Effects of malnutrition on epithelia-microbe interactions in the intestinal tract of Drosophila melanogaster

Malnutrition is defined by an imbalance between the supply of nutrients and energy and the body’s demand to ensure optimal growth, maintenance and specific bodily functions. The term malnutrition covers 2 broad groups of conditions. One is undernutrition, which includes wasting, stunting and insufficiencies in mineral or vitamins, whereas the other group comprises overweight and obesity. Today’s major health challenges in both developing and in more economically developed countries arise from excessive intake of high-energy dense food and/or the lack of dietary protein and calories, leading to overweight, obesity and protein-energy malnutrition (PEM), respectively. On the other hand, dietary restriction (DR), which is a reduction of particular nutrient intake without causing malnutrition, is believed to mediate positive effects of a plethora of health-associated parameters. The intestine is in close contact to dietary components and is a central mediator between the microbial community and the host. Maintaining the intestinal epithelial homeostasis requires an equilibrium between the microbial community and the intestinal epithelium and dietary interventions are believed to have an impact on this equilibrium. In my research, I focused on the effect of nutritional stressors, such as high-fat dieting (HFD), PEM and DR on epithelia-microbe interactions in the intestine of Drosophila melanogaster. I revealed that high fat dieting led to an increased hyperproliferation of intestinal stem cells and to an elevated number of enteroendocrine cells. The HFD-induced activation of stem cells depended on JNK pathway-mediated secretion of the cytokine Upd3 in enterocytes. Upd3 in turn activated JAK/Stat signaling in stem cells and enteroblasts. The increased stem cell activity upon high fat dieting critically depended on the presence of the indigenous microbiota as the observed hyperproliferation of stem cells was completely repressed in germ-free flies. I showed that a HFD led to a changed microbial composition and increased bacterial abundancy. Microbiota transplantation experiments failed to recapitulate the HFD-associated hyperproliferation phenotype suggesting that the increased abundance of bacteria is responsible for the activation of intestinal stem cells. For the purpose of standardization and reproducibility of PEM and DR experiments, I used a chemically welldefined holidic diet. However, existing holidic diet protocols were not able to support the development of conventional and germ-free flies. Therefore, I optimized holidic diet protocols that now allows development of conventional and germ-free flies comparable to standard complex Drosophila diets. I used this diet to investigate the effect of DR and PEM on the host-microbiota interaction in the intestinal ecosystem. PEM and DR led to changes of the intestinal structure, stem cell activity, enterocyte size and cellular composition, whereas some of these observations were depended on the indigenous microbiota. DR and PEM induced an increasedsusceptibility to pathogenic S. marcescens infection and genotoxic chemicals. To study how host genetics contributes to DR and PEM-mediated intestinal phenotypes, I focused on the Tor pathway, which is a central mediator of amino acid and energy sensing in the cell. The DR and PEM induced changes in the intestinal structure were absent in Tor deficient flies. Moreover, Tor deficient flies revealed a decreased infection susceptibility. I showed that DR and PEM induced substantial changes in the transcriptional profile of the intestine. The impact of the indigenous microbiota on the intestinal transcriptome increased with lower amino acid contents in the diet. Furthermore, I analyzed the intestinal transcriptional profile of flies that lived for 14 days on the control diet after a 7 days period of PEM. Thereby, I revealed that a short-term intervention of PEM led to long-lasting memory effects in the transcriptome.


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