Tritrichomonas muris sensitizes the intestinal epithelium to doxorubicin-induced apoptosis

• Type of Material: Article
• Authors: Nicolas V. Janto, Emory University; Antoine R. Gleizes, Emory University; Siyang Sun, Emory University; Gurel Ari, Emory University; Adam D. Gracz, Emory University
• Language: English
• Date: 2024-08-09
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101/2024.08.08.607206
• Title of Journal or Parent Work: bioRxiv
• Start Page: 607206
• Grant/Funding Agency: Emory University; NIH/NCI; NIH/NIGMS; NIH/NIDDK
• Grant/Funding Information: This work was funded by the NIH/NIGMS under award number R35GM142503 (Gracz) and by the NIH/NIDDK under award number F31DK136254 (Janto). Research reported in this publication was supported in part by the Cancer Tissue and Pathology Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292, and by the Emory University Integrated Cellular Imaging Core Facility (RRID:SCR_023534).
• Keywords: Tritrichomonas muris; doxorubicin; microbiome; intestinal epithelium; apoptosis
• Subject - Topics: Microbiology

Abstract

Doxorubicin (DXR) is a widely used chemotherapy drug that can induce severe intestinal mucositis. While the influence of gut bacteria on DXR-induced damage has been documented, the role of eukaryotic commensals remains unexplored. We discovered Tritrichomonas muris (Tmu) in one of our mouse colonies exhibiting abnormal tuft cell hyperplasia, prompting an investigation into its impact on DXR-induced intestinal injury. Mice from Tmu-colonized and Tmu-excluded facilities were injected with DXR, and tissue morphology and gene expression were evaluated at acute injury (6 h) and peak regeneration (120 h) phases. Contrary to previous reports, DXR did not significantly alter villus height, crypt depth, or crypt density in any mice. However, we did observe apoptosis, measured by cleaved caspase 3 (CC3) staining, in intestinal crypts at 6 h post-DXR that was significantly higher in mice colonized by Tmu. Interestingly, while DXR did not alter the expression of active and facultative intestinal stem cell (ISC) marker genes in control mice, it significantly reduced their expression in Tmu+ mice. Tmu, but not DXR, is also associated with increased inflammation and expression of the type 2 cytokines IL-5 and IL-13. However, pre-treatment of intestinal organoids with these cytokines is not sufficient to drive elevated DXR-induced apoptosis. These findings highlight the significant influence of commensal microbiota, particularly eukaryotic organisms like Tmu, on intestinal biology and response to chemotherapy, underscoring the complexity of gut microbiota interactions in drug-induced mucositis.