Critical Role of the Interaction Gut Microbiota - Sympathetic Nervous System in the Regulation of Blood Pressure - PubMed (original) (raw)
Critical Role of the Interaction Gut Microbiota - Sympathetic Nervous System in the Regulation of Blood Pressure
Marta Toral et al. Front Physiol. 2019.
Abstract
Association between gut dysbiosis and neurogenic diseases, such as hypertension, has been described. The aim of this study was to investigate whether changes in the gut microbiota alter gut-brain interactions inducing changes in blood pressure (BP). Recipient normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were orally gavaged with donor fecal contents from SHR and WKY. We divided the animals into four groups: WKY transplanted with WKY microbiota (W-W), SHR with SHR (S-S), WKY with SHR (W-S) and SHR with WKY (S-W). Basal systolic BP (SBP) and diastolic BP (DBP) were reduced with no change in heart rate as a result of fecal microbiota transplantation (FMT) from WKY rats to SHR. Similarly, FMT from SHR to WKY increased basal SBP and DBP. Increases in both NADPH oxidase-driven reactive oxygen species production and proinflammatory cytokines in brain paraventricular nucleus linked to higher BP drop with pentolinium and plasmatic noradrenaline (NA) levels were found in the S-S group as compared to the W-W group. These parameters were reduced by FMT from WKY to SHR. Increased levels of pro-inflammatory cytokines, tyrosine hydroxylase mRNA levels and NA content in the proximal colon, whereas reduced mRNA levels of gap junction proteins, were found in the S-S group as compared to the W-W group. These changes were inhibited by FMT from WKY to SHR. According to our correlation analyses, the abundance of Blautia and Odoribacter showed a negative correlation with high SBP. In conclusion, in SHR gut microbiota is an important factor involved in BP control, at least in part, as consequence of its effect on neuroinflammation and the sympathetic nervous system activity.
Keywords: gut dysbiosis; hypertension; neuroinflammation; oxidative stress; sympathetic nervous system.
Figures
FIGURE 1
Effects of fecal microbiota transplantation (FMT) on blood pressure. Systolic blood pressure (SBP), measured by tail-cuff plethysmography during 4 weeks of FMT (A), and SBP, diastolic blood pressure (DBP), and heart rate (HR), measured by direct register (B), in spontaneously hypertensive rats (SHR) with stool transplant from SHR (S-S) or from Wistar Kyoto rats (WKY) (S-W) and in WKY with stool transplant from WKY (W-W) or from SHR (W-S) at the end of the experimental period. Strain factor, FMT factor and I interaction between strain and FMT factors. ++p < 0.01, +p < 0.05 and ns (not significant) for the probability based on a two-way analysis of variance. Values are means ± SEM (n = 5–8). ∗P < 0.05 and ∗∗P < 0.01 vs. W-W; ##P < 0.01 vs. S-S statistical significance for the probability based on a Sidak’s correction multiple comparisons test.
FIGURE 2
Effects of fecal microbiota transplantation (FMT) on sympathetic tone. Decrease induced by acute intravenous administration of pentolinium (10 mg/kg) on systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), in conscious rats (A). Plasma noradrenaline (NA) levels (B), and plasma renin activity (PRA) (C) found in all experimental groups. Strain factor, FMT factor and I interaction between strain and FMT factors. ++p < 0.01, +p < 0.05 and ns (not significant) for the probability based on a two-way analysis of variance. Values are means ± SEM (n = 5–8). ∗P < 0.05 and ∗∗P < 0.01 vs. WKY with stool transplant from WKY (W-W); #P < 0.05 and ##P < 0.01 vs. SHR with stool transplant from SHR (S-S), statistical significance for the probability based on a Sidak’s correction multiple comparisons test.
