Project Details
Projekt
Restoring intestinal barrier function in obesity and diabetes.
Applicant
Professor Dr. Kai Markus Schneider
Subject Area
Gastroenterology
Term
from 2020 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 443107077
The obesity and diabetes pandemic has reached alarming magnitudes, affecting more than 2 billion people worldwide and accounting for more than 3 million deaths per year. A very common but poorly understood complication of obesity and associated diseases is the dysfunction of the intestinal barrier, leading to enhanced permeability and translocation of microbial molecules from the gut into the portal vein and systemic circulation. It is well described that this influx of immune-stimulatory microbial ligands perpetuates the chronic multi-organ inflammatory processes of metabolic diseases including Type 2 diabetes, Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. However, molecular mechanisms that induce barrier dysfunction during obesity are incompletely understood. Preliminary work from the applicant and the host institution demonstrate that gut microbiota, intestinal immune cells and glucose metabolism act in concert in regulating barrier function during health and disease. Recently, the lab of the host institution has discovered that hyperglycemia leads to alterations in tight and adherence junction integrity in intestinal epithelial cells (IECs), which is associated with loss of intestinal barrier function, influx of microbial molecules, and systemic dissemination of enteric infection. This effect of hyperglycemia requires GLUT2-mediated entry of glucose into IECs, glucose metabolism, and changes in the transcriptional profile of the cell. Based on this work, the aim of the proposed research fellowship is to elucidate the molecular mechanism by which hyperglycemia metabolically and transcriptionally reprograms IECs and affects barrier function. We will experimentally address the mechanisms by which hyperglycemia results in intestinal barrier dysfunction in a stepwise approach that will take advantage of recently developed in vivo and in vitro systems. Technologically, the proposed study combines approaches from the fields of epigenetics and gene regulation, cellular metabolism, and epithelial cell biology. The combination of these techniques is suitable to enable valuable new insights into this biologically intriguing and medically highly relevant question. The proposed research project builds up on the applicant’s previous work on the role of gut barrier function for the progression of chronic liver diseases. The premise of this proposal is that understanding the pathway by which IEC-intrinsic glucose metabolism drives the loss of barrier integrity will provide the ground for future efforts to identify targets for therapeutic intervention with the goal of restoring intestinal impermeability in diabetic individuals.
DFG Programme
Research Fellowships
International Connection
USA
