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

Recovery after ischemic stroke is often compromised by delayed neuronal death in the perilesional tissue, known as penumbra, even when cerebral blood flow is restored. The causes of this secondary neuronal death are still poorly understood. Our findings indicate the formation of thrombi in penumbral microvessels, associated with a disruption of the blood-brain barrier (BBB) and leading to localized microglial activation. Microglia in proximity to the thrombi displayed reactive phenotypes, while those further away remained in a surveillant state. This suggests that microvasculature thrombosis (MT) drives localized microglial reactivity, contributing to delayed neuronal death. Additionally, perturbation of the gut microbiome critically affect microglial function and the BBB, influencing neurological diseases. Therefore, we here hypothesize a potential interaction between the microbiome and microglia in mediating MT and aim to investigate this interaction contributes to delayed neuronal death. To explore this, we will first characterize MT-mediated BBB dysfunction and phenotypic changes of MT-associated microglia (MTAMs) using spatial transcriptomics and in vivo two-photon imaging in a mouse model of cerebral ischemia-reperfusion. Next, we will assess how microbial metabolites and migration of immune cells from the gut to the brain affects microglial behavior, BBB integrity and MT formation in mice with an altered microbiome. Finally, we will examine the long-term effects of MTAMs on post-stroke recovery by directly targeting microglial phenotypes or the microbiome. This project leverages expertise in microthrombosis and the BBB (French partner) and microglia and microbiome research (German partner), highlighting an interdisciplinary collaboration. The findings could identify new therapeutic targets to improve stroke recovery by influencing cerebral blood flow through the modulation microglia and the microbiome.