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.
Highlights
Ulcerative colitis (UC) is an idiopathic chronic inflammatory bowel disease primarily involving the colonic mucosa and submucosa (Ungaro et al, 2017)
When stratified by age and sex, the reduction in serum bilirubin levels was more pronounced in males compared to females, and in the middle-aged patients (30–50 years old)
Multiple clinical studies have reported that bilirubin levels correlate negatively with the risk of inflammatory bowel disease (IBD) (Lenicek et al, 2014; FIGURE 4 | unconjugated bilirubin (UCB) reduced colonic oxidative stress in mice with dextran sodium sulfate (DSS)-induced colitis. (A) Relative reactive oxygen species (ROS) levels (A) and (B) total antioxidant capacity (TAC) in the indicated groups
Summary
Ulcerative colitis (UC) is an idiopathic chronic inflammatory bowel disease primarily involving the colonic mucosa and submucosa (Ungaro et al, 2017). Multiple pro-inflammatory mediators including reactive oxygen species (ROS), cytokines and neutrophils have been implicated in the pathogenesis of UC (Sands, 2015). Studies increasingly show that oxidative stress through reactive oxygen metabolites (ROMs) is the fundamental mechanism of intestinal tissue damage (Simmonds et al, 1992; Barbosa et al, 2003; Aviello and Knaus, 2017). ROS or free radicals are a byproduct of mitochondrial oxidative phosphorylation, and are quenched by the antioxidant system defense under physiological conditions. The antioxidant enzymes are usually impaired in pathological conditions (Pisoschi and Pop, 2015), resulting in excessive production of ROS that correlates with the pathogenesis and development of inflammatory diseases. Studies show that activated neutrophils in the intestinal mucosa produce high levels of ROS, which can induce
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