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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Effect of artesunate supplementation on bacterial translocation and dysbiosis of gut microbiota in rats with liver cirrhosis
Yun-Xia Chen, Li-Na Lai, Hui-Ying Zhang, Yang-Hui Bi, Li Meng, Xu-Jiong Li, Xiao-Xia Tian, Li-Min Wang, Yi-Min Fan, Zhong-Fu Zhao, De-Wu Han, Cheng Ji
Yun-Xia Chen, Li Meng, Department of Microbiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
Li-Na Lai, Yang-Hui Bi, Department of Pharmacology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
Hui-Ying Zhang, Xiao-Xia Tian, Department of Pathophysiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
Xu-Jiong Li, Department of Physiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
Li-Min Wang, Yi-Min Fan, Functional Integrative Laboratory, Department of Pathophysiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
Zhong-Fu Zhao, Institute of Hepatology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
De-Wu Han, Institute of Hepatology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Cheng Ji, USC Research Center for Liver Disease, Department of Medicine, University of Southern California, Los Angeles, CA 90033, United States
Author contributions: Chen YX and Lai LN contributed equally to this work; Chen YX, Lai LN, Zhang HY, Bi YH, Meng L, Li XJ and Tian XX performed the majority of experiments and analyzed the data; Wang LM and Fan YM participated in treatment of animals; Zhao ZF, Han DW and Ji C designed and coordinated the research; Chen YX and Lai LN wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81070339; the International Science and Technology Cooperation Project of Shanxi, No. 2010081068; the Key Laboratory Foundation of Cellular Physiology Department of Shanxi Medical School and Provincial Ministry of Education, No. 2010-09; the Fund for Returned Students of Shanxi, No. 211-091; the Fund for Returned Medical Doctors of Changzhi Medical College, No. 2010-01; Science and Technology Innovation Team Project of Changzhi Medical College, No. CX201409; College Student Innovation and Entrepreneurship Training Project of Shanxi Province, No. 2014308; and the US NIH (to Cheng Ji), No. R21AA023952 and No. P30DK48522-21.
Institutional review board statement: This study has been reviewed by Changzhi Medical College (Changzhi, China).
Institutional animal care and use committee statement: All animals were cared and used carefully during the study, under a protocol that was in accordance with institutional guidelines for animal research and was approved by the Ethical and Research Committee of Changzhi Medical College (Changzhi, China).
Conflict-of-interest statement: All authors declare no financial or non-financial competing interests.
Data sharing statement: No additional data.
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: Hui-Ying Zhang, MD, Professor, Department of Pathophysiology, Changzhi Medical College, 161 Jiefang Dongjie, Changzhi 046000, Shanxi Province, China.
zhanghy2001@163.com
Telephone: +86-355-3031235 Fax: +86-355-3034065
Received: September 15, 2015
Peer-review started: September 16, 2015
First decision: October 14, 2015
Revised: October 28, 2015
Accepted: November 19, 2015
Article in press: November 19, 2015
Published online: March 14, 2016
Processing time: 171 Days and 1.9 Hours
AIM: To evaluate the effect of artesunate (AS) supplementation on bacterial translocation (BT) and gut microbiota in a rat model of liver cirrhosis.
METHODS: Fifty-four male Sprague-Dawley rats were randomly divided into a normal control group (N), a liver cirrhosis group (M) and a liver cirrhosis group intervened with AS (MA). Each group was sampled at 4, 6 and 8 wk. Liver cirrhosis was induced by injection of carbon tetrachloride (CCl4), intragastric administration of 10% ethanol, and feeding a high fat diet. Rats in the MA group were intragastrically administered with AS (25 mg/kg body weight, once daily). Injuries of the liver and intestinal mucosa were assessed by hematoxylin-eosin or Masson’s trichrome staining. Liver index was calculated as a ratio of the organ weight (g) to body weight (g). The gut microbiota was examined by automated ribosomal intergenic-spacer analysis of fecal DNA. BT was assessed by standard microbiological techniques in the blood, mesenteric lymph nodes (MLNs), liver, spleen, and kidney.
RESULTS: Compared to group N, the body weight was reduced significantly in groups M and MA due to the development of liver cirrhosis over the period of 8 wk. The body weight was higher in group MA than in group M. The liver indices were significantly elevated at 4, 6 and 8 wk in groups M and MA compared to group N. AS supplementation partially decreased the liver indices in group MA. Marked histopathologic changes in the liver and small intestinal mucosa in group M were observed, which were alleviated in group MA. Levels of pro-inflammatory interleukin-6 and tumor necrosis factor-α were significantly elevated at 8 wk in ileal homogenates in group M compared to group N, which were decreased after AS supplementation in group MA. The dysbiosis of gut microbiota indicated by the mean diversity (Shannon index) and mean similarity (Sorenson index) was severe as the liver cirrhosis developed, and AS supplementation had an apparent intervention effect on the dysbiosis of gut microbiota at 4 wk. The occurrence of BT was increased in the liver of group M compared to that of group N. AS supplementation reduced BT in group MA at 8 wk. BT also occurred in the MLNs, spleen, and kidney, which was reduced by AS supplementation. BT was not detected in the blood in any group.
CONCLUSION: Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other non-antimalarial effects that modulate gut microbiota, inhibit BT and alleviate inflammation, resulting in a reduction in CCl4, alcohol and high fat-caused damages to the liver and intestine.
Core tip: Artesunate (AS) is antimalarial yet potentially anti-inflammatory. We evaluated the effect of AS supplementation on bacterial translocation (BT) and the gut microbiota in a rat model of liver cirrhosis. Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other non-antimalaria effects that modulate gut microbiota, inhibit BT and alleviate inflammation, leading to a reduction in carbon tetrachloride, alcohol and high fat-caused damages to the liver and intestine.
