Fasting Protects Mice from Lethal DNA Damage by Promoting Small Intestinal Epithelial Stem Cell Survival

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Dec 9

PMID 26644583

Citations 51

Authors

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

Affiliations

Soon will be listed here.

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 high-dose 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.

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