Examining the Role of Gut Dysbiosis in Neuroinflammation and Hypertension in a Model of Obstructive Sleep Apnea
Authors: Durgan David , Ganesh Bhanu Priya , Nelson James , Eskew Joshua , Ajami Nadim , Petrosino Joseph , Bryan Robert 
Published: June 2021

Obstructive sleep apnea (OSA), characterized by repeated closure of the upper airway during sleep, is a significant clinical problem and an independent risk factor for systemic hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We have previously demonstrated that gut dysbiosis is associated with the development of hypertension in a rat model of OSA. Transplanting the dysbiotic microbiota from a hypertensive OSA rat into a normotensive rat induces hypertension, demonstrating 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 impairs gut barrier function, causing systemic inflammation and neuroinflammation, 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=6, p<0.05). OSA resulted in a 3‐fold increase in gut permeability (n=6, p<0.05). Consistent with impaired gut barrier function and bacterial translocation, we observed increased bacterial 16S rRNA signatures in the mesenteric lymph node and visceral adipose tissue following OSA (n=4–7, p<0.05). Flow cytometric analysis using whole brain revealed a significant increase in the number of activated microglia following OSA (n=4–6, p<0.05). Short chain fatty acids play a key role in maintaining gut barrier integrity and regulating immune responses. We found that OSA significantly reduced the acetate concentraction in the cecum (n=5, p<0.05). To increase short chain fatty acid production in the gut, rats were treated with a prebiotic (diet enriched with 20% resistant starch), or probiotic (Clostridium butyricum; 109 CFU by gavage every three days) during the 2 weeks of sham or OSA. Pre‐ and probiotics each prevented OSA‐induced decrease in cecal acetate concentration, prevented OSA‐induced loss of goblet cells, and prevented increased TNFα expression in the cecum of OSA rats (n=5–6, p<0.05 for each). Additionally, pre‐ and probiotics prevented OSA‐induced activation of microglia in brain (n=6–8, p<0.05). Importantly, both the pre‐ and probiotic successfully prevented the development of hypertension in OSA rats. To test the direct effects of acetate, we chronically infused 20μmol/(kg‐min) acetate into the cecum during the 2 weeks of sham or OSA. Cecal acetate infusion prevented OSA‐induced hypertension. These data demonstrate a causal role for gut dysbiosis in the development of hypertension, which involves reduced acetate production, gut barrier disruption, bacterial translocation, and neuroinflammation. Our data suggest that manipulation of the gut microbiota may serve as a novel therapy in the prevention of hypertension.Support or Funding InformationThis project was funded by NINDS R01NS080531 (RMB), AHA 16SDG29970000 (DJD), and by Public Health Service grant DK56338, which funds the Texas Medical Center Digestive Diseases Center (DJD).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.