Abstract
ObjectiveMucositis is a side effect of chemotherapy seen in the digestive tract, with symptoms including pain, diarrhoea, inflammation and ulcerations. Our aim was to investigate whether endogenous glucagon-like peptide -1 and -2 (GLP-1 and GLP-2) are implicated in intestinal healing after chemotherapy-induced mucositis.DesignWe used a transgenic mouse model Tg(GCG.DTR)(Tg) expressing the human diphtheria toxin receptor in the proglucagon-producing cells. Injections with diphtheria toxin ablated the GLP-1 and GLP-2 producing L-cells in Tg mice with no effect in wild-type (WT) mice. Mice were injected with 5-fluorouracil or saline and received vehicle, exendin-4, teduglutide (gly2-GLP-2), or exendin-4/teduglutide in combination. The endpoints were body weight change, small intestinal weight, morphology, histological scoring of mucositis and myeloperoxidase levels.ResultsAblation of L-cells led to impaired GLP-2 secretion; increased loss of body weight; lower small intestinal weight; lower crypt depth, villus height and mucosal area; and increased the mucositis severity score in mice given 5-fluorouracil. WT mice showed compensatory hyperproliferation as a sign of regeneration in the recovery phase. Co-treatment with exendin-4 and teduglutide rescued the body weight of the Tg mice and led to a hyperproliferation in the small intestine, whereas single treatment was less effective.ConclusionThe ablation of L-cells leads to severe mucositis and insufficient intestinal healing, shown by severe body weight loss and lack of compensatory hyperproliferation in the recovery phase. Co-treatment with exendin-4 and teduglutide could prevent this. Because both peptides were needed, we can conclude that both GLP-1 and GLP-2 are essential for intestinal healing in mice.
Highlights
Mucositis in the oral cavity and the gastrointestinal (GI) tract is a common side effect in patients receiving chemotherapy
Ablation of L-cells led to impaired glucagon-like peptide-2 (GLP-2) secretion; increased loss of body weight; lower small intestinal weight; lower crypt depth, villus height and mucosal area; and increased the mucositis severity score in mice given 5-fluorouracil
The ablation of L-cells leads to severe mucositis and insufficient intestinal healing, shown by severe body weight loss and lack of compensatory hyperproliferation in the recovery phase
Summary
Mucositis in the oral cavity and the gastrointestinal (GI) tract is a common side effect in patients receiving chemotherapy. Elting et al 2003 [1] reported that in approximately 50% of cancer patients oral and/or GI mucositis developed during a chemotherapy treatment period, and 11% of patients needed total parenteral nutrition (TPN) [1]. Severe GI mucositis can have clinical and economical implications, including need for TPN, hospitalisation, opioid usage and reduction in chemotherapy drug dose [1,2,3]. There is currently no method to prevent severe GI mucositis and the current treatment consists of symptom relief, antibiotics and rehydration. The underlying mechanism for the development of mucositis is not fully understood, but Sonis et al 2004 suggested a model with five phases, ending with healing of the GI tract as a consequence of continued proliferation and regeneration of the intestinal epithelium [3;4]
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