Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 7, 2017; 23(1): 60-75
Published online Jan 7, 2017. doi: 10.3748/wjg.v23.i1.60
Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier
Da Zhou, Qin Pan, Feng-Zhi Xin, Rui-Nan Zhang, Chong-Xin He, Guang-Yu Chen, Chang Liu, Yuan-Wen Chen, Jian-Gao Fan
Da Zhou, Qin Pan, Feng-Zhi Xin, Rui-Nan Zhang, Chong-Xin He, Yuan-Wen Chen, Jian-Gao Fan, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Guang-Yu Chen, Clinical Epidemiology Center, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
Chang Liu, Department of Medical Microbiology and Parasitology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Author contributions: Zhou D and Pan Q are performed the majority of experiments; Zhou D and Chen GY analyzed the data; Xin FZ, Zhang RN, He CX and Liu C are participated in treatment of animals; Chen YW and Fan JG designed and coordinated the research; Zhou D and Fan JG wrote the paper.
Supported by the State Key Development Program for Basic Research of China, No. 2012CB517501; National Natural Science Foundation of China, No. 81070322, No. 81270491, No. 81470840 and No. 31400001; and 100 Talents Program, No. XBR2011007h.
Institutional review board statement: The study was reviewed and approved by the Xinhua Hospital Ethics Committee Affiliated to Shanghai Jiaotong University School of Medicine.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Xinhua hospital affiliated to Shanghai Jiao Tong University School of Medicine.
Conflict-of-interest statement: The authors declare no competing financial interests.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at fattyliver2004@126.com. Participants gave informed consent for data sharing.
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: Dr. Jian-Gao Fan, Professor, Director, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. fattyliver2004@126.com
Telephone: +86-21-25077340 Fax: +86-21- 63846590
Received: September 12, 2016
Peer-review started: September 12, 2016
First decision: October 20, 2016
Revised: October 25, 2016
Accepted: November 15, 2016
Article in press: November 16, 2016
Published online: January 7, 2017
Processing time: 115 Days and 10.7 Hours
Abstract
AIM

To investigate whether gut microbiota metabolite sodium butyrate (NaB) is an effective substance for attenuating non-alcoholic fatty liver disease (NAFLD) and the internal mechanisms.

METHODS

Male C57BL/6J mice were divided into three groups, normal control were fed standard chow and model group were fed a high-fat diet (HFD) for 16 wk, the intervention group were fed HFD for 16 wk and treated with NaB for 8 wk. Gut microbiota from each group were detected at baseline and at 16 wk, liver histology were evaluated and gastrointestinal barrier indicator such as zonula occluden-1 (ZO-1) were detected by immunohistochemistry and realtime-PCR, further serum or liver endotoxin were determined by ELISA and inflammation- or metabolism-associated genes were quantified by real-time PCR.

RESULTS

NaB corrected the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria Christensenellaceae, Blautia and Lactobacillus. These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, increased the expression of ZO-1 in small intestine, further decreased the levels of gut endotoxin in serum and liver compared with HF group. Endotoxin-associated genes such as TLR4 and Myd88, pro-inflammation genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat were obviously downregulated after NaB intervention. Liver inflammation and fat accumulation were ameliorated, the levels of TG and cholesterol in liver were decreased after NaB intervention, NAS score was significantly decreased, metabolic indices such as FBG and HOMA-IR and liver function indicators ALT and AST were improved compared with HF group.

CONCLUSION

NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which is suggested to be a potential gut microbiota modulator and therapeutic substance for NAFLD.

Keywords: Non-alcoholic fatty liver disease; Sodium butyrate; Gut microbiota; Gastrointestinal barrier; Endotoxin

Core tip: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic metabolic health crisis that lacks effective therapeutic strategies. We found that NaB could correct the high-fat diet (HFD)-induced gut microbiota imbalance in mice, while it considerably elevated the abundances of the beneficial bacteria. These bacteria can produce butyric acid in what seems like a virtuous circle. And butyrate restored HFD induced intestinal mucosa damage, improved tight junction structure, reduced gut endotoxin into liver, leading to attenuate HFD induced liver inflammation and lipid accumulation, which may be a potential gut microbiota modulator and therapeutic substance for NAFLD.