Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicininduced small intestinal damage in mice

Jacquelyn S. Carr, Stephanie King, Christopher M. Dekaney

Research output: Contribution to journalArticle

Abstract

Background & aims While enteric bacteria have been shown to play a critical role in other forms of intestinal damage, their role in mediating the response to the chemotherapeutic drug Doxorubicin (Doxo) is unclear. In this study, we used a mouse model of intestinal bacterial depletion to evaluate the role enteric bacteria play in mediating Doxo-induced small intestinal damage and, more specifically, in mediating chemokine expression and leukocyte infiltration following Doxo treatment. An understanding of this pathway may allow for development of intervention strategies to reduce chemotherapy-induced small intestinal damage. Methods Mice were treated with (Abx) or without (NoAbx) oral antibiotics in drinking water for four weeks and then with Doxo. Jejunal tissues were collected at various time points following Doxo treatment and stained and analyzed for apoptosis, crypt damage and restitution, and macrophage and neutrophil number. In addition, RNA expression of inflammatory markers (TNFα, IL1-β, IL-10) and cytokines (CCL2, CC7, KC) was assessed by qRT-PCR. Results In NoAbx mice Doxo-induced damage was associated with rapid induction of apoptosis in jejunal crypt epithelium and an increase weight loss and crypt loss. In addition, we observed an increase in immune-modulating chemokines CCL2, CCL7 and KC and infiltration of macrophages and neutrophils. In contrast, while still positive for induction of apoptosis following Doxo treatment, Abx mice showed neither the overall weight loss nor crypt loss seen in NoAbx mice nor the increased chemokine expression and leukocyte infiltration. Conclusion Enteric bacteria play a critical role in Doxo-induced small intestinal damage and are associated with an increase in immune-modulating chemokines and cells. Manipulation of enteric bacteria or the damage pathway may allow for prevention or treatment of chemotherapyinduced small intestinal damage.

LanguageEnglish (US)
Article numbere0173429
JournalPloS one
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2017

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doxorubicin
Enterobacteriaceae
intestinal microorganisms
Infiltration
Doxorubicin
infiltration (hydrology)
leukocytes
Bacteria
Leukocytes
mice
chemokines
Chemokines
apoptosis
Macrophages
Apoptosis
neutrophils
Weight Loss
Chemokine CCL7
macrophages
weight loss

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicininduced small intestinal damage in mice. / Carr, Jacquelyn S.; King, Stephanie; Dekaney, Christopher M.

In: PloS one, Vol. 12, No. 3, e0173429, 01.03.2017.

Research output: Contribution to journalArticle

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