A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

PLoS Genet. 2020 May 26;16(5):e1008789. doi: 10.1371/journal.pgen.1008789. eCollection 2020 May.


Over-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, composed of triglycerides with saturated fatty acids, triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and dependent on the presence of an intestinal microbiota, as it was completely absent in germ free animals. Moreover, major components of the signal transduction pathway have been elucidated. Here, JNK (basket) in enterocytes was necessary to trigger synthesis of the cytokine upd3 in these cells. This ligand in turn activated the JAK/STAT pathway in intestinal stem cells. Chronic subjection to a HFD markedly altered both the microbiota composition and the 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / classification*
  • Bacteria / drug effects
  • Cell Proliferation / drug effects
  • Diet, High-Fat / adverse effects*
  • Drosophila
  • Drosophila Proteins / metabolism
  • Gastrointestinal Microbiome / drug effects*
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / drug effects
  • MAP Kinase Kinase 4 / metabolism
  • Models, Animal
  • Signal Transduction / drug effects
  • Stem Cells / cytology
  • Stem Cells / drug effects


  • Drosophila Proteins
  • Upd3 protein, Drosophila
  • MAP Kinase Kinase 4

Grants and funding

TR and PR received funds from the German ScienceFoundation (DFG) as part of the CRC 1182 (Subproject C2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.