Effects of metformin on intestinal barrier repair in radiation proctitis and its mechanism
10.3760/cma.j.cn101480-20200701-00076
- VernacularTitle:二甲双胍促进放射性肠炎黏膜屏障修复的作用及机制
- Author:
Zhongqiu WANG
1
;
Tao LIU
;
Qingxin WANG
;
Linlin GONG
;
Zhiyong YUAN
;
Wei WANG
Author Information
1. 天津医科大学肿瘤医院放射治疗科 国家肿瘤临床医学研究中心 天津市肿瘤防治重点实验室 天津市恶性肿瘤临床医学研究中心，天津 300060
- Publication Type:Journal Article
- Keywords:
Pelvic radiation;
Radiation proctitis;
Metformin;
Intestinal barrier function
- From:
Chinese Journal of Inflammatory Bowel Diseases
2020;04(4):298-303
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the effects and mechanism of metformin on intestinal barrier repair in radiation proctitis (RP) .Methods:Serum and urine samples were collected from 61 cervical cancer patients with radiation proctitis during radiotherapy. ELISA and tachypleus amebocyte lysate was used to detect levels of TNF-α, IL-1β and endotoxin. High pressure liquid chromatography was used to detect lactulose/mannital (L/M) ratio. A radiation-induced mouse proctitis model was established, and HE staining, immunohistochemical (IHC) staining as well as electron microscope observation and fluorescein tracer were applied to analyze the changes of intestinal tissue pathology and tight junction. Western blot was applied to detect protein expressions of ZO-1, MUC2, p-AMPK and p-mTOR. ELISA was used to detect the levels of TNF-α and IL-1β.Results:In RP patients, compared to control group (without metformin) , serum levels of TNF-α [ (37.60 ± 11.93) μg/L vs. (89.40 ± 7.52) μg/L, P<0.001] and IL-1β [ (0.29 ± 0.03) pg/L vs. (0.84 ± 0.01) pg/L, P<0.001] were decreased, and urine L/M ratio (0.07 ± 0.02 vs. 0.04 ± 0.03, P = 0.020) was increased in metformin group. In RP mice model, DAI index increased gradually. Histopathological examination revealed incomplete intestinal mucosa. After metformin treatment, the above changes were alleviated. Meanwhile, compared to mice in RP group, plasma FD4 [ (26.60±3.84) mg/L vs. (54.26 ± 5.28) mg/L, P<0.001], TNF-α[ (0.35 ± 0.26) μg/L vs. (0.71 ± 0.20) μg/L, P<0.001] and IL-1β [ (0.24 ± 0.16) pg/L vs. (0.45 ± 0.23) pg/L, P<0.001] were all decreased, protein expression of ZO-1, MUC2 and p-AMPK were up-regulated, while p-mTOR was down-regulated in RP+Metformin group. Conclusions:Metformin can improve intestinal inflammation and promote the repair of intestinal barrier in radiation proctitis. The mechanism may be related to the role of metformin′s activating the AMPK pathway, inhibiting the mTOR pathway, maintaining the intestinal tight junction and promoting the synthesis of MUC2.
