Modulation of microglial function by microbiota-derived metabolites in cerebral ischemia

• Applicant: Dr. Corinne Benakis
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536691735

Microglia, the brain resident immune cells, actively contribute to the progression of the ischemic lesion or exert functions important for tissue repair. As such, microglia are at the forefront of receiving a wide range of signals, including extrinsic factors derived from the gut microbiota. It is now well established that the gut microbial ecosystem shapes the host immune system via the synthesis of thousands of metabolites. These microbial molecules can interact with intestinal immune cells, stimulate the vagus nerve, or reach the systemic circulation to signal to the brain and potentially, through one or more of these three modes of actions, modulate the microglial response. However, how microglial function is fine-tuned by microbial metabolites in the context of stroke is largely unknown. In previous experiments, we identified that the synthesis of the gut metabolites secondary bile acids is strongly impaired after stroke and that the bile acid signaling pathway is dysregulated in microglia. Therefore, we aim to investigate how bile acids derived from the gut microbiota that enter the brain modulate the acute and chronic inflammatory state of microglia after stroke. To address this research question, we will make use state-of-the-art technologies including engineered bacteria, single cell RNA sequencing, microglia depletion, and newly developed bioinformatic tools to identify similar microbiota between humans and mice as a translational approach. The results of this research proposal may lead to the development of new therapeutic targets using the microbiota to modulate microglial function and promote functional regeneration after stroke.

• DFG Programme: Research Grants