The role of FoxO factors in maintaining intestinal homeostasis in Drosophila melanogaster

FoxO transcription factors are evolutionary conserved and involved in numerous molecular processes, such as DNA repair, apoptosis and cell death, life span, immune functions, cell cycle arrest, regulation of growth, metabolism and energy homeostasis. Therefore, FoxO presumably plays an important role in the maintenance of the intestinal tissue homeostasis and microbiota. Intestinal epithelial integrity and an intact intestinal microbiota are important for maintaining a healthy organism. Thus, a dysbiosis and a deregulation of epithelial regeneration and proliferation may result in loss of intestinal integrity and chronic inflammatory diseases such as inflammatory bowel diseases (IBD). Both, a dysbiosis and a dysfunctional gut epithelium are also associated with aging. Moreover, the digestive tract with its microbiome has a significant influence on immunity, maintaining energy homeostasis, physiology and even the behavior. The fruit fly Drosophila melanogaster was used as a model organism to investigate how FoxO activity affects the regulation of tissue homeostasis, the overall physiology and the intestinal microbial composition. Flies with an overall deficiency of dFoxO as well as flies with an overexpression of dFoxO in different cell types of the Drosophila intestine (ECs or ISCs and EBs) were used. Surprisingly, the deficiency of dFoxO and the overexpression of dFoxO in ECs had the same negative effect on physiological features such as the survival, the gut functionality, locomotor activity, metabolic functions, starvation resistance and gut integrity. The overexpression in ISCs and EBs seems to have a rather positive effect on these physiological functions. Moreover, the fecal microbiota in young dFoxO-deficient flies and those overexpressing dFoxO in ECs was not significant different compared to their controls. With aging, the microbial profiles of flies with a modified dFoxO expression showed increasing differences to their controls, which lead to a dysbiosis in older flies. The treatment with DSS, a substance known to induce colitis in mammals, results in a reduced life span, an increased stem cell proliferation and a disorganized basement membrane structure in Drosophila. The deficiency of dFoxO as well as the overexpression in ISCs and EBs had a beneficial impact on the survival, possibly due to inhibition of overproliferation and consequential dysplasia. In contrast, the overexpression of dFoxO in ECs appears not to influence the response to DSS.


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