Unconjugated bilirubin alleviates experimental ulcerative colitis by regulating intestinal barrier function and immune inflammation

Abstract

BACKGROUND Unconjugated bilirubin (UCB) is generally considered toxic but has gained recent prominence for its anti-inflammatory properties. However, the effects of it on the interaction between intestinal flora and organisms and how it influences immune responses remain unresolved. AIM To investigate the role of UCB in intestinal barrier function and immune inflammation in mice with dextran-sulfate-sodium-induced colitis. METHODS Acute colitis was induced by 3% ( w / v ) dextran sulfate sodium salt in drinking water for 6 d followed by untreated water for 2 d. Concurrently, mice with colitis were administered 0.2 mL UCB (400 μmol/L) by intra-gastric gavage for 7 d. Disease activity index (DAI) was monitored daily. Mice were sacrificed at the end of the experiment. The length of the colon and weight of the spleen were recorded. Serum level of D-lactate, intestinal digestive proteases activity, and changes to the gut flora were analyzed. In addition, colonic specimens were analyzed by histology and for expression of inflammatory markers and proteins. RESULTS Mice treated with UCB had significantly relieved severity of colitis, including lower DAI, longer colon length, and lower spleen weight (colon length: 4.92 ± 0.09 cm vs 3.9 ± 0.15 cm; spleen weight: 0.33 ± 0.04 vs 0.74 ± 0.04, P < 0.001). UCB administration inactivated digestive proteases (chymotrypsin: 18.70 ± 0.69 U/g vs 44.81 ± 8.60 U/g; trypsin: 1.52 ± 0.23 U/g vs 9.05 ± 1.77 U/g, P < 0.01), increased expression of tight junction (0.99 ± 0.05 vs 0.57 ± 0.03, P < 0.001), decreased serum level of D-lactate (31.76 ± 3.37 μmol/L vs 54.25 ± 1.45 μmol/L, P < 0.001), and lowered histopathological score (4 ± 0.57 vs 7 ± 0.57, P < 0.001) and activity of myeloperoxidase (46.79 ± 2.57 U/g vs 110.32 ± 19.19 U/g, P < 0.001). UCB also regulated the intestinal microbiota, inhibited expression of tumor necrosis factor (TNF) α and interleukin 1β (TNF-α: 52.61 ± 7.81 pg/mg vs 105.04 ± 11.92 pg/mg, interleukin 1β: 13.43 ± 1.68 vs 32.41 ± 4.62 pg/mg, P < 0.001), decreased expression of Toll-like receptor 4 (0.61 ± 0.09 vs 1.07 ± 0.03, P < 0.001) and myeloid differentiation primary response gene 88 (0.73 ± 0.08 vs 1.01 ± 0.07, P < 0.05), and increased expression of TNF-receptor-associated factor 6 (0.79 ± 0.02 vs 0.43 ± 0.09 ...

Heme Catabolic Pathway in Inflammation and Immune Disorders

“…Additionally, in IBD disease, BR treatment could prevent DSS-induced murine colitis by inhibiting the migration of leukocytes across the vascular endothelium and suppressing iNOS expression (Zucker et al, 2015). Consistent with this result, another study also found that bilirubin could relieve colitis by protecting intestinal barrier function, suppressing inflammation via the TLR4 or NF-κB signaling pathway (Zheng et al, 2019). Therefore, BR treatment holds promise as a therapeutic strategy for immune diseases including lupus, RA and IBD.…”

Pingkui Enema Alleviates TNBS‐Induced Ulcerative Colitis by Regulation of Inflammatory Factors, Gut Bifidobacterium, and Intestinal Mucosal Barrier in Rats

“…The serum levels of diamine oxidase (DAO) and D -lactic acid ( D -LA) are important biochemical markers for evaluating epithelial barrier function. UC models have been reported to increase serum levels of DAO and D -LA [ 12 , 13 ], suggesting there is a defection of epithelial barrier in UC. Clinical data also supported that there are high serum levels of DAO and D -LA in UC patients [ 14 ].…”

Bilirubin Safeguards Cardiorenal and Metabolic Diseases: a Protective Role in Health

“…Recent investigations have found a role of the immune system in hypertension [19–21]. Bilirubin modulates the immune response at several levels including modulation of regulatory T cells, modulation of T helper type 17 (Th17) cells, inactivation of the Nlrp3 inflammasome, and inhibition of the Toll-like receptor 4/nuclear factor kappaB signaling pathway [22–25]. Not only can bilirubin modulate the immune system, but also, the BVR enzyme plays a vital role in immune function [26].…”