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
Processing time: 76 Days and 13 Hours
Abstract
AIM

To determine the efficacy of rifaximin for hepatic encephalopathy (HE) with the linkage of gut microbiome in decompensated cirrhotic patients.

METHODS

Twenty patients (12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis (Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test (NCT)-A. Changes in whole blood endotoxin activity (EA) was analyzed by endotoxin activity assay. Fecal microbiome was assessed by 16S ribosome RNA (rRNA) gene sequencing.

RESULTS

Treatment with rifaximin for 4 wk improved hyperammonemia (from 90.6 ± 23.9 μg/dL to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT (from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced (from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels (r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator (Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups (3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered.

CONCLUSION

Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

Keywords: Gut microbiome; Hepatic encephalopathy; Liver cirrhosis; Endotoxin; Rifaximin

Core tip: 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. 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. This is the first report of systemic and local effects of rifaximin in Japanese patients.