AbstractOver-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here, we show that a HFD triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and preceded by induction of JNK signaling in enterocytes. JNK (basket) within enterocytes was essential for activation of stem cells in response to a HFD. Moreover, this nutritional intervention leads to upregulation of the cytokine upd3 in enterocytes, a reaction that is known to trigger STAT signaling in intestinal stem cells followed by their activation. We also showed that the indigenous microbiota was essential for HFD-induced stem cell activation because this response was blunted in germ-free flies lacking a microbiota. Moreover, chronic HFD feeding of flies markedly altered both the microbiota composition and bacterial load. Although HFD-induced stem cell activity was transient, long-lasting changes to the cellular composition, including a substantial increase in the number of enteroendocrine cells, were observed. Taken together, a HFD enhances stem cell activity in the Drosophila gut and this effect is completely reliant on the indigenous microbiota and also dependent on JNK signaling within intestinal enterocytes.Author summaryHigh-fat diets have been associated with a plethora of morbidities. The major research focus has been on its effects on obesity related disorders, mostly omitting the intestine, although it is the organ that makes the first contact with all diet components. Here, we aimed to understand the direct effects of HFD on the intestine itself. Using Drosophila as a model, we showed that HFD induced a transient activation of intestinal stem cells. This response completely depended on JNK signaling in enterocytes. Mechanistically, we found that HFD induces JNK signaling in enterocytes, which triggers production of the cytokine upd3. This, in turn activates STAT signaling in intestinal stem cells, leading to their activation. Surprisingly, we found that a HFD triggered induced stem cell activation critically depends on the indigenous microbiota, as in germ free flies this reaction was completely abolished. Moreover, HFD changed both, composition and abundance of the microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we assume that the increased bacterial load is the major cause for the HFD triggered stem cell activation in the intestine.
FXR regulates intestinal stem cells response to bile acids in a high fat diet