Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Hamid Akbarali
Second Advisor
David Gewirtz
Third Advisor
Katherine Nicholson
Fourth Advisor
Jennifer Myers
Fifth Advisor
John Grider
Abstract
Treatment of all cancer types with both targeted and non-targeted chemotherapy regimens often result in significant toxicities. The most common side effects associated with chemotherapy treatment are hematological and gastrointestinal in nature. Gastrointestinal toxicities are pervasive and may present as diarrhea, mucositis, constipation, vomiting, and nausea. The gastrointestinal tract is the site of a rapidly renewing epithelial layer thus non-targeted chemotherapeutics such as irinotecan indiscriminately inhibit efficient epithelial cell turnover resulting in both acute/chronic diarrhea and mucositis. These chemotherapy-induced gastrointestinal toxicities are pervasive, clinically significant, and may present with an enhanced rate of dose-limiting complications in combination treatment regimens. Central to maintaining homeostatic function in the gastrointestinal tract is a dynamic neuronal population, tightly regulated epithelial barrier, and resident microbiome. The extensive cell death produced by irinotecan results in a damaged and inflamed epithelial barrier that impairs interaction with microbiota, interaction with luminal contents, and altered enteric neuronal control. Thus, maintaining epithelial barrier integrity may be of therapeutic benefit in patients treated with irinotecan. Intestinal microbiota are pivotal in the transformation of complex carbohydrates and indigestible fibers into short-chain fatty acids used in cellular energy production, epigenetic modification, and maintenance of immune response. The four-carbon short chain fatty acid butyrate has been demonstrated to attenuate breakdown of epithelial barrier and aberrant immune response. In this dissertation, we explore the utility of oral butyrate supplementation as an adjunctive therapy for the remediation of irinotecan-induced gastrointestinal (GI) toxicity in mice. To this end we utilized a multifaceted approach to characterize the gastrointestinal toxicity produced by irinotecan. We demonstrated a dose dependent development of gastrointestinal toxicity consisting of increased fecal water content, presentation of diarrhea, and decreased intestinal transit times. Isolated intestinal tissues and cultured neurons in irinotecan treated mice were shown to have increased sensitivity to cholinergic stimulation in ex-vivo and in-vitro settings. While treatment with conventional anti-diarrheal therapy (loperamide) proved to be efficacious in acute settings, upon repeated administration of loperamide tolerance develops to its inhibitory effects. Histological assessment of small intestines and colons of irinotecan treated mice exhibited severe degradation of crypt/villi architecture that produced enhanced apical to basolateral transit of luminal contents within the epithelial barrier. Examination of resident microbiota in irinotecan treated animals revealed a significant alteration in beta-diversity when compared to all other treatment groups. Lastly, we demonstrated that supplementation of butyrate in irinotecan treated mice reduced the GI toxicity and markedly returned microbiota composition to a niche similar to that of control groups.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
3-6-2026