Project Summary: Obstructive sleep apnea (OSA) is a significant risk factor for systemic hypertension and other cardiovascular diseases. While this relationship has been firmly established, an understanding of how OSA leads to hypertension is poorly understood. Recently, scientists have begun to recognize that neuroinflammation is an important factor in the development of hypertension, including that hypertension associated with OSA. However, the underlying source and the steps that illicit neuroinflammation with OSA is unknown. In this proposal, we will develop the idea that the gut microbiota is responsible for initiating and maintaining neuroinflammation required for the development of hypertension. In recent years, it has been recognized that a microbiota-gut-brain axis exists, whereby microorganisms residing in the gut play a critical role in regulating brain homeostasis and function. We propose the overall hypothesis that OSA promotes neuroinflammation and hypertension through gut dysbiosis and modification of the microbiota-gut-brain axis. We have found through preliminary studies that OSA alters the makeup of the gut microbiota, leads to gut barrier disruption and the introduction of bacteria and endotoxins into the systemic circulation. We have also shown that OSA promotes a pro-inflammatory phenotype in innate immune cells in both the gut and brain. Additionally, we have linked OSA- induced dysbiosis to the development of hypertension by demonstrating that the hypertensive phenotype can be transferred to a normotensive rat by transplantation with a dysbiotic microbiota. Lastly, we provide the foundation for a therapeutic strategy using oral prebiotics and probiotics, which were able to prevent dysbiosis, reduce gut inflammation and neuroinflammation, and prevent OSA-induced hypertension. The main goal of this proposal is to understand how components of the microbiota-gut-brain axis are altered by OSA and contribute to neuroinflammation and hypertension, with a focus on activated immune cell signaling (Aim 1), altered metabolite signaling (Aim 2), and methods of preventing OSA-induced hypertension (Aims 1-3). In each aim we will manipulate the microbiome by diet or next generation probiotics to determine the effects on OSA-induced hypertension, a disease becoming more common in our overweight and aging population.