Prebiotics, Probiotics, and Acetate Supplementation Prevent Hypertension in a Model of Obstructive Sleep Apnea - PubMed (original) (raw)
Prebiotics, Probiotics, and Acetate Supplementation Prevent Hypertension in a Model of Obstructive Sleep Apnea
Bhanu P Ganesh et al. Hypertension. 2018 Nov.
Abstract
Disruption of the gut microbiota, termed gut dysbiosis, has been described in animal models of hypertension and hypertensive patients. We have shown that gut dysbiosis plays a causal role in the development of hypertension in a rat model of obstructive sleep apnea (OSA). Functional analysis of the dysbiotic microbiota in OSA demonstrates a loss of short chain fatty acid-producing bacteria. However, measurements of short chain fatty acid concentrations and testing of their role in blood pressure regulation are lacking. We hypothesized that reduced short chain fatty acids in the gut are responsible for OSA-induced hypertension. OSA significantly increased systolic blood pressure at 7 and 14 days ( P<0.05), an effect that was abolished by the probiotic Clostridium butyricum or the prebiotic Hylon VII. The 16S rRNA analysis identified several short chain fatty acid-producing bacteria that were significantly increased by Cbutyricum and Hylon treatment. Acetate concentration in the cecum was decreased by 48% after OSA ( P<0.05), an effect that was prevented by Cbutyricum and Hylon. Cbutyricum and Hylon reduced OSA-induced dysbiosis, epithelial goblet cell loss, mucus barrier thinning, and activation of brain microglia ( P<0.05 for each). To examine the role of acetate in OSA-induced hypertension, we chronically infused acetate into the cecum during 2 weeks of sham or OSA. Restoring cecal acetate concentration prevented OSA-induced gut inflammation and hypertension ( P<0.05). These studies identify acetate as a key player in OSA-induced hypertension. We demonstrate that various methods to increase cecal acetate concentrations are protective from the adverse effects of OSA on the microbiota, gut, brain, and blood pressure.
Keywords: acetates; blood pressure; cecum; dysbiosis; hypertension; microbiota; obstructive sleep apnea.
Conflict of interest statement
Conflict(s) of Interest / Disclosure(s)
none
Figures
Figure 1.
C.butyricum and Hylon prevent OSA-induced hypertension.A, On HFD OSA rats exhibited significantly higher SBP, as compared to sham rats, after 7 and 14 days of OSA (n=7 per group). OSA-induced hypertension was prevented by C.butyricum(B, n=7 (OSA) and 13 (Sham)) or Hylon treatment (C, n=6). Data are shown as the mean ± S.E.M., *p<0.05 for sham vs. OSA.
Figure 2.
C.butyricum and Hylon alter the makeup of the gut microbiota. Weighted Unifrac principal coordinate analysis shows separation of HFD+Hylon treated microbiota from HFD and HFD+C.butyricum(A). LEFSe analysis identified several taxa that characterize HFD vs HFD+C.butyricum vs HFD+Hylon. Major SCFA produced by genera are shown to the right of each bar (B; A=acetate, B=butyrate, P=propionate). Relative abundance of taxa identified by LEFSe analysis (LDA Score >4) to characterize HFD (C, RC4–4, Akkermansia, and Coprococcus), C.butyricum(D, Clostridiales and Parabacteroides), and Hylon (E, Bifidobacterium, Ruminococcus, Blautia, and Colinsella). Data are shown as the mean ± S.E.M. n=6 (HFD and HFD+Hylon) or 7 (HFD+C.butyricum) for all analyses, *p<0.05 vs HFD alone, **p<0.01 vs HFD alone, ****p<0.0001 vs HFD alone.
Figure 3.