FIGURE 3
Effects of fecal microbiota transplantation (FMT) on ROS production and NADPH oxidase pathway in the brain PVN. CM-H2DCFDA-detected intracellular ROS in absence and presence of NADPH oxidase inhibitor apocynin (50 μM) (A) and NADPH oxidase activity measured by DHE fluorescence measured in the microplate reader (B) in homogenates from brain PVN. mRNA levels of NADPH oxidase subunits NOX-1, NOX-4, p47phox and p22phox (C) in the brain PVN from all experimental groups. Strain factor, FMT factor and I interaction between strain and FMT factors. ++p < 0.01 and ns (not significant) for the probability based on a two-way analysis of variance. Values are means ± SEM (n = 5–8). ∗P < 0.05 and ∗∗P < 0.01 vs. WKY with stool transplant from WKY (W-W); #P < 0.05 vs. SHR with stool transplant from SHR (S-S), statistical significance for the probability based on a Sidak’s correction multiple comparisons test.
FIGURE 4
Effects of fecal microbiota transplantation (FMT) on brain PVN pro-inflammatory markers expression. mRNA levels of TNF-α (A), IL-β (B), IL-6 (C), IL-17a (D), interferon-γ (IFNγ) (E), IL-10 (F), C-C chemokine ligand 2 (CCL2) (G) and macrophage marker CD11b (H) measured by RT-PCR in brain PVN from all experimental groups. Strain factor, FMT factor and I interaction between strain and FMT factors. ++p < 0.01, +p < 0.05 and ns (not significant) for the probability based on a two-way analysis of variance. Values are means ± SEM (n = 5–8). ∗P < 0.05 and ∗∗P < 0.01 vs. WKY with stool transplant from WKY (W-W); #P < 0.05 vs. SHR with stool transplant from SHR (S-S), statistical significance for the probability based on a Sidak’s correction multiple comparisons test.
FIGURE 5
Effects of fecal microbiota transplantation (FMT) on brain PVN SCFA-sensing receptors expression. mRNA levels of Olfr 59 (A), GPR-41 and GPR-43 (B) measured by RT-PCR in brain PVN from all experimental groups. Strain factor, FMT factor and I interaction between strain and FMT factors. ++p < 0.01, +p < 0.05 and ns (not significant) for the probability based on a two-way analysis of variance. Values are means ± SEM (n = 5–8). ∗P < 0.05 and ∗∗P < 0.01 vs. WKY with stool transplant from WKY (W-W); #P < 0.05 and ##P < 0.01 vs. SHR with stool transplant from SHR (S-S), statistical significance for the probability based on a Sidak’s correction multiple comparisons test.
FIGURE 6
Effects of fecal microbiota transplantation (FMT) on changes of the gut microbiome. Comparisons of microbiome changes in WKY with stool transplant from WKY versus SHR with stool transplant from SHR (A) WKY-WKY versus WKY-SHR (B) and SHR-SHR versus SHR- WKY (C). Cladograms (top panes) show the significantly enriched taxa, the taxa are identified in the key to the right of each pane. The larger the circles the greater the difference in abundance between the groups. The lower panels show the results of linear discriminant analysis effect size at p < 0.05 and LDA score of > 2.5 and detail the taxa most enriched by WKY, SHR or SHR-WKY. n = 6 animals per treatment group in each comparison.
FIGURE 7
Effects of fecal microbiota transplantation (FMT) on changes of composition of gut microbiota. Time-dependent changes of fecal microbiota upon in all experimental groups (n = 6 rats per group).
FIGURE 8
Effects of fecal microbiota transplantation (FMT) on colonic pro-inflammatory, epithelial integrity, and sympathetic activity markers. Colonic occludin (A), zonula occludens-1 (ZO-1) (B), mucin (MUC)-2 (C), TNF-α (D), IL-6 (E), IL-β (F) and GPR-43 (G) mRNA levels, plasma endotoxin concentrations (EU/mL, endotoxin units/mL) (H), mRNA levels of tyrosine hydroxylase (TH) (I), and noradrenaline (NA) content (J), in all experimental groups. Strain factor, FMT factor and I interaction between strain and FMT factors. ++p < 0.01, +p < 0.05 and ns (not significant) for the probability based on a two-way analysis of variance. Values are means ± SEM (n = 5–8). ∗P < 0.05 and ∗∗P < 0.01 vs. Wistar-Kyoto (WKY) with stool transplant from WKY (W-W); #P < 0.05 and ##P < 0.01 vs. SHR with stool transplant from SHR (S-S), statistical significance for the probability based on a Sidak’s correction multiple comparisons test.
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