Stroke is a leading cause of morbidity and mortality. The gut microbiota-immune-brain axis is a key regulator of the immune response to stroke. Immune cells constantly adapt to the gut environment using specialized receptors such as the ligand-activated transcription factor, aryl hydrocarbon receptor (AHR). AHR integrates environmental, dietary, microbial, and metabolic cues to control the immune system. Moreover, accumulating evidence implicates AHR in the inflammatory response to stroke. For example, elevated plasma levels of endogenous AHR activators are positively correlated with infarct volume and mortality in stroke patients. Recent data suggests that post-stroke inhibition of AHR can be neuroprotective. However, these data were obtained from young male animal models. This distinction is important because stroke prevalence increases with age and it disproportionately affects women. In this project, I will investigate whether age and sex affect the neuroprotective effect of AHR inhibitors (AHRI). Further, age-related changes in the microbiota are associated with shifts in the metabolic pathways that regulate AHR ligands. I hypothesize that the benefits of post-stroke AHRI therapy are due to a reduction in the detrimental effects of gut dysbiosis. Using a reversible middle-cerebral artery occlusion model (MCAO), I will examine whether post-stroke AHRI treatment of aged mice of both sexes improves neurological outcomes. Additionally, I will determine whether AHRI reduces the deleterious effects of experimentally-induced dysiosis after MCAO. Lastly, I will examine whether a combination therapy with AHRI and fecal microbiota transplant (FMT) from youthful donors act synergistically to improve stroke outcomes. Our preliminary data shows that AHR expression on flow-sorted immune cells decreases with aging in the brain but increases with aging in the lamina propria of distal ileum and cecum. Our results show that AHR expression is increased in gut immune cells of young mice after FMT from aged donors (i.e. reflects the age of the donors). The results from this proposal can identify a molecular mechanism of the gut-immune-brain axis dysfunction after stroke. Future management of stroke patients may involve acute AHRI therapy with sub-acute manipulation of the gut microbiota via FMT from healthy donors.
Age and sex are major risk factors for stroke and preclinical studies focused on developing stroke therapies must consider age and sex, as two independent biological variables. The bidirectional communications in the ?gut- immune-brain axis? is increasingly recognized as a key player in health, in disease, and in response to various therapies. This proposal will determine whether potential stroke therapies targeting a sensor of the microbiota?s metabolites that controls the immune system, the aryl hydrocarbon receptor or AHR), are beneficial in preclinical stroke models of aging and sex differences, and whether these AHR therapies work by blocking the deleterious effects of gut dysbiosis after stroke.
