Abstract 084: Gut Dysbiosis Impairs Serotonergic Gut-Brain Axis and Increases Blood Pressure

Abstract

Introduction: Fecal microbiota transfer (FMT) from hypertensive to normotensive rats elevates blood pressure (BP). As gut microbiota can affect synthesis of serotonin (5-HT), a major neurotransmitter predominantly synthesized in the gut, our objective was to investigate the effect of gut dysbiosis on gut-derived 5-HT in control of BP. Methods: Gut microbiota was depleted in normotensive adult male Wistar Kyoto (WKY) rats (N=24) using a cocktail of Vancomycin/Meropenem/Omeprazole at 50mg/kg/day for 5 days, followed by FMT from either adult male spontaneously hypertensive rats (SHR) (SHR-WKY, N=12) or age-, sex-matched WKY (WKY-WKY, N=12). At 8 weeks post-FMT, the following parameters were measured: BP by tailcuff and radiotelemetry; autonomic variables by spectral analysis of waveform BP; activity of cardioregulatory brain regions by manganese-enhanced MRI; fecal and proximal colonic 5-HT levels by HPLC; and levels of 5-HT 3 receptors in the proximal colon, nodose ganglia and the nucleus of the solitary tract (NTS) by qPCR. Lastly, BP and heart rate (HR) responses to intra-mesenteric i.v. injection of 5-HT 3 receptor agonist 1-phenylbigunide (35μg) were determined in anesthetized rats. Results: Compared with WKY-WKY, SHR-WKY showed a significant increase in systolic BP (Δ=34mmHg, P<0.05). This was associated with increased low frequency (by 13%, P<0.05) and decreased high frequency of BP (by 14%, P<0.05), indicative of sympathetic and parasympathetic variables respectively. A suppression of neural activity in the NTS (by 2 fold, P=0.06), and a reduction in 5HT 3 receptors in the NTS (by 1.5 fold, P<0.01), nodose ganglia (by 2 fold, P<0.05) and proximal colon (by 1.5 fold, P=0.09) in SHR-WKY resembled those in the SHR. Lower level of 5-HT in the proximal colon (by 4 fold, P<0.01), but not in the feces of SHR-WKY were observed. Similar to SHR, WKY-SHR showed significantly blunted drop in BP (by 5 fold, P<0.05) and HR (by 2 fold, P<0.05) in response to intra-mesenteric i.v. injection of 1-phenylbigunide, compared with WKY-WKY. Conclusions: FMT from SHR to WKY is associated with imbalanced autonomic variables and perturbations in serotonergic gut-brain axis that may contribute to hypertension partly via a dampened afferent vagal feedback to the NTS.