Sub‐diaphragmatic vagal nerve stimulation alleviates rodent hypertension associated with gut dysbiosis and reduced serotonergic vagal afferent signaling

Abstract

IntroductionThe gut‐brain vagal axis, of which serotonin (5HT) is an important mediator, can be altered by the gut microbiota. Low vagal tone and autonomic imbalance is present in conditions marked by gut dysbiosis including in hypertension (HTN); however, the effect of gut dysbiosis on vagal sensory/afferent function in HTN is unknown. We hypothesized that HTN‐associated gut dysbiosis will decrease serotonergic vagal afferent signaling from the gut and cause autonomic imbalance leading to increased blood pressure (BP). Moreover, we propose that restoring the vagal gut‐brain axis by chronic vagal stimulation will alleviate HTN.MethodsFecal matter transplant (FMT) was performed from either the spontaneously hypertensive (SHR) or Wistar‐Kyoto rats (WKY) to control WKY. BP and autonomic variables were recorded using radiotelemetry. Colonic 5HT, expression of 5HT3a receptors (5HT3aR) along the vagal gut‐brain axis, and cardiovascular responses to systemic 5HT3aR agonist injection were determined in the FMT rats, WKY and SHR. In vivo Ca2+ imaging was performed in gCAMP‐labeled nodose ganglia (NG) neurons in response to 5HT3aR agonist in WKY and SHR. Lastly, SHR were implanted with cuff electrodes on the sub‐diaphragmatic ventral vagal trunk for chronic vagal stimulation (sVNS) while measuring BP and autonomic variables using radiotelemetry. Endpoint bacterial 16s sequencing determined the effects of sVNS on SHR gut dysbiosis.ResultsFMT from SHR but not WKY significantly increased BP (P<0.05 vs baseline) and resulted in autonomic imbalance (P<0.05 vs baseline) in control WKY. This was associated with reduced colonic 5HT levels (P<0.01 vs FMT from WKY), as well as reduced 5HT3aR gene expression in vagal sensory (NG) neurons (p<0.05 vs FMT from WKY) and the brainstem region receiving vagal sensory projections (P<0.01 vs FMT from WKY). Furthermore, NG neuronal firing in response to 5HT3aR agonist corresponded with a time‐locked reduction in the HR in WKY, but both 5HT3aR agonist‐induced NG firing rates and HR responses were significantly blunted in the SHR (P<0.05). In addition, 5HT3aR agonist‐dependent HR responses were also reduced in the WKY following FMT from SHR (P<0.05 vs FMT from WKY). Crucially, chronic sVNS alleviated SHR HTN over eight weeks (P<0.05 vs SHAM SHR), without reversing gut dysbiosis, suggesting that the observed BP effect may primarily be due to restoration of the vagal afferent gut‐brain signaling.ConclusionsHTN‐associated gut dysbiosis reduces serotonergic gut‐brain vagal signaling and increases BP. Restoring vagal afferent tone is effective in alleviating HTN in the SHR.