Mouse Genetics and Inflammation

Libert Claude

Libert Claude

Group Leader VIB
Supervisor

Sepsis, Nuclear Receptors and Metabolism


The research group has only one mission, namely to understand the mechanism(s) leading to death in sepsis, i.e. after acute polymicrobial infection. Sepsis hits 49 million people, worldwide yearly, killing 11 million of them (4 million children) each year. This means that a person diagnosed with sepsis has 22% chance to succumb from it, and that 20% of the annual deaths on Earth are due to sepsis. These high numbers reflect the huge scale of sepsis, as well the lack of efficient therapeutics. Despite sepsis is associated with inflammation, inhibitors of inflammatory pathways or cytokines have been very disappointing in clinical trials. We believe that the death of patients and animals to sepsis is the result of an acute interplay between severe metabolic issues, as such being the result of a dysregulation of food intake and the resulting starvation response. Our hypothesis, indeed, is that sepsis causes central reprogramming (in the hypothalamus), leading to quick lipolysis and muscle wasting, leading to numerous circulating substrates for beta oxidation and gluconeogenesis. These hepatic processes, essential to turn these energy-rich (and dangerous) molecules into useful ATP, ketone bodies and glucose are orchestrated by several transcription factors (GR, PPARa) which, however, in sepsis quickly abandon their duties. The ensuing accumulation of toxic metabolites, and lack of production of vital metabolites leads to coma and hear arrest. We aim at understanding and preventing or correcting the loss of activity of these and other (such as RXRa and HNF4a) nuclear receptors, as well as understanding the central (hypothalamic) decisions. In a second approach, we also study how acute inflammation is able to lead to bacterial translocation from the gut (ileum) into the liver, there causing a sepsis, and the role that Paneth cells, in the crypts of Lieberkuhn play in this.

Areas of Expertise

  • Mouse models of sepsis (peritonitis and pneumonia), endotoxemia and SIRS
  • Functional studies and structure-function work of nuclear receptors with a focus on Glucocorticoid Receptor GR, PPARa, RXRa and HNF4a, in vivo in mice using bulk RNASEQ, single-cell RNASEQ, CHIP-SEQ, ATAC-SEQ and BIO-IT
  • Metabolic studies in vitro and in vivo, using Seahorse, C13-labelled metabolite tracing and other assays
  • The role of Paneth cells in control of microbiome composition and function
  • Mouse genome mutagenesis and whole-genome studies

Technology Transfer Potential

  • Discovery of novel sepsis therapeutics
  • Discovery of new interventions for appetite control, with function on hypothalamic neurons
  • Novel insights in the (therapeutic) role of zinc and other trace elements

Selected publications

  • Wallaeys, C., Garcia-Gonzalez, N. & Libert, C. Paneth cells as the cornerstones of intestinal and organismal health: a primer. EMBO Mol Med 15, e16427 (2023). Visit ➚
  • Timmermans, S., Vandewalle, J. & Libert, C. Mousepost 2.0, a major expansion of the resource. Nucleic Acids Res 51, 1652-1661 (2023). Visit ➚
  • Vandewalle, J. et al. Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis. Cell Metab 33, 1-14 (2021). Visit ➚
  • Van Wyngene, L. et al. Hepatic PPARalpha function and lipid metabolic pathways are dysregulated in polymicrobial sepsis. EMBO Mol Med, e11319 (2020). Visit ➚
  • Souffriau, J. et al. Zinc inhibits lethal inflammatory shock by preventing microbe-induced interferon signature in intestinal epithelium. EMBO Mol Med, e11917 (2020). Visit ➚

Bibliography


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RNAscope™ staining for tnfrsf1a and a typical Paneth cell marker, lysozyme, in the ileum of TNFR1PanethKO mice