Alkaabi, Maryam (2025) Gastrointestinal Dysfunction Induced by Chemotherapy: The Role of Intestinal Barrier and Submucosal Neurons. PhD thesis, Victoria University,.

Abstract

Colorectal cancer (CRC) is a leading cause of morbidity and mortality globally, with irinotecan and oxaliplatin being key chemotherapeutic agents for this disease. While effective in improving survival rates, these treatments often cause severe gastrointestinal (GI) side effects, leading to dose reductions or treatment discontinuation. Approximately 80% of CRC patients experience chemotherapy-induced nausea, vomiting, constipation, or diarrhoea, with chronic post-treatment constipation (CIC) and diarrhoea (CID) persisting for up to 10 years. CIC and CID affect 40% of patients on standard doses and nearly all on high-dose chemotherapy, significantly impacting quality of life. While intestinal mucositis is recognized as a primary cause, the roles of tight junction proteins and the submucosal plexus in chemotherapy-induced GI toxicity remain underexplored. This thesis investigates the effects of irinotecan and oxaliplatin on intestinal barrier integrity and permeability, focusing on inflammatory responses, oxidative stress, DNA damage, and apoptosis. It also examines the impact of these treatments on submucosal neurons and enteric glial cells, complementing existing research on myenteric neurons. Male Balb/c mice received intraperitoneal irinotecan or oxaliplatin injections (three times weekly for 14 days) at doses equivalent to standard human treatments. In vivo experiments assessed functional and clinical parameters, while ex vivo analyses including physiological assessments, immunohistochemistry (IHC), western blotting, histology, and intestinal secretion experiments examined the mechanisms underlying chemotherapy-induced intestinal dysfunction. This study demonstrated that irinotecan and oxaliplatin administration causes mucosal damage, intestinal epithelial disruption, decreased tight junction protein expression and increased permeability. Irinotecan-induced changes were linked to extrinsic apoptotic activation, while oxaliplatin triggered intrinsic apoptotic pathways. Irinotecan-induced neuronal loss correlated with colonic mucosal inflammation, whereas oxaliplatin-induced loss was associated with oxidative stress in the submucosal plexus. Both treatments caused significant submucosal neuronal loss, altered neuronal subpopulations, and activated enteric glial cells in the ileum and colon, contributing to faecal water imbalance and symptoms of constipation and diarrhoea. These findings highlight potential therapeutic targets for CIC and CID, aiming to improve patient quality of life and chemotherapy outcomes.

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