Background
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 use a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (DSS colitis) to demonstrate the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells.
Results
We demonstrate that high sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, ATP levels and the accumulation of pyruvate. Treatment of colonoids with DCA, which forces pyruvate into the TCA cycle, restored their growth. In concert, DSS 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 revealed a reduction in the expression of ISC genes, impeded proliferative potential and increased glycolytic potential without a commensurate increase in aerobic respiration.
Conclusion
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
https://www.cmghjournal.org/article/S2352-345X(23)00063-2/fulltext
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