Medical University (Nara, Japan; Approval number 994).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper.
Data sharing statement: Informed consent for data sharing was not obtained but the presented data are anonymized and risk of identification is low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Kosuke Kaji, MD, PhD, Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. kajik@naramed-u.ac.jp
Telephone: +81-744-22-3051 Fax: +81-744-24-7122
Received: October 4, 2017
Peer-review started: October 5, 2017
First decision: October 25, 2017
Revised: October 30, 2017
Accepted: November 14, 2017
Article in press: November 14, 2017
Published online: December 21, 2017
ARTICLE HIGHLIGHTS
Research background

Hepatic encephalopathy (HE) is characterized by deficits in cognitive, psychiatric, and motor function and ranges in severity from minimal to overt HE and coma. Rifaximin is used for standard treatment of HE, targeting reduction of ammonia and gut bacterial translocation. Currently, rifaximin has been suggested to partially affect gut microbiome in the patients with HE.

Research motivation

The effects of rifaximin on the gut microbiome in patients from the Eastern countries have not been assessed. Moreover, the relationship between the endotoxin activity and microbial alteration at the gene level has not been elucidated. Recently, 16S rRNA gene sequencing has been established as a novel method to directly access the genetic content of entire communities of organisms. Some evidence reveals the effects of rifaximin on HE with the linkage of gut microbiota in patients from Western countries. Because the microbial taxa involved are slightly different in cirrhotic patients from Eastern and Western countries, we undertook this study to assess the effects of rifaximin on HE in cirrhotic patients from Eastern countries. Moreover, the relationship between the endotoxin activity and microbial alteration at the gene level.

Research objectives

To determine the efficacy of rifaximin for hepatic encephalopathy (HE), evaluated with serum ammonia level, NCT and endotoxin activity, with the linkage of gut microbiome in decompensated cirrhotic patients.

Research methods

Twenty patients with decompensated cirrhosis were enrolled for this study. They were treated with rifaximin 400 mg three times a day for 4 wk. The measurement of serum ammonia level and number connection test (NCT)-A were performed to evaluate their status of hepatic encephalopathy before and after treatment of rifaximin. Endotoxemia was assessed by blood endotoxin activity assay (EAA). The 16S ribosome RNA gene sequencing was performed for analysis of fecal microbiome, and the diversity and compositions of gut microbiome were compared between before and after treatment of rifaximin.

Research results

This study demonstrates that rifaximin improves hyperammonemia and cognitive impairment with the linkage of decreased endotoxin activity in patients with decompensated cirrhosis. The diversity and major components of gut microbiome analyzed by 16S rRNA gene sequencing are not altered by treatment with rifaximin, although the relative abundances of genus Veillonella and Streptococcus were lowered.

Research conclusions

This study demonstrates that rifaximin significantly improves hepatic encephalopathy with minor modification of the gut microbiome in Japanese patients with decompensated cirrhosis. Rifaximin markedly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome indicating that the effect of rifaximin is independent of modification of gut microbial diversity. This effect of rifaximin on gut microbiome in Japanese cirrhotic patients is similar to the patients in the West. On the other hands, rifaximin modified minor compositions of gut microbiome such as decreased relative abundances of genus Veillonella and Streptococcus in current subjects. So far, the mechanism of decreased endotoxin activity by rifaximin is still obscure, but we speculate that it is possibly related to the pharmacological action of rifaximin to improve intestinal barrier function. In conclusion, rifaximin is an effective medical agent for the patients with hepatic encephalopathy.

Research perspectives

This study demonstrates that rifaximin improves hyperammonemia and cognitive impairment with the linkage of decreased endotoxin activity in patients with decompensated cirrhosis. These effects of rifaximin are independent of alteration of gut microbial diversity, indicating that rifaximin has a potential capacity to decrease ammonia and endotoxin level other than the effect on gut microbiome such as the improvement of intestinal barrier function. Therefore, we will examine the effect of rifaximin on intestinal tight junction protein in the clinical practice to elucidate above hypothesis in near future after the approval of ethical committee. We consider that the best method is to analyze the alteration of intestinal tight junction protein before and after treatment with rifaximin in the biopsy tissues from the patients with decompensated cirrhosis.