Efficacy And Immune Mechanism Of Compound Glutamine Entersoluble Capsules In The Treatment Of 5-FU-induced Intestinal Mucositis

Objective:Compound Glutamine Entersoluble Capsules(CGECs)are Chinese-Western compound preparation composed of L-glutamine and Sijunzi extract.It has been used in clinical practice for many years,but the efficacy and function characteristics are still unclear.The purpose of this study is to evaluate the clinical efficacy of CGECs in the treatment of enteritis induced by radiation or chemotherapy,and to explore the efficacy and immune mechanism of CGECs in the treatment of5-FU-induced intestinal mucositis in mice,finally provides the basis for the clinical application.Methods:(1)The efficacy of oral CGECs in the treatment of chemoradiotherapy enteritis:A systematic review Electronic databases,including China National Knowledge Infrastructure,VIP medicine information system,Wangfang,China Biomedical Literature Database,Embase,Cochrane Library and PubMed,were searched for randomized controlled trials investigating the effect of CGECs on chemoradiotherapy enteritis with the key words of"complex glutamine","chemotherapy","radiotherapy"and so on.The primary outcome measures including total clinical efficacy,the incidence of chemoradiotherapy intestinal mucositis,the incidence of diarrhea symptoms,and the serum TNF-αlevel in patients were evaluated by Meta-analysis.In addition,we discussed and analyzed the improvement of patients’quality of life.Meta-analysis was performed by Review Manager 5.3.(2)Therapeutic effects of CGECs on 5-FU-induced intestinal mucositis in mice According to the body weight,male ICR mices were randomly divided into control group,model group,montmorillonite powder group(1.5 g/kg),CGECs high,medium and low dose group(3.2,1.6,0.8 g/kg),L-glutamine group(1.92 g/kg),Sijunzi decoction group(1.28 g/kg).Then,the drugs were administered by oral gavage for 13days.50 mg/kg 5-FU was administered by intraperitoneal injection from day 6 to day10 to establish the model of chemotherapeutic intestinal mucositis.Next,the daily food intake,body weight,and diarrhea scores of mice were recorded every day.Finally the mice were sacrificed on day 13,the histopathological changes of small intestine was observed by histopathological methods,and the pathological injury score of small intestine were obtained.The level of myeloperoxidase(MPO)in homogenate of small intestinal tissue was detected by ELISA.(3)The immune mechanism of CGECs in the treatment of intestinal mucositis induced by 5-FU in mice After the mice were sacrificed,the thymus and spleen were taken to measure the organ index,and the whole small intestine was taken to record the number of Peyer’s patch(PP).Then,the content of secretory immunoglobulin A(SIgA),interleukin-4(IL-4),interleukin-10(IL-10),tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ)in homogenate of small intestinal tissue were detected by ELISA.And the percentage of CD4~+T cells and IgA~+B cells in small intestine tissues were detected by flow cytometry.Results:(1)The efficacy of oral CGECs in the treatment of chemoradiotherapy enteritis:A systematic review The results of Meta-analysis showed that,compared with conventional therapy,the rate of clinical total efficacy of CGECs alone was significantly higher(P=0.0002),and the incidence of chemoradiotherapy intestinal mucositis was significantly lower(P=0.0008).Compared with conventional therapy,the clinical efficacy of CGECs combined with conventional therapy was significantly higher(P<0.0001),the incidence of diarrhea symptoms(P=0.0007)and serum TNF-αlevels(P<0.0001)were significantly lower.In addition,CGECs alone or in combination with conventional therapy could significantly improve the quality of life in patients.(2)Therapeutic effects of CGECs on 5-FU-induced intestinal mucositis in mice Compared with the model group,the food intake of mice was improved in various degrees in each dose group of CGECs.Compared with the model group,the weight of mice was significantly increased(P<0.01 or P<0.05),the diarrhea score(P<0.01 or P<0.05)and the pathological injury score of small intestine was significantly decreased(P<0.01 or P<0.05),the small intestinal pathological damage has improved in CGECs high and medium dose group.The intestinal MPO levels were significantly reduced(P<0.05)in CGECs medium dose group than that in model group.Compared with the model group,the L-glutamine group showed a significant increase in body weight(P<0.05 or P<0.01),the diarrhea score and pathological injury score were significantly lower(P<0.05).The diarrhea score of the Sijunzi decoction group was significantly lower(P<0.05)than model group.(3)The immune mechanism of CGECs in the treatment of intestinal mucositis induced by 5-FU in mice Compared with the model group,the organ index of CGECs groups showed no significant change.The number of PP in the small intestine significantly increased(P<0.05),the percentage of CD4~+T and SIgA~+B cells was no significant change,the level of SIgA in intestinal homogenate significantly increased(P<0.01 or P<0.05)in each dose group of CGECs compared with model group.The level of IL-4(P<0.05)and IL-10 significantly higer(P<0.05),IFN-γconcentration was significantly lower(P<0.05)in the high dose group of CGECs than that in model group.Compared with the model group,the SIgA level in the L-glutamine group was significantly increased(P<0.05),and the IFN-γlevel was significantly decreased(P<0.05).The IFN-γlevel in the Sijunzi decoction group was significantly lower(P<0.05)than model group.Conclusion:The results of systematic review showed that CGECs can improve clinical efficacy,reduce the incidence of chemoradiotherapy intestinal mucositis and alleviate symptoms.Experimental studies showed that CGECs have protective effects on 5-FU-induced intestinal mucositis in mice,and the mechanism of CGECs maybe related to improve intestinal immune function.Moreover,the protective effect of CGECs on intestinal mucositis may be better than that of L-glutamine and Sijunzi decoction extract.