Nutritional status dictates the rate and mode of intestinal epithelial stem cell proliferation
Authors: McGeever Katherine Anne , Dailey Megan 
Published: November 2023

The intestinal epithelium plays an integral role in digestion and immune function. Maintenance of the epithelium is driven by continuous proliferation of stem cells localized near the base of the crypts, differentiation of the newly produced cells and replacement of cells normally lost by apoptosis at the villus tip. The amount and type of diet is known to influence these processes and changes the size and cellular make‐up of the tissue. More specifically, an increase in food results in a greater number of epithelial cells, villi height and crypt depth. In Drosophila, this nutrient‐driven expansion of the tissue is the result of an increase in the rate and change in the mode of division of the intestinal epithelial stem cells. Specifically, high nutrient availability induces greater symmetric division, which results in two stem cells. Low nutrient availability results in greater asymmetric division, where a stem cell divides to produce one new stem cell and one daughter cell. We hypothesized that this same nutrient‐driven change in stem cell proliferation also occurs in mammals and that there is a difference in stem cell proliferation along the proximal to distal axis of the intestinal epithelium. To test this hypothesis we utilized 3‐D intestinal epithelial organoids to study the effect of glucose on the mode of stem cell division. Epithelial organoids were treated with differing amounts of glucose and were immunohistochemically processed to visualize tubulin. Mitotic spindle orientation was determined by measuring the angle between the apical border and the spindle poles of dividing cells. We also studied nutrient driven expansion in vivo using 24 male C57/B6 mice. Mice were fed varying amounts of chow diet and were separated into 4 groups; 1) ab libitum fed 2) fifty‐percent of their average consumption 3) fasted or 4) fasted‐refed. Four hours prior to sacrifice BRDU injections were given to track stem cell proliferation. Mice were sacrificed immediately following the dark cycle and duodenal, ileal and juejunal sections were excised and immunohistochemically processed. Spindle orientation was measured as described above. In vitro, high glucose conditions greatly increased the number of symmetrically dividing cells when compared to low glucose conditions. Our in vitro results showed similar trends when the intestine was analyzed as a whole organ. Adlib fed animals showed higher amounts of symmetrically dividing cells when compared to the 50% fed animals. However, fasted animals showed equal symmetric and asymmetric division but had very little cell division in the duodenum and jejunum, but hyper proliferation in the ileum. Duodenal sections showed high symmetric division regardless of diet but jejunal segments showed similar trends to that of our whole organ analysis. These data suggest that high nutrient availability increases symmetric division of intestinal epithelial stem cells with differential changes across the distal to proximal axis. These differences may reflect environmental conditions or independent cell proliferation mechanisms influencing stem cell proliferation at each axis.

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Department of Animal Sciences, University of Illinois at Urbana‐Champaign