Stumps and Lipin in the Drosophila midgut enteroendocrine cells independently regulate intestinal regeneration and permeability

Abstract

Leaky Gut Syndrome is a condition characterised by increased intestinal permeability that may lead to increased flow of lumen contents, such as nutrients, biomolecules, toxins, microbes, and chemicals, into the bloodstream. Intestinal permeability may increase as a result of infection and concomitant induction of intestinal regeneration. Here, we assessed the role of gut leakiness of genes 6 7

expressed in the Drosophila midgut enteroendocrine cells (EEs) upon infection with Pseudomonas aeruginosa. We found that downregulating Stumps/Dof or Lipin in the Drosophila midgut EEs leads to a leaky gut. Stumps/Dof is an adaptor binding to the Fibroblast Growth Factor Receptor (FGFR). Accordingly, the expression of a dominant-negative mutation of the FGFR in the midgut EEs leads to a leaky gut. Interestingly, higher activity of the Drosophila FGFR in the EEs also leads to leaky gut. This indicates that either overstimulation or suppression of FGFR signalling increases gut leakiness. Lipin is a phosphatide phosphatase involved in lipid metabolism. Lipin inactivation via phosphorylation is controlled by the insulin receptor (InR) in mammals. We found that InR downregulation in EEs does not increase gut leakiness, but InR overexpression does, mimicking Lipin downregulation. Increased leakiness upon Stumps/Dof and Lipin downregulation in EEs coincides with increased intestinal stem cell (ISC) activity and improved survival upon infection, without any apparent effect on Armadillo expression at the cell junctions. Moreover, Lipin downregulation changes EE density in the midgut, while downregulation of Stumps/Dof does not. Thus, Lipin and Stumps/Dof act via different pathways that converge in their ability to restrain midgut regeneration potential upon intestinal infection and suppress midgut leakiness as a consequence