Combination of Ursodeoxycholic Acid and Glutathione Improves Intestinal Morphology in Cholestasis by Downregulating TNF-α Expression

Abstract

BACKGROUND: Cholestasis caused by obstruction of the common bile duct and may developed gut-derived sepsis due to reactive oxygen species (ROS) accumulation. Ursodeoxycholic acid (UDCA) and glutathione are widely known for their antioxidant properties, that might be beneficial against ROS. However, the effects of UDCA-glutathione combination against ROS have not been well elucidated in previous studies. Thus, this study was conducted to evaluate tumor necrosis factor (TNF)-α level and height of terminal ileal mucosal villus after UDCA-glutathione administration in cholestasis rat model.METHODS: Twenty-eight male Sprague Dawley rats were randomly grouped into four treatment groups, each group consisted of seven rats that had previously undergone bile duct ligation. Three groups received treatment of UDCA-glutathione combination on stratified dose, while the other one only received UDCA. Each treatment was given for 21 days. Ileal samples were collected from the rats and stained with mouse anti TNF-a antibody and hematoxylin-eosin (HE). Immunohistochemistry and histopathological examination were done using microscope and then calculated with ImageJ.RESULTS: The combination of UDCA and glutathione treatment decreased the TNF-α expression (p<0.05) compared to UDCA only group, particularly in group that received 20 mg UDCA and 15 mg glutathione supplementation (p<0.05) and group that received 30 mg UDCA and 20 mg glutathione supplementation (p<0.05). The height of the mucosa villous was higher in the UDCA-glutathione combination groups for all the three dosage variations given (p<0.05) compared to UDCA only group.CONCLUSION: UDCA-glutathione combination downregulates TNF-α expression and improves ileum mucosal villus height in cholestasis.KEYWORDS: cholestasis, glutathione, intestinal villus height, TNF-α, UDCA

Effects of ursodeoxycholic acid and glutathione combination in spleen TNF-α and apoptotic index in rats with cholestasis

“…TNF-α induced apoptosis is mediated primarily through activation of the type I receptor, a death domain that recruits several different signalling proteins, which together are thought to be part of the apoptotic cascade. 15 This study did not examine other inflammatory mediators released by liver cells, such as IL-1β and IL-6, which could cause bile secretion failure and affect the spleen. This study also did not examine the dose of UDCA and glutathione, which could significantly reduce TNF-α and splenic cell apoptosis.…”

“…19 UCDA, a constituent of human bile salts, exhibits promising therapeutic potential in addressing liver fibrosis and cirrhosis. 15 Its mechanism involves stimulating hepatobiliary secretion, which aids in resolving cholestasis-related issues by promoting the excretion of bile from the liver. Additionally, UCDA contributes to the enhancement of glutathione synthesis.…”

“…14 Here, 28 rats were divided into four treatment groups (7 rats each) using simple randomisation: the control group (K) was administered 20 mg UDCA; treatment group 1 (P1) was administered 10 mg UDCA and 10 mg glutathione; treatment group 2 (P2) was administered UDCA 20 mg and glutathione 15 mg; treatment group 3 (P3) was administered UDCA 30 mg and glutathione 20 mg. UDCA was administered orally, while glutathione was administered intramuscularly. 15 The entire treatment protocol was administered continuously for 21 consecutive days. 16 On day 22, rats were sacrificed humanely euthanised randomly between 9:00 and 11:00 AM following an overnight fasting period.…”