Regulation and functional relevance of GLP-2 in sepsis

• Applicant: Professor Dr. Michael Lehrke
• Subject Area: Gastroenterology ; Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468418471

Systemic infection and sepsis are frequent complications of critical ill patients. In many cases no infectious focus can be found, suggesting the physiological microflora to act as an infectious source in the stressed organism. Critical illness impairs intestinal barrier function and allows translocation of microorganisms to the organism. Improvement of gut barrier function might provide a valuable strategy to prevent bacterial translocation of critical ill patients and to reduce infectious burden by sealing bacterial entry sites. In this study we are aiming to evaluate the regulation and mechanistic relevance of GLP-2 as a preproglucagon cleavage product released from the gut and the pancreas to improve gut barrier function under inflammatory conditions. In preliminary results we demonstrate marked elevation of GLP-2 levels in critical ill patients, while GLP-2 was increased in response to inflammatory stimuli in an IL6 dependent manner in mice. Using tissue specific preproglucagon expressing mice we found inflammatory GLP-2 secretion to originate from the pancreas but not from the gut. Functionally, GLP-2 application strongly modified the inflammatory response of mice challenged by colon ligation puncture (CLP) or endotoxin induced sepsis, while absence of GLP-2 in preproglucagon knockout mice caused the opposite. It is the aim of this proposal to characterise the relevance of endogenous GLP-2 secretion for inflammatory response and outcome in sepsis. In the first step we will characterize the inflammatory cascade leading to endotoxin dependent GLP-2 secretion in mice by employing preproglucagon reporter mice (Aim 1). We will then study the anti-inflammatory capacities of GLP-2 in murine sepsis by use of gain and loss of function models (Aim 2), investigate the relevance of pancreatic vs. intestinal GLP-2 production (Aim 3) and study the functional relevance of IL6 as a GLP-2 inducing stimulus in murine sepsis (Aim 4).

• DFG Programme: Research Grants