# Impact of fasting on intestinal stem cells and cancer

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $366,357

## Abstract

PROJECT SUMMARY
Fasting regimens can increase lifespan, improve health or both in diverse species including mammals. Fasting
also has an emerging role in inhibiting tumor growth, yet little is known about how it impacts tumor initiation or
how fasting-imposed metabolism can be therapeutically exploited to treat established tumors. Given that adult
stem cells coordinate tissue adaptation and drive tumorigenesis, understanding the mechanism(s) that mediate
their response to fasting has important implications for enhancing tissue repair after injury or aging where stem
cell function declines, and may provide new therapeutic inroads for cancer. In the mouse intestine, where
LGR5+ intestinal stem cells (ISCs) drive the rapid renewal of the intestinal lining, we showed that fasting
augments ISC function by inducing a peroxisome proliferator-activated receptor delta (PPARd) driven fatty acid
oxidation (FAO) program, which breaks down free fatty acids into acetyl-CoA units. This work raises the critical
question of how fasting functions through the FAO pathway to regulate intestinal stemness. We hypothesize
that beta-hydroxybutyrate (βOHB), a ketone body and biosynthetic product of FAO generated acetyl-
CoA, functions as a signaling metabolite and energetic substrate that mediates the ISC fasting
response. In support of this idea, we recently found that the LGR5+ ISCs strongly express enzymes of the
ketogenic pathway that produce βOHB, including its rate-limiting enzyme HMGCS2 (3-hydroxy-3-
methylglutaryl-CoA synthetase 2), compared to non-stem cell populations and that fasting strongly elevates
HMGCS2 and βOHB levels in ISCs. HMGCS2 loss in the small intestine reduces βOHB levels in LGR5+ ISCs
and skews their differentiation towards secretory cell fates, which we showed can be rescued by exogenous
βOHB and class I histone deacetylases (HDACs) inhibitor treatment. Mechanistically, βOHB acts as a
signaling metabolite to reinforce the NOTCH program in ISCs by inhibiting HDAC-mediated transcriptional
repression. Dynamic control of βOHB levels in ISCs, therefore, could enable the rapid adaptation of the
intestine to diverse physiological states like fasting. Many important questions that form the basis of our aims
remain regarding the role ketone bodies as effectors of the fasting response in ISCs such as understanding the
in vivo signaling (Aim 1) and energetic (Aim 2) roles of βOHB in this process. Another critical question is to
decipher how the fasting-induced FAO program in ISCs influences tumor initiation and progression (Aim 3).
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## Key facts

- **NIH application ID:** 10839872
- **Project number:** 5R01CA245314-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Omer Yilmaz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $366,357
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839872

## Citation

> US National Institutes of Health, RePORTER application 10839872, Impact of fasting on intestinal stem cells and cancer (5R01CA245314-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10839872. Licensed CC0.

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