Contribution of microglia-microbiome interaction in microthrombus formation in ischemic stroke

• Applicant: Dr. Corinne Benakis
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568738346

Recovery after ischemic stroke is often compromised by delayed neuronal death in the perilesional region, known as the penumbra, even when cerebral blood flow is successfully restored. The mechanisms driving this secondary neuronal loss remain poorly understood and present a critical barrier to improving long-term stroke outcomes. Recent findings from Partner 1 (Dr. Igor Khalin, France/ANR) suggest that microthrombus formation in penumbral microvessels is a key contributor, coinciding with local blood-brain barrier (BBB) disruption and spatially restricted microglial activation. Microglia in close proximity to microthrombi adopt reactive phenotypes, while those farther away retain a surveillant state, indicating that microvascular thrombosis triggers localized microglial reactivity that may exacerbate neuronal injury. Adding a novel dimension to this hypothesis, emerging evidence implicates the gut microbiome as a critical regulator of cerebrovascular health and disease. Microbiota-derived metabolites have been shown to modulate both BBB integrity and microglial function. Partner 2 (Dr. Corinne Benakis, Germany/DFG) has demonstrated that pre-stroke modulation of the microbiome promotes an anti-inflammatory immune profile and improves outcomes, while stroke-induced dysbiosis can worsen injury via gut-brain immune interactions. These findings raise the possibility that microbiome perturbations influence post-stroke microvascular pathology and secondary neurodegeneration. The MICROStroke project aims to elucidate how microthrombus formation, BBB dysfunction, and microglial activation interact, and how these processes are modulated by the gut microbiome. Specifically, we will: Characterize microthrombus-associated BBB breakdown and microglial phenotypes using spatial transcriptomics and advanced imaging; Investigate how microbial metabolites impact microglial activation, BBB integrity, and microthrombus formation in vivo; Examine the long-term effects of microthrombi-associated microglia on stroke recovery through microbiome and microglial modulation. This interdisciplinary collaboration combines expertise in thrombosis and BBB imaging (Partner 1) with microbiome and microglia research (Partner 2). By integrating in vivo two-photon imaging, spatial transcriptomics, and microbial manipulation, MICROStroke introduces a novel framework wherein the microbiome is explored as a modifiable factor influencing post-recanalization microthrombosis. The project aims to identify new therapeutic targets to improve stroke recovery by restoring neurovascular integrity and modulating brain-immune-microbiome interactions.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Igor Khalin, Ph.D.