Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2019; 25(15): 1865-1878
Published online Apr 21, 2019. doi: 10.3748/wjg.v25.i15.1865
Unconjugated bilirubin alleviates experimental ulcerative colitis by regulating intestinal barrier function and immune inflammation
Jia-Dong Zheng, Yan He, Heng-Yuan Yu, Yuan-Li Liu, Yi-Xuan Ge, Xue-Ting Li, Xue Li, Yan Wang, Meng-Ru Guo, Yi-Lin Qu, Xiao-Fa Qin, Ming-Shan Jiang, Xiu-Hong Wang
Jia-Dong Zheng, Yan He, Heng-Yuan Yu, Yuan-Li Liu, Yi-Xuan Ge, Xue-Ting Li, Xue Li, Yan Wang, Meng-Ru Guo, Yi-Lin Qu, Xiu-Hong Wang, Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Xiao-Fa Qin, Founder, GI Biopharma Inc., Westfield, NJ 07090, United States
Ming-Shan Jiang, Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Author contributions: Wang XH and Zheng JD contributed to study concept and design; He Y, Ge YX, Yu HY, Li X, Wang Y, Guo MR, Liu YL, Qu YL and Li XT contributed to acquisition of data; Zheng JD analyzed and interpreted the data; Zheng JD and He Y drafted the manuscript; Jiang MS and Qin XF contributed to critical revision of the manuscript for intellectual content; Wang XH contributed to study supervision.
Supported by grants from the National Natural Foundation of China, No. 81703232.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Harbin Medical University, Harbin, China (HMUIRB20180015).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Harbin Medical University.
Conflict-of-interest statement: No conflict of interest exists in this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Xiu-Hong Wang, MSc, PhD, Academic Research, Professor, Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, 157 Baojian Rd, Harbin 150086, Heilongjiang Province, China. wangxiuhong@hrbmu.edu.cn
Telephone: +86-13836111380 Fax: +86-13836111380
Received: January 4, 2019
Peer-review started: January 4, 2019
First decision: January 30, 2019
Revised: March 5, 2019
Accepted: March 15, 2019
Article in press: March 16, 2019
Published online: April 21, 2019
Processing time: 105 Days and 0.4 Hours
ARTICLE HIGHLIGHTS
Research background

Clinical treatment of ulcerative colitis consists of drugs that are both expensive and have side effects. Unconjugated bilirubin (UCB) has gained recent prominence for its anti-inflammatory and antioxidant properties. How UCB influences UC remains unresolved.

Research motivation

Patients with UC require lifelong treatment, and drugs for UC are linked to many adverse effects. Therefore, there is an urgent need to develop effective and safe drugs for UC.

Research objectives

To investigate the significance of UCB in intestinal barrier function and immune inflammation of mice with dextran sodium sulfate (DSS)-induced colitis.

Research methods

UC was induced by 3% (w/v) DSS in drinking water for 6 d followed by untreated water for 2 d. Concurrently, colitis mice were administered 0.2 mL UCB (400 μM) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. The length of the colon and weight of the spleen were recorded. Serum level of D-lactic acid, intestinal digestive proteases activity, and changes in gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins.

Research results

UCB significantly relieved the severity of colitis, including lower DAI, longer colon length, and smaller spleen weight (P < 0.001). UCB inactivated digestive proteases (P < 0.01), increased expression of tight junction protein occludin (P < 0.001), decreased serum level of D-lactate (P < 0.001), and lowered histopathological score and activity of myeloperoxidase compared with those in colitis mice (P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF)-α and interleukin-1β (P < 0.001), decreased expression of Toll-like receptor (TLR) 4 (P < 0.001) and myeloid differentiation primary response gene 88 (P < 0.05), and increased expression of TNF-receptor-associated factor 6 (P < 0.05) and IκBα (P < 0.05) in the colon.

Research conclusions

UCB has a beneficial regulatory effect on intestinal barrier function and regulates normal intestinal homeostasis, and can suppress inflammation via the TLR4/NF-κB signaling pathway. This provides a theoretical basis for use of UCB as a clinical drug.

Research perspectives

UCB plays a pivotal role in intestinal innate immunity and inflammation. Thus, the findings of this study indicate a novel potential mechanism by which UCB can treat UC. More studies are needed to investigate the effect of UCB on chronic UC or colon cancer.