Intestinal permeability is a key measure of gastrointestinal function and studies have associated increased intestinal permeability with several different pathologies. Clinically, increased intestinal permeability could contribute to disease pathophysiology by allowing unwanted substances to enter circulation and stimulate inflammatory processes. Thus, a better understanding of the factors and mechanisms that affect intestinal permeability could offer new insights on how to manage these diseases and disorders. The aim of this thesis was to investigate intestinal permeability changes under three separate settings. Chemotherapy-induced gastrointestinal toxicity is a major complication of cancer treatment and we examined if measuring intestinal permeability to iohexol could be used to assess the severity of this complication. We also hypothesized that chemotherapeutics affect the composition of intestinal microbiota and the global metabolome and studied how these alterations relate to increased intestinal permeability. In another study setting, we investigated whether intestinal permeability changes explain individual’s susceptibility to gastrointestinal symptoms during exercise. Finally, we treated intestinal tissue segments with a deoxycholic acid (DCA) concentration associated with high-fat feeding and examined the mechanisms by which it affects macromolecular permeability. Our results show that commonly used chemotherapeutics, running at a challenging pace for 90 min, and DCA concentration associated with high-fat feeding increase intestinal permeability. The observed increase in intestinal permeability after chemotherapy also correlated with the severity of gastrointestinal toxicity. Chemotherapy-induced gastrointestinal toxicity was also associated with unfavorable changes in the composition of intestinal microbiota which may play a role in the pathophysiology of intestinal complications during chemotherapy. Running-induced increase in intestinal permeability seems to result from intestinal ischemia but it did not explain the occurrence of gastrointestinal symptoms during the running test. The DCA-induced increase in macromolecular permeability appears to stem from direct interaction with the mucosa. However, we also observed evidence that DCA affects the intestine via a neural mechanism. Overall, these results demonstrate how different stressors can impair intestinal barrier function and possibly lead to various symptoms and complications.
|Status||Publicerad - 2018|
|MoE-publikationstyp||G5 Doktorsavhandling (artikel)|
Bibliografisk informationM1 - 112 s. + liitteet
- 3111 Biomedicinska vetenskaper