# Elucidating the role of fasting in intestinal stemness and tissue regeneration

> **NIH NIH K99** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $90,000

## Abstract

7. Project Summary/Abstract
 Fasting interventions improve health in mice and in humans. Given that adult stem cells coordinate
tissue adaptation, understanding the mechanism(s) that mediate the fasting response has important
implications for enhancing tissue repair after injury and in aging where stem cell function declines. In the
mammalian intestine, LGR5+ intestinal stem cells (ISCs) drive the rapid renewal of the intestinal lining. We
previously showed that fasting augments ISC function by inducing a peroxisome proliferator-activated receptor
delta (PPARδ) driven fatty acid oxidation (FAO) program. However, the in vivo role of PPARδ or downstream
effector(s) of FAO metabolism that mediate the ISC fasting response remains unknown. In this proposal, we
will test the hypotheses that 1) PPARδ signaling is necessary for the in vivo ISC fasting response, 2) PPARδ-
activated FAO stimulates intestinal stemness through the production of the ketone body β-hydroxybutyrate
(βOHB) in fasting, and 3) changes in the gut microbiome are necessary, sufficient or both in mediating the ISC
fasting response. In support of these notions, we find that PPARδ agonist treatment emulates the effects of
fasting on ISCs. Furthermore, we find that enzymes of the ketogenic pathway that produce the ketone
metabolite βOHB, including its rate-limiting step HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2),
highly enrich for LGR5+ ISCs. Also, elevation of HMGCS2 expression and βOHB levels upon fasting correlates
with enhanced ISC function while loss of HMGCS2 dampens ISC capacity to propagate organoids and biases
their differentiation towards the secretory lineage. Importantly, these deficits can be rectified by βOHB
treatment in cultures. Thus, these observations provide a possible pathway for fasting through the modulation
of HMGCS2-mediated ketogenesis to augment the regenerative function of ISCs. Lastly, fasting regimens are
known to alter the gut microbiome composition but the extent to which these changes underlie the ISC fasting
response requires elucidation. Remaining questions regarding the specific in vivo role of PPARδ as an
upstream regulator of HMGCS2 expression and ISC fasting response, the in vivo role of HMGCS2 and βOHB
as mediators of intestinal stemness and the contribution of the fasting gut microbiota in these processes.

## Key facts

- **NIH application ID:** 10007811
- **Project number:** 5K99DK123407-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Chia-Wei Cheng
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,000
- **Award type:** 5
- **Project period:** 2019-09-04 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007811

## Citation

> US National Institutes of Health, RePORTER application 10007811, Elucidating the role of fasting in intestinal stemness and tissue regeneration (5K99DK123407-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10007811. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*