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

Jakob Von Frieling,Stella Solveig Nolte,Philip Rosenstiel,Femke Sporn,Muhammed Naeem Faisal,Roxana Pfefferkorn,Thomas Roeder,Felix Sommer,Aurelio A Teleman

doi:10.1371/journal.pgen.1008789

Jakob Von Frieling, Stella Solveig Nolte + Show 7 more

Open Access

https://doi.org/10.1371/journal.pgen.1008789

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Journal: PLoS Genetics	Publication Date: May 26, 2020
Citations: 29	License type: CC BY 4.0

Affiliation: Kiel University, German Center for Lung Research

Abstract

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.

Highlights

High caloric intake and especially high-fat diets (HFDs) are major causes of the epidemic increases in obesity-associated diseases [1]
Using Drosophila as a model, we showed that a HFD and trigylcerides with saturated fatty
We found that HFD induces JNK signaling in enterocytes, which triggers production of the cytokine upd3

Summary

Introduction

High caloric intake and especially high-fat diets (HFDs) are major causes of the epidemic increases in obesity-associated diseases [1]. HFDs directly enhance the activity of ISCs, leading to increased villi lengths in the small intestines via a mechanism involving ß-catenin signaling [8] This HFD-induced activation of ISCs appears to be directly caused by the lipid content of food [3, 9]. A recent study showed that food with high lipid contents induces very robust PPAR-δ activation in ISCs and thereby increases the number of mitotically active cells in the intestines [9, 10] This response increases the tumorigenicity of intestinal progenitors [2, 9]. HFDs increase the prevalence of colon cancers [13, 14] In this context, deregulated stem cell activities appear to be directly associated with alterations in intestinal JAK/STAT signaling [15]

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