Carnegie Science | Spring 2019 15 which cholesterol causes these changes in cell fates, and to show that it is closely related to the way human intestinal cells regulate cholesterol production. What does this mean? It shows that low nutrient availability, especially early in life, such as from the low-cholesterol diet for the fruit flies, triggers changes in intestinal structure and metabolism that have long-term effects. These changes persist for a while even if the diet changes, which can increase the risk of metabolic health problems down the road. “Children born to malnourished mothers often struggle with obesity later in life and our findings could explain the physiology of why that happens,” Obniski explained. She and her colleagues say that further understanding how nutrient availability affects intestinal function could help researchers find ways to use diet to mitigate aging and disease in adults. For example, the biochemical signaling pathways that were shown to underpin this developmental metabolic programming explain why a high-fat diet can promote the formation of certain types of intestinal cancer. “The intestines are the organs most directly responsible for balancing an organism’s long- and short-term needs with its nutritional environment,” Spradling said. “The power of the fruit fly as a model system allows one of the complex mechanisms that balance these needs with diet to be understood at a mechanistic Rebecca Obniski (front, sitting) was lead author on the study. She, with colleagues Matthew Sieber (left) and Allan Spradling (right), found that changes in dietary cholesterol particularly alter the cellular programming, driving the production of new, specialized cells from stem cells. Image courtesy Matt Sieber level, something that is very difficult to do directly in mammalian systems or in human patients.”  SUPPORT: The Jane Coffin Childs Memorial Fund and Howard Hughes Medical Institute funded this research. The cellular structure of the intestine responds to specific nutrients in the diet. Here, a fruit fly gut—each blue circle is the nucleus of an intestinal cell—has doubled its normal number of hormone-producing cells (pink dots) following a diet high in cholesterol. The paper by Obniski, Sieber, and Spradling reports such changes in several tissues, shows they have long-lasting effects on metabolism and cancer susceptibility, and documents the likely underlying mechanism. Image courtesy Rebecca Obniski, Matthew Sieber, and Allan Spradling