Effects of Gabexate Mesylate on the Gut Microbiota and Metabolomics in Rats with Sepsis

Wenju Sun; Yuqing Cui; Xiaojuan Zhang; Yuze Wang; Zihao Zhang; Xianfei Ding; Huoyan Liang; Dong Wang; Yali Sun; Shaohua Liu; Xiaoguang Duan; Yibin Lu; Tongwen Sun

doi:10.2147/JIR.S392060

Effects of Gabexate Mesylate on the Gut Microbiota and Metabolomics in Rats with Sepsis

J Inflamm Res. 2022 Dec 5:15:6581-6594. doi: 10.2147/JIR.S392060. eCollection 2022.

Authors

Wenju Sun^#¹, Yuqing Cui^#¹, Xiaojuan Zhang^#¹, Yuze Wang¹, Zihao Zhang², Xianfei Ding¹, Huoyan Liang¹, Dong Wang¹, Yali Sun¹, Shaohua Liu¹, Xiaoguang Duan¹, Yibin Lu³, Tongwen Sun¹

Affiliations

¹ General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, 450052, People's Republic of China.
² Department of Clinical Medicine, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, People's Republic of China.
³ Department of Critical Care Medicine, Xinyang Hospital Affiliated to Zhengzhou University, Xinyang, 464000, People's Republic of China.

^# Contributed equally.

Abstract

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. However, there is still no single drug that could reduce septic mortality. Previous studies have reported gabexate mesylate (GM) significantly reduced serum inflammatory factors, alleviated sepsis-induced lung injury and improved clinical outcomes. This study aimed to combine with microbiome sequencing and metabolomics analysis to explore the effects of GM administration in septic rats.

Methods: Sixty SD rats were randomly divided into the sham control (SC), cecal ligation and puncture (CLP), and GM injection (GM) groups. The mortality was measured and colonic feces were collected to examine the gut microbiota and metabolism 24 h after the procedure. The lung tissues were collected for hematoxylin-eosin staining.

Results: We observed the relative abundance of Pygmaiobacter, which contributed to short-chain fatty acids (SCFAs) promotion, Lactobacillus and Erysipelotrichaceae UCG-003 increased in the GM-treated rats, while Escherichia-Shigella and Akkermansia decreased compared to the sepsis-induced lung injury group. Furthermore, these 3 metabolites including Palmitoylethanolamide, Deoxycholic acid and Chenodeoxycholic acid correlated significantly to CLP- and GM-rich genus (P < 0.05). Besides, the lung tissues of CLP group showed more severe inflammatory infiltration and edema, and the mortality rate in the CLP group (10/20) was significantly higher than in the SC group (0/20) (P < 0.001) and GM group (4/20) (P < 0.05).

Conclusion: Our findings showed that GM attenuated sepsis-induced lung injury rats and regulated metabolites related to gut microbiota, which may provide an effective treatment for sepsis patients.

Keywords: gabexate mesylate; gut microbiota; metabolomics; rats; sepsis.

Grants and funding

This study was supported by Grant of NSFC-Henan Joint Foundation of China (Grant No. U2004110), the National Natural Science Foundation of China (Grant No. 82172129); Medical Science and Technology Tackling Plan Provincial and Ministerial Major Projects of Henan Province (Grant No. SBGJ202101015); The study of mechanism of Gabexate Mesilate in the treatment of sepsis and septic shock (Grant No. 2019-hx-45); The special fund for young and middle-aged medical research of China International Medical Exchange Foundation (Grant No. Z-2018–35); The integrated thinking research foundation of the China foundation for International Medical Exchange (Grant No. Z-2016-23-2001-23); The central government guides local science and technology development funds (grant number Z20221343037).