Experimental Disruption of Intestinal Mucosal Homeostasis : Exploring the Protective Potential of Melatonin and Misoprostol

Abstract: The intestinal mucosa serves as a protective layer that separates the intestinal contents from the underlying tissues. It restricts harmful substances, pathogens, and undigested particles from entering the bloodstream. This mucosa also facilitates selective absorption of nutrients, electrolytes, and fluids, allowing essential substances to pass while maintaining a defense against potential threats. The integrity of the mucosa can be disrupted, such as in diseases or by off-target toxicities of chemotherapeutic drugs. A dysfunctional intestinal mucosa can result in inflammation, altered epithelial secretory and absorptive functions, as well as an increased mucosal permeability that may enable bacterial translocation. Chemotherapy-induced intestinal side effects may lead to dose reduction or even discontinuation of the treatment, but also decreasing the patient’s quality of life. The aim of this thesis was to explore the protective potential of melatonin and misoprostol on experimental disruption of small intestinal mucosal permeability and chemotherapy-induced mucositis. In Papers I and II an increase in intestinal mucosal permeability was induced by perfusing the jejunal segment with the surfactant sodium dodecyl sulfate (SDS) in rats. Melatonin and misoprostol were found to mitigate the induced increase in permeability. In Paper II it was shown that the melatonin receptor antagonist luzindole completely abolished the protective effect of melatonin on SDS-induced increase in mucosal permeability, showing that the effect of melatonin is receptor-mediated. In Papers III and IV off-target intestinal toxicity of the chemotherapeutic agents doxorubicin (DOX) and 5-fluorouracil (5-FU) were evaluated. In Paper III the progression of intestinal mucositis during seven consecutive days after a single injection of DOX was monitored. It was found that villus atrophy was most distinct after three days. In addition, within the first 24 hours after administration of DOX the most pronounced effect on a decrease in cell proliferation and an increase in crypt cell apoptosis was observed. In Paper IV it was found that daily administration of melatonin fully prevented villus atrophy and reduced the number of apoptotic crypts cells induced by a single injection of 5-FU. Administration of misoprostol increased colonic water contents but had no effect on 5-FU-induced villus atrophy or apoptosis. Furthermore, melatonin reduced 5-FU-induced cytotoxicity in murine intestinal organoids.In conclusion, the results suggest that melatonin might be a potential candidate for supportive therapy in diseases affecting the small intestinal mucosal barrier and in chemotherapy-induced mucositis.