Hypertension‐associated dysbiosis leads to elevated sympathetic drive and alterations in neurotransmitter signaling in the nucleus of the solitary tract in WKY

Abstract

IntroductionGut dysbiosis is linked to hypertension (HTN), and fecal microbiota transplantation (FMT) from hypertensive subjects to normotensive recipients induces high blood pressure (BP). Therefore, manipulation of gut microbiota is a potential therapeutic target in HTN. Here, we demonstrate a role for the central nervous system and particularly the nucleus of the solitary tract (NTS) in the dysbiosis‐mediated HTN in Wistar Kyoto (WKY) rats receiving cecal feces from the spontaneously hypertensive rats (SHR).Methods12 week‐old male WKY rats were orally gavaged with a combination of antibiotics (Vancomycin, Meropenem, and Omeprazole) at 50mg/kg/day for five days. Following two days of recovery, rats were given an oral cecal content suspension from either the male adult WKY (group WKY‐WKY, n=6), or age‐ and sex‐matched hypertensive SHR (group SHR‐WKY, n=6), initially every day for six days, and thereafter once a week for seven weeks. BP was measured by radio telemetry, and spectral analysis was performed on systolic BP (SBP) waveform signal (Ponemah) to derive autonomic variables. NTS was punched out from all rats at the end of study, and relative expression of genes associated with molecular signaling of several neurotransmitters and proinflammatory factors was measured by real time PCR, and normalized to GAPDH using the relative ΔΔCt method.ResultsFollowing FMT, a significant increase in SBP at night (6pm‐5am) was observed in SHR‐WKY vs WKY‐WKY group by week 6 (WKY‐WKY 134.8±1.34 mmHg vs SHR‐WKY 141.8±1.05 mmHg, P=0.0023), which continued through week 7 (WKY‐WKY 133.8±1.3 mmHg vs SHR‐WKY 139.1±2.16 mmHg, P=0.028). This was associated with a significant increase in low frequency (LF) of SBP (indicating vasomotor tone), and LF/high frequency (HF) ratio (indicating vasovagal balance) at night in the SHR‐WKY (LF: WKY‐WKY 1.21±0.014 vs SHR‐WKY 1.36±0.059, P=0.031; LF/HF: WKY‐WKY 1.433±0.75 vs SHR‐WKY 1.869±0.17, P=0.0485), suggesting elevated sympathetic drive at night in the SHR‐WKY group. Real time PCR revealed increased expression of pro‐inflammatory Tlr4 (WKY‐WKY 0.00267±0.000234 vs SHR‐WKY 0.00346±0.000197, P=0.0351) and Il1b (WKY‐WKY 0.000116±9.53e‐006 vs SHR‐WKY 0.000171±9.98e‐006, P=0.0119) in the NTS of SHR‐WKY rats. Moreover, relative expression levels of serotonin receptor subtype Htr1a (WKY‐WKY 0.00582±0.0011 vs SHR‐WKY 0.00372±0.00033, P=0.0608), as well as serotonin re‐uptake transporter (SERT) Slc6a4 (WKY‐WKY 0.0012±0.00028 vs SHR‐WKY 0.00028±3.82e‐005, P=0.0052) were reduced in the NTS of SHR‐WKY. Finally, relative expression levels of two major subunits of glutamate receptors, NR1 (WKY‐WKY 0.064±0.0015 vs SHR‐WKY 0.082±0.0042, P=0.009) and NR2A (WKY‐WKY 0.024±0.0014 vs SHR‐WKY 0.03224±0.0013, P=0.0042) were significantly increased in the NTS of SHR‐WKY rats.ConclusionsGut dysbiosis‐induced increase in BP is associated with significant elevation in the sympathetic drive, perturbations in neurotransmitter signaling and increased inflammatory markers in the NTS. These changes indicate a role for microbiota in regulation of the gut‐brain axis in HTN.Support or Funding InformationAHA Grant 14SDG18300010 to JZ and University of Florida College of Veterinary Medicine (UFCVM) Start Up Funds to JZ.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.