# Understanding the Role and Regulation of Epithelial Ketogenesis in the Colon

> **NIH DK F31** · HARVARD MEDICAL SCHOOL · 2026 · $37,704

## Abstract

Abstract
Intestinal stem cells (ISCs) play pivotal roles in intestinal epithelium renewal during homeostasis and after injury.
The metabolic demands faced by ISCs require high mitochondrial oxidative phosphorylation (OXPHOS) activity
compared to other differentiated cells. ISCs’ mitochondrial dysfunction has been implicated in the
etiopathogenesis of intestinal bowel diseases (IBD), which afflicts over 2 million people in the US. The carbon
sources that fuel ISC OXPHOS have been broadly described in the small intestine (SI) but not in the colon.
I seek to understand how ISC metabolic demands are met in the colon.
The colonic epithelium is organized into the colonic crypt. ISCs localize to the base of the crypt (base-crypt), and
this protects them from microbial metabolites and microbe-associated molecular patterns (MAMPs). Top-crypt
differentiated colonic epithelial cells (CECs) oxidize microbial-derived short-chain fatty acid (SCFA) butyrate
making it inaccessible to base-crypt cells. This shields ISCs, as butyrate suppresses ISC proliferation. This
metabolic interaction between CECs and ISCs has focused my interest in CEC-ISC metabolic cross-talk.
Ketones (acetoacetate, β-hydroxybutyric acid (βHB), and acetone) are important metabolic substrates. I
hypothesize that CECs generate ketones that are used by ISCs as their principal energy source. This hypothesis
is supported by the localization of rate-limiting enzymes (RLE) for the generation of ketones to the CECs and my
preliminary data demonstrating that loss of these enzymes in CECs compromises ISC self-renewal and
differentiation. My proposal focuses on this metabolic cooperation between epithelial cells within the crypt where
top-crypt CECs shuttle ketones to base-crypt ISCs thus maintaining their turnover capacity. Understanding
colonic ketone biosynthesis and function could lead to new treatments and therapeutic targets for IBD.
Beyond defining this proposed metabolic crosstalk between CEC and ISC, I am intere

## Key facts

- **NIH application ID:** 11310967
- **Project number:** 1F31DK143670-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Natalia  Andreeva
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** DK
- **Fiscal year:** 2026
- **Award amount:** $37,704
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11310967

## Citation

> US National Institutes of Health, RePORTER application 11310967, Understanding the Role and Regulation of Epithelial Ketogenesis in the Colon (1F31DK143670-01A1). Retrieved via AI Analytics 2026-06-27 from https://api.ai-analytics.org/grant/nih/11310967. Licensed CC0.

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