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Important Endpoints and Proliferative Markers to Assess Small Intestinal Injury and Adaptation using a Mouse Model of Chemotherapy-Induced Mucositis

Intestinal adaptation is the natural compensatory mechanism that occurs when the bowel is lost due to trauma. The adaptive responses, such as crypt cell ...

University of Copenhagen

Gastrointestinal mucositis is an unwanted and often dose-limiting side effect to most cancer treatments. Glucagon-like peptide-2 (GLP-2) is a peptide secreted from intestinal L-cells in response to nutrient intake. The peptide is involved in the regulation of apoptosis and proliferation in the intestine. We aimed to investigate the role of GLP-2 in experimental chemotherapy-induced mucositis. METHODS STUDY 1: Rats were given a single injection with 5-fluorouracil (5-FU) and killed in groups of five each day for 5 days. Blood samples were analysed for GLP-2 concentrations. The intestine was analysed for weight loss, morphometric estimates and proliferation. STUDY 2: Rats were treated with GLP-2 or control vehicle 2 days before a single injection of 5-FU or saline. The treatments continued until kill 2 days after. The intestine was investigated for influx of myeloperoxidase (MPO)-positive cells and morphometric estimates, such as villus height, as a marker of mucositis. RESULTS STUDY 1: Two days after chemotherapy, there was a rise in endogenous GLP-2, followed by a marked increase in proliferation. STUDY 2: Exogenous GLP-2 was able to protect the intestine from severe weight loss and completely prevented the reduction in villus height in the control rats. Furthermore, there was a significant decrease in influx of MPO-positive cells in the GLP-2-treated rats.

Exogenous glucagon-like peptide-2 (GLP-2) prevents chemotherapy-induced mucositis in rat small intestine.

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth hormone and is shown to promote growth of colonic adenomas in carcinogen treated mice. Both peptides are degraded by dipeptidyl peptidase-4 (DPP-4) into inactive metabolites. DPP-4 inhibitors are therefore also in use for treatment of T2DM. It is possible that DPP-4 inhibition by enhancing the exposure of endogenous GLP-2 to the intestinal epithelia also might mediate growth and promote neoplasia. We investigated the intestinal growth effect of the GLP-1 receptor agonists (GLP-1 RAs) (liraglutide and exenatide) and DPP-4 inhibition (sitagliptin) in healthy mice. We also investigated the potential tumour promoting effect of liraglutide and sitaglitin in the colon of carcinogen treated mice. We used GLP-2 as a positive control.

Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice.

The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P < .001). Survival proportions were significantly increased in GLP-1R agonist-treated mice (P < .01). SFTPB and SFTPA were down-regulated and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but levels were largely unaffected by GLP-1R agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression. 

Hannelouise Kissow

University of Copenhagen

Important Endpoints and Proliferative Markers to Assess Small Intestinal Injury and Adaptation using a Mouse Model of Chemotherapy-Induced Mucositis