Observational Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2020; 26(2): 199-218
Published online Jan 14, 2020. doi: 10.3748/wjg.v26.i2.199
Rifaximin improves survival in cirrhotic patients with refractory ascites: A real-world study
Xin-Yue Lv, Hui-Guo Ding, Jun-Fu Zheng, Chun-Lei Fan, Lei Li
Xin-Yue Lv, Hui-Guo Ding, Jun-Fu Zheng, Chun-Lei Fan, Lei Li, Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
Author contributions: Li L designed the study and performed scientific edits to the manuscript; Lv XY and Ding HG analysed and interpreted the data, and wrote the manuscript; Zheng JF was responsible for the patient follow-up; Lv XY and Fan CL were responsible for data collection.
Supported by the State Key Projects Specialized on Infectious Diseases, No. 2017ZX10203202-004 and No. 2017ZX10203202003008; the Digestive Medical Coordinated Development Centre of the Beijing Municipal Administration of Hospitals, No. XXZ0303; Beijing High-level Health Technicians, No. 2013-03-073; Beijing Municipal Administration of Hospitals’ Ascent Plan, No. DFL20151602.
Institutional review board statement: The study protocol conformed to the Declaration of Helsinki and was approved by the Biomedical Research Ethics Committee of Peking University First Hospital.
Informed consent statement: All participants provided written informed consent for using samples and materials prior to study enrollment.
Conflict-of-interest statement: All authors declare no conflict of interest. Additionally, they have substantially contributed to this current study and approved the content of the manuscript.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of item.
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/
Corresponding author: Lei Li, MD, PhD, Associate Professor, Chief Physician, Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, 8 Xitoutiao, Youanmenwai, Beijing 100069, China. m13699119545@163.com
Received: October 18, 2019
Peer-review started: October 18, 2019
First decision: November 22, 2019
Revised: December 6, 2019
Accepted: December 21, 2019
Article in press: December 21, 2019
Published online: January 14, 2020
Research background

Patients with refractory ascites have a poor prognosis and there is no effective treatment except for liver transplantation. Rifaximin has been shown to reduce the incidence of hepatic encephalopathy and other complications in patients with cirrhosis. However, few studies have investigated the effect of rifaximin in cirrhotic patients with refractory ascites. And the mechanism of rifaximin in cirrhotic patients with refractory ascites remains unclear.

Research motivation

Previous studies have shown that rifaximin treatment can reduce the concentrations of interleukin-6, tumour necrosis factor alpha, and endotoxin in blood, thus improving systemic haemodynamics and decreasing the hepatic venous pressure gradient in patients with cirrhosis. Rifaximin has been demonstrated to exert positive effects in the prevention and treatment of hepatic encephalopathy and to prevent the development of esophagogastric and gastric variceal bleeding, spontaneous bacterial peritonitis, and hepatorenal syndrome. These provided ideas for the study and treatment in cirrhotic patients with refractory ascites.

Research objectives

The role of the gut-liver axis in the occurrence and development of complications of cirrhosis has aroused great attention. Microbiota dysbiosis and bacterial translocation have been shown to be involved in the progression of cirrhosis. Bacteria and their products are introduced into blood via the intestines and then increase the blood levels of endotoxin and inflammatory factors, which in turn accelerate liver fibration and stimulate the production of vasodilator substances. These events cause reduced systemic vascular resistance and an activated sympathetic nervous system and renin-angiotensin-aldosterone system, eventually leading to hyperdynamic circulation, which plays an important role in the pathogenesis of refractory ascites. Therefore,improving the gut microenvironment may benefit cirrhotic patients with refractory ascites. We conducted this study to explore the effects of rifaximin in cirrhotic patients with refractory ascites.

Research methods

All patients received conventional treatment for refractory ascites, while patients in the rifaximin group received oral rifaximin-α 200 mg four times daily for at least 2 wk. The ascites grade, fasting weight, liver and kidney function, and the inflammatory factors in the plasma were evaluated before and after treatment. In addition, the gut microbiota was determined by metagenomics sequencing (Illumina HiSeq) to analyse the changes in the characteristics of the gut microbiota before and after rifaximin treatment. The patients were followed for 6 mo. This study evaluated the effects of rifaximin in cirrhotic patients with refractory ascites with regard to clinical efficacy, laboratory indicators, inflammatory factors, and intestinal microbiota. The concentrations of interleukin-6, interleukin-8, tumour necrosis factor alpha, monocyte chemoattractant protein-1, interferon-inducible protein 10, and lipopolysaccharide-binding protein were determined with Luminex (Magnetic Luminex Assay; R&D Systems Europe, Ltd., Abingdon OX14 3NB, United Kingdom), which was highly reliable. Intestinal microbiota can be annotated to the level of species and the study of the intestinal microbiota can be deepened to the level of genes and functions using metagenomic sequencing, compared to 16S rDNA sequencing.

Research results

Compared with the control group, the fasting weight of patients decreased and the ascites significantly subsided after treatment with rifaximin. The 6-mo survival rate of patients in the rifaximin group was significantly higher than that in the control group. The concentration of interferon-inducible protein 10 decreased significantly in the rifaximin group compared with that in the control group. The abundance of Roseburia, Haemophilus, and Prevotella was significantly reduced after rifaximin treatment, while the abundance of Lachnospiraceae_noname, Subdoligranulum, and Dorea decreased and the abundance of Coprobacillus increased after treatment with rifaximin plus intravenous antibiotics. The gene expression of virulence factors was significantly reduced after treatment in both subgroups treated with rifaximin or rifaximin plus intravenous antibiotics. These findings provide new ideas for study in cirrhotic patients with refractory ascites-targeting the gut microbiota. The functions of these changed intestinal bacteria remain to be explored in the future.

Research conclusions

This study evaluated the clinical efficacy of rifaximin and its effects on intestinal flora characteristics and the systemic inflammatory state in cirrhotic patients with refractory ascites, targeting the gut microbiota. We concluded that rifaximin mitigates ascites and improves survival of cirrhotic patients with refractory ascites, and a possible mechanism is that rifaximin regulates the structure and functions of intestinal bacteria, thus improving the systemic inflammatory state. These provide new ideas for clinical dealing with cirrhotic patients with refractory ascites-targeting the gut microbiota.

Research perspectives

Further research is needed to assess the effect of long-term treatment with rifaximin on the prognosis of cirrhotic patients with severely disordered haemodynamics and a high inflammatory state. Randomized controlled studies with a large sample size are still needed to verify our conclusions, and the role of these floras remains to be further explored, since the changes in the gut microbiota in cirrhotic patients with refractory ascites remain unavailable.