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 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.stem cells | DNA damage | chemotherapy | fasting C ancer patients undergoing chemotherapy experience high rates of morbidity, despite regimens that attempt to balance timing and dose intensity to mitigate off-target effects and doselimiting toxicities (1-3). Interestingly, fasting has been shown to provide host-protective effects against high-dose chemotherapyinduced toxicity in preclinical and clinical studies. For example, etoposide, which forms a ternary complex with DNA and topoisomerase II causing DNA double-strand breaks (DSBs), is far less toxic if mice are fasted before treatment (4). Fasting has also been shown to protect normal, but not cancer cells, from the toxicity of chemotherapy, thereby extending the lifespan of tumorbearing mice (4-8).Because of the rapid rate of epithelial cell proliferation in the small intestine (SI), gastrointestinal (GI) toxicity is one of the most common complications for a variety of chemotherapeutic treatments (9). Therefore, we investigated if fasting was capable of mitigating the GI toxicity normally associated with high-dose chemotherapy. Herein, we demonstrate that mice allowed to feed ad libitum before receiving high-dose chemotherapy showed marked histological changes to SI epithelium before death. These histological changes reflected loss of regenerative capacity as a result of stem cell depletion as well as structural damage from inflammatory cell infiltrates, similar to the SI response to high-dose ionizing radiation (10). In contrast, SI homeostasis was preserved in fasted mice by protection of stem cell viability and prevention of proinflammatory cell infiltrates. These results indicate that fasting mitigates GI side effects associated with chemotherapy by activating pathways that preserve SI stem cell integrity and by maintaining barrier function.

Protective effects of short-term dietary restriction in surgical stress and chemotherapy

“…For example, PF prior to lethal oxidative stress induced by etopo-side protects from chemotoxicty and causes a significant increase in survival in five different mouse strains (Raffaghello et al, 2008; Tinkum et al, 2015). Similarly, 72 h of a water-only fast before treatment with doxorubicin protects CD-1 mice against oxidative stress-related cardiotoxicity (Lee et al, 2010).…”

“…DSR therefore presents a dietary intervention that increases the cellular resistance against cytotoxic chemotherapy or other drugs through detoxification systems in normal cells without affecting the efficacy of these agents against malignant cells (Raffaghello et al, 2008). The fasting-induced protection against otherwise lethal doses of the chemotherapeutic drugs has been demonstrated in vivo : fasting protects various mouse strains from high-dose etoposide toxicity (Raffaghello et al, 2008; Tinkum et al, 2015), protects CD-1 mice from high-dose doxorubicin (Lee et al, 2010), and protects FabplCre;Apc 15lox/+ mice against irinotecan induced weight loss, reduced activity, ruffled coat, hunched-back posture, diarrhea, and leukopenia (Huisman et al, 2015). Fasting reduces the delayed-type chemotherapy-induced nausea and vomiting in cancer-bearing dogs receiving doxorubicin (Withers et al, 2014).…”

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

“…ability of Bmi-1 to promote survival 14 and inhibit apoptosis in a variety of cell types, including T cells. 15 The enrichment of Mel-18 targets was also important, given that Mel-18 has been observed to be a key component in Th17 cell programming.…”

Effects of Dietary Restriction on Cancer Development and Progression

“…CR protects mice from high dose etopoxide toxicity 4, nausea and vomiting induced by doxorubicin, and irinotecan-induced weight loss (Raffaghello et al 2008;Tinkum et al 2015). It has also been found that IGF-1 gene deletion protects against chemotherapeutic toxicity of doxorubicin and cyclophosphamide (Brandhorst et al 2017).…”

“…Probably, the protective effect induced by DR and starvation is due to a change in microenvironment of the intestinal cryptic stem cells. Indeed, fasting before chemotherapy preserves the correct architecture and functioning of intestinal cells by maintaining the expression of genes such as Lgr5, Bm1, and HopX (Tinkum et al 2015).…”