title: Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival.
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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Tinkum
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Stemler
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Lynn S
authors.initials: LS
authors.lastname: White
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Loza
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jeter-Jones
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Basia M
authors.initials: BM
authors.lastname: Michalski
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Catherine
authors.initials: C
authors.lastname: Kuzmicki
authors.affiliation: Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130;
authors.forename: Robert
authors.initials: R
authors.lastname: Pless
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 dpiwnica-worms@mdanderson.org hpiwnica-worms@mdanderson.org.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110; dpiwnica-worms@mdanderson.org hpiwnica-worms@mdanderson.org.
authors.forename: Helen
authors.initials: H
authors.lastname: Piwnica-Worms
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005215:Fasting / Q000378:metabolism*; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D005047:Etoposide
keywords: DNA damage; chemotherapy; fasting; stem cells