Understanding the role and regulation of epithelial ketogenesis in the colon

The National Institute of Diabetes and Digestive and Kidney Diseases awarded $113,688 to President and Fellows of Harvard College on September 13, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct research investigating epithelial ketogenesis in the colon and its role in intestinal stem cell metabolism.

The research examines how colonic epithelial cells generate ketones that serve as energy substrates for intestinal stem cells, with implications for understanding inflammatory bowel disease pathogenesis. The work focuses on metabolic cross-talk between differentiated epithelial cells and stem cells within colonic crypts, hypothesizing that ketone biosynthesis and shuttling maintain stem cell renewal capacity. Understanding these mechanisms could identify new therapeutic targets for inflammatory bowel disease, which affects over 2 million people in the United States.

The recipient, operating through Harvard Medical School's Office of Research Administration, is located in Boston, Massachusetts. The period of performance extends through April 30, 2028. This is a Project Grant assistance type.

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 interested in factors regulating CEC metabolic enzymes. I have identified microbial features that regulate the expression of the CEC RLE for ketone generation. I will determine the receptor and pathways downstream of this receptor by which they regulate the expression of this RLE. This research will help to decipher how microbial signals and metabolites contribute to epithelial repair and regeneration.