Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage

Burr, Ansen HP, Ji, Junyi, Ozler, Kadir, Mentrup, Heather L, Eskiocak, Onur, Yueh, Brian, Cumberland, Rachel, Menk, Ashley V, Rittenhouse, Natalie, Marshall, Chris W, Chiaranunt, Pailin, Zhang, Xiaoyi, Mullinax, Lauren, Overacre-Delgoffe, Abigail, Cooper, Vaughn S, Poholek, Amanda C, Delgoffe, Greg M, Mollen, Kevin P, Beyaz, Semir, Hand, Timothy W (2023) Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage. Cellular and Molecular Gastroenterology and Hepatology, 16 (2). pp. 287-316. ISSN 2352-345X (Public Dataset)

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Abstract

BACKGROUND & AIMS: The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown. METHODS: Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. RESULTS: We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose-fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration. CONCLUSIONS: Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.

Item Type:	Paper
Subjects:	organism description > animal organism description > animal > mammal organs, tissues, organelles, cell types and functions > organs types and functions > metabolism organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent
CSHL Authors:	Ozler, Kadir Eskiocak, Onur Yueh, Brian Beyaz, Semir
Communities:	CSHL labs > Beyaz lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	2023
Date Deposited:	22 Sep 2023 14:57
Last Modified:	20 Jun 2024 19:38
PMCID:	PMC10394273
Related URLs:	Publisher
Dataset ID:	PRJNA972287 PRJNA690134 PRJNA971990 PRJNA972422
URI:	https://repository.cshl.edu/id/eprint/40973

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