Effects of OSA on the microbiota of HFD, HFD+C.butyricum, and HFD+Hylon treated rats. Weighted Unifrac principal coordinate analysis shows separation of Hylon treated microbiota, but no effect of OSA (A). Relative abundance of major phyla in HFD, HFD+C.butyricum, and HFD+Hylon sham and OSA rats (B). OSA altered the relative abundance of multiple bacterial taxa in HFD alone and HFD+C.butyricum, but not HFD+Hylon (C). LEFSe analysis was used to identify and calculate a linear discriminate analysis (LDA) score for taxa that characterize sham vs. OSA. In panel C, positive LDA scores indicate the enrichment of taxa in sham relative to OSA (green), and negative LDA scores indicate the enrichment of taxa in OSA relative to sham (red). Data are shown as the mean. n=6 (HFD and HFD+Hylon) or 7 (HFD+C.butyricum) for all analyses, *p<0.05 vs. HFD group.
Figure 4.
Adverse effects of OSA on the cecum wall are reduced by_C.butyricum_ and Hylon. A and B, Goblet cells (arrowhead) per crypt were reduced in the cecum following OSA in HFD, but not HFD+C.butyricum or HFD+Hylon rats. C and D, Separation of luminal bacteria (red, EUB338 FISH probe) and epithelium (blue, DAPI) was reduced in the cecum following OSA in HFD, but not HFD+C.butyricum or HFD+Hylon rats. E, Epithelial barrier integrity was impaired in HFD and HFD+C.butyricum OSA rats, as compared to shams. Data are shown as the mean ± S.E.M. n=6 for A, n=5 (HFD Sham and OSA), 6 (HFD+Hylon Sham and HFD+C.butyricum OSA) or 7 (HFD+C.butyricum Sham and HFD+Hylon OSA) in E, n=3 for C. *p<0.05 vs sham of same treatment, **p<0.01 vs sham of same treatment.
Figure 5.
OSA reduces cecal acetate concentration, which is prevented by_C.butyricum_, Hylon, and acetate infusion. OSA reduced cecal acetate concentrations in HFD alone, but not HFD+C.butyricum or HFD+Hylon treated rats (A). Portal plasma concentration of acetate (B) was not significantly different between sham and OSA in any treatment group. Hylon, independent of OSA, increased cecal and plasma acetate concentrations (A and B). PBS (vehicle) treated rats had decreased cecal acetate concentrations following OSA, which was prevented by cecal acetate infusion (C). OSA significantly increased cecal IL-1α and IL-6 mRNA, which was prevented with cecal acetate infusion (D and E). Cecal acetate infusion prevented OSA-induced increase in SBP at 7 and 14 days of OSA (F). Data are shown as the mean ± S.E.M. n=5 (HFD+C.butyricum OSA) or 6 (all other groups) for A and B, n=6 for all groups in C-F, *p<0.05 vs sham of same treatment, #p<0.05 vs HFD.
Figure 6.
OSA increases activated microglia in brain, which is prevented by_C.butyricum_ and Hylon treatment.A, Gating strategy used to identify activated microglia in brain by flow cytometry.B, Activated microglia were increased in brain following 2 weeks of OSA in HFD treated rats. No difference in activated microglia was observed following OSA in HFD+C.butyricum or HFD+Hylon treated rats.C, The percentage of T regulatory cells was not different between sham and OSA in any of the treatment groups. Two-way ANOVA showed a main effect of treatment, with Hylon treatment increasing T regulatory cells in brain. Data are shown as the mean ± S.E.M. n=4 (HFD OSA), or 5 (HFD Sham, HFD+C.butyricum Sham and OSA), or 6 (HFD+Hylon Sham and OSA) for all analyses. *p<0.05 vs sham, #p<0.05 vs. HFD sham.
Comment in
- Too Fatty, Too Salty, Too Western.
Mishima RS, Hohl M, Linz B, Sanders P, Linz D. Mishima RS, et al. Hypertension. 2018 Nov;72(5):1078-1080. doi: 10.1161/HYPERTENSIONAHA.118.11832. Hypertension. 2018. PMID: 30354835 No abstract available.
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