The Role of Gut Dysbiosis in Obstructive Sleep Apnea Induced Hypertension

Abstract

Obstructive sleep apnea (OSA), characterized by repeated closure of the upper airway during sleep, is a significant clinical problem. OSA is an independent risk factor for systemic hypertension, and the most common underlying cause of resistant hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We have previously observed that gut dysbiosis is associated with the development of hypertension in a rat model of OSA. Furthermore we have shown that transplantation of the dysbiotic microbiota from a hypertensive OSA rat into a normotensive rat is capable of inducing hypertension. These studies demonstrate, for the first time, a causal relationship between gut dysbiosis and hypertension. The mechanisms linking gut dysbiosis to hypertension are unknown. We tested the hypothesis that OSA‐induced gut dysbiosis leads to impaired gut barrier function, systemic inflammation, and inflammation of the brain, which is linked to hypertension. Using an in vivo model of OSA, we exposed high fat fed rats to 2 weeks of sham or OSA (60 apneas/hr). Relative to sham rats, OSA led to a significant increase in TNFα mRNA expression in the cecum wall as well as decreased goblet cells/crypt in the cecum and colon (n=4, p<0.05). Consistent with impaired gut barrier function and bacterial translocation, we observed bacterial 16S rRNA signatures in the mesenteric lymph node and visceral adipose tissue, as well as elevated adipose IL‐6 mRNA expression following OSA (n=4–7, p<0.05). Flow cytometric analysis revealed a significant decrease in the number of anti‐inflammatory T‐regulatory cells in the brain of OSA vs. sham rats. This was associated with an increase in the number of activated microglia following OSA (n=3, p<0.05). Short chain fatty acids play a key role in maintaining gut barrier integrity and regulating immune responses. To further examine the role of gut dysbiosis in the development of OSA‐induced hypertension we treated sham and OSA rats with a prebiotic (diet enriched with 20% resistant starch) or probiotic (Clostridium butyricum; 109 CFU by gavage every three days) to increase short chain fatty acids and improve gut barrier function. Pre‐ and probiotics successfully prevented OSA‐induced loss of goblet cells and TNFα expression in the cecum and colon. Compared to vehicle treated rats, the probiotic C. butyricum prevented the OSA‐induced increase in adipose IL‐6 expression, increased total T‐regulatory cells in the brain, and decreased activated microglia (n=3–6, p<0.05). Importantly, both the pre‐ and probiotic successfully prevented the development of hypertension in OSA rats. These data demonstrate a causal role for gut dysbiosis in the development of hypertension, which involves gut barrier disruption, bacterial translocation, and brain inflammation. Our data suggest that manipulation of the gut microbiota, through pre‐ or probiotics, may serve as a novel therapy in the prevention of hypertension.Support or Funding InformationNINDS R01NS080531 (RMB), PHS DK56338 and AHA 16SDG29970000 (DJD)