Unconjugated Bilirubin Attenuates DSS-Induced Colitis Potentially via Enhancement of Bilirubin Reabsorption

Chong Zhao; Hongli Huang; Qiuhua Pan; Wenqi Huang; Wu Peng; Haoming Xu; Zhiqiang Feng; Yanlei Du; Yuqiang Nie; Yongjian Zhou

doi:10.3389/fphar.2021.654808

Unconjugated Bilirubin Attenuates DSS-Induced Colitis Potentially via Enhancement of Bilirubin Reabsorption

Front Pharmacol. 2021 May 20:12:654808. doi: 10.3389/fphar.2021.654808. eCollection 2021.

Authors

Chong Zhao^{1

2

3}, Hongli Huang^{1

2}, Qiuhua Pan^{1

2}, Wenqi Huang^{1

2}, Wu Peng^{1

2}, Haoming Xu^{1

2}, Zhiqiang Feng^{1

2}, Yanlei Du^{1

2}, Yuqiang Nie^{1

2}, Yongjian Zhou^{1

2}

Affiliations

¹ Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
² Guangzhou Key Laboratory of Digestive Disease, Guangzhou First People's Hospital, Guangzhou, China.
³ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.

Abstract

Studies increasingly show that ulcerative colitis (UC) is a consequence of an imbalance between oxidative stress and antioxidant capacity. Bilirubin exerts an anti-inflammatory effect by scavenging reactive oxygen species (ROS), although the exact mechanism is not completely understood. The aim of this study was to determine the role of serum bilirubin in UC using patient data and a mouse model of dextran sodium sulfate (DSS)-induced colitis. We found that low levels of serum bilirubin correlated to a higher risk of UC in a retrospective case-control population. Pre-treatment with exogenous unconjugated bilirubin (UCB) significantly enhanced colonic bilirubin absorption in mice, and attenuated the DSS-induced body weight loss, colon shortening and histopathological damage. Mechanistically, bilirubin prevented the infiltration of inflammatory cells, and decreased the levels of myeloperoxidase and pro-inflammatory cytokines in the serum and colon. Moreover, bilirubin inhibited ROS and malondialdehyde production, scavenged superoxide anions (O₂ ^·-) from the colon and enhanced the total antioxidant capacity. In conclusion, exogenous UCB attenuated DSS-induced colitis by directly scavenging O₂ ^·- and enhancing bilirubin reabsorption in the colon via enterohepatic cycling.

Keywords: antioxidant; bilirubin; enterohepatic cycling; superoxide (O2·−); ulcerative colitis.