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15 million people suffer from stroke per year. Fundamentally, stroke is caused by a lack of oxygenated blood to brain tissue which results in tissue death. This entails a complex pathophysiology which encompasses 3 phases. Within minutes to hours, brain resident cells initiate excitotoxicity leading to irreversible neuronal death. From days to months, peripheral recruitment of immune cells to the brain drives neuroinflammation and exacerbates stroke outcome. Finally, within months to years, there is an increase in neuronal plasticity which enables reorganisation of cortical networks and restoration of broken circuits. Despite decades of research and intricate understanding of the physiological processes occurring after stroke, only one acute therapy is approved for use in clinics. An interesting therapeutic target for scientific researchers is modulation of the peripheral host immune system. Experimental research has shown that polarisation of the immune cell sub populations towards pro-/anti-inflammatory state can exacerbate or alleviate stroke outcome respectively. Polarised immune cell subsets migrate from peripheral secondary lymphoid organs to the brain lesion. While the intestinal immune compartment contains the majority of the immune cells in the body, it is the intestinal lumen that is the home to 1000 different readily adapting bacterial species. The gut microbiota has been shown to intimately interact with the immune system and alter the function of particular immune cell subsets. Recent experimental evidence has indicated a potential role for the interaction the gut microbiota and immune system in brain disease. We hypothesised that the gut microbiota could therefore play a role in the outcome of stroke. Within this thesis we explore the gut microbiota and its derived metabolites in experimental ischemic stroke models. This thesis incorporates four publications which have unravelled different aspects of how the gut microbiota affects stroke. The key experimental findings within this thesis can be summarised in five key concepts. 1) The gut microbiota and stroke have a bidirectional interaction, both having the ability to change the other. 2) The gut microbiota alters peripheral immune cells which after stroke, were shown to migrate to the brain and alter the inflammatory milieu. 3) The presence of the gut microbiota, or treatment with healthy gut microbiota transfer, improved stroke outcome. 4) Small changes in the gut microbiota can alter response to stroke immunotherapies. 5) Short-chain fatty acids, the dietary metabolites derived from the gut microbiota, improve functional post stroke recovery. Taken together, I hope this thesis reflects and demonstrates the interesting therapeutic potential of gut microbiota manipulation for treatment of stroke. The addition of microbiota-based treatments may not only be a stand-alone therapy to aid recovery after stroke, but additionally could be a practical add-on for existing procedural treatments. |
