Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival

Kelsey L. Tinkum, Kristina M. Stemler, Lynn S. White, Andrew J. Loza, Sabrina Jeter-Jones, Basia M. Michalski, Catherine Kuzmicki, Robert Pless, Thaddeus S. Stappenbeck, David Piwnica-Worms, Helen Piwnica-Worms

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to highdose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.

Original languageEnglish
Pages (from-to)E7148-E7154
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number51
DOIs
StatePublished - Dec 22 2015

Keywords

  • Chemotherapy
  • DNA damage
  • Fasting
  • Stem cells

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