# Ketone body metabolites in intestinal stem cell homeostasis and disease.

> **NIH NIH F32** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $86,488

## Abstract

Project Summary/Abstract
 Diet has a profound impact on organismal health. Fasting improves human health in part by reducing
inflammation, decreasing oxidative damage and extending longevity, however, the mechanisms by which fasting
improves intestinal regeneration remains poorly understood. The intestinal epithelium renews fastidiously every
5-7 days via Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5+) expressing intestinal stem
cells (ISCs) found at the base of the intestinal crypt. LGR5+ ISCs balance differentiation and epithelial cell
divisions to influence tissue regeneration by integrating metabolic and signaling cues from their environment like
diet. Fasting has a profound effect on ISC function in young and aged mice and can improve the age-associated
decline in tissue regeneration through the induction of fatty acid oxidation (FAO), a process that oxidizes fatty
acids into acetyl-CoA units. In addition, LGR5+ ISCs strongly express 3-hydroxy-3-methylglutaryl-CoA
synthetase 2 (HMGCS2), the rate-limiting enzyme in the ketogenic pathway whereby acetyl-CoA units are
converted to ketone bodies such as beta-hydroxybutyrate (bOHB) and acetoacetate (AcAc). Mechanistically,
bOHB reinforces the NOTCH signaling pathway by inhibiting class I histone-deacetylases (HDACs) to instruct
ISC cell fate decisions. These findings further support a nuanced relationship between host nutritional state and
stem cell function whereby dynamic control of ISC bOHB levels enable their rapid adaptation to diverse
physiological states such as fasting. Other roles for ISC-derived ketone body metabolites have yet to be
elucidated and, as such, we propose that bOHB and AcAc function as distinct signaling metabolites regulating
ISC fasting responses (Aim 1) and have unique roles as energetic substrates (Aim 2). To test this hypothesis,
we will use key genetic mouse models to understand how perturbed bOHB/AcAc ratios alter intestinal stem cell
function in vivo and in vitro (Aim 1), as well as labelled substrate administration and novel techniques for rapid
mitochondrial isolation to determine key ISC metabolic adaptations to fasting (Aim 2). Taken together, the
experiments proposed will mechanistically delineate the signaling and energetic roles of ketone body metabolites
on intestinal stemness and improve our understanding of how the fasting response via ketone bodies influences
intestinal regeneration. We expect this approach will identify therapeutic options exploiting ketone bodies and
the signaling and energetic pathways engaged by them to enhance intestinal regeneration in cases of injury and
age-related decline of stem cell function.

## Key facts

- **NIH application ID:** 10745679
- **Project number:** 5F32DK128872-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jessica Elizabeth Stewart Shay
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $86,488
- **Award type:** 5
- **Project period:** 2022-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745679

## Citation

> US National Institutes of Health, RePORTER application 10745679, Ketone body metabolites in intestinal stem cell homeostasis and disease. (5F32DK128872-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10745679. Licensed CC0.

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