Mitochondrial function in the regulation of intestinal tissue regeneration and inflammation-related pathologies

• Applicant: Professor Dr. Dirk Haller
• Subject Area: Nutritional Sciences ; Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 469152594

The intestinal epithelium plays a key role in the pathogenesis of inflammatory bowel diseases (IBD). Recurrent inflammatory episodes in IBD damage the epithelium and represent insults to the intestinal barrier. Tissue regeneration in response to injuries is an essential mechanism to maintain/restore barrier and immune homeostasis, requiring a tight regulation of epithelial renewal, proliferation and (de)differentiation. We suggest that impaired mitochondrial metabolism and uncontrolled mitochondrial stress signaling (mitochondrial unfolded protein response, MT-UPR) in the epithelium contribute to aberrant intestinal tissue responses (referred to as metabolic injury). Considering the pivotal role of Interleukin 22 (IL-22) and IL-10 in regulating intestinal barrier function and immune responses, the aim of the present project is to understand the contribution of these cytokines to the resolution of mitochondria-related injuries in the epithelium and to identify disruptive mechanisms responsible for the progression of inflammation-related pathologies. We implement our novel epithelial cell-specific mouse models for metabolic injury (conditional deficiency of the mitochondrial heat shock protein 60; Hsp60IEC) and MT-UPR activation (conditional deficiency of the caseinolytic mitochondrial matrix peptidase; ClpPIEC). In these models, resolution or progression of tissue pathology and inflammation will be analyzed in the absence of IL-22 signaling and in the IL-10 deficient host. In addition, we apply the FDA approved investigational drug Dichloroacetate (DCA), exploring the therapeutic role of a metabolic shift towards mitochondrial respiration. Tissue samples from IBD patients (N=80) will be used to validate the clinical relevance of metabolic injury and regenerative tissue responses during remission and relapse. Finally, we intend to identify signals and mechanisms crucial for controlling regulatory circuits in response to metabolic injury using intestinal organoid (co-)cultures from mice and patients. In summary, we test the hypothesis that IL-22 and IL-10 regulate metabolic fitness of epithelial cells, and thereby contribute to the resolution of metabolic injury in the intestine. We propose that mitochondrial function of the epithelium is critically determining disease susceptibility and progression of IBD-related pathologies.

• DFG Programme: Research Grants