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      Prebiotics, Probiotics, and Acetate Supplementation Prevent Hypertension in a Model of Obstructive Sleep Apnea

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          Abstract

          <p class="first" id="P1">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 (SCFA) producing bacteria. However, measurements of SCFA concentrations and testing of their role in blood pressure regulation is lacking. We hypothesized that reduced SCFAs in the gut are responsible for OSA-induced hypertension. OSA significantly increased SBP at 7 and 14 days (p&lt;0.05), an effect that was abolished by the probiotic <i>Clostridium butyricum</i> or the prebiotic Hylon VII. 16S rRNA analysis identified a number of SCFA producing bacteria that were significantly increased by <i>C.butyricum</i> and Hylon treatment. Acetate concentration in the cecum was decreased by 48% following OSA (p&lt;0.05), an effect that was prevented by <i>C.butyricum</i> and Hylon. <i>C.butyricum</i> and Hylon reduced OSA-induced dysbiosis, epithelial goblet cell loss, mucus barrier thinning, and activation of brain microglia (p&lt;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&lt;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. </p>

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          Is Open Access

          Diabetes, obesity and gut microbiota.

          The gut microbiota composition has been associated with several hallmarks of metabolic syndrome (e.g., obesity, type 2 diabetes, cardiovascular diseases, and non-alcoholic steatohepatitis). Growing evidence suggests that gut microbes contribute to the onset of the low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. Recently, enteroendocrine cells and the endocannabinoid system have been shown to control gut permeability and metabolic endotoxaemia. Moreover, targeted nutritional interventions using non-digestible carbohydrates with prebiotic properties have shown promising results in pre-clinical studies in this context, although human intervention studies warrant further investigations. Thus, in this review, we discuss putative mechanisms linking gut microbiota and type 2 diabetes. These data underline the advantage of investigating and changing the gut microbiota as a therapeutic target in the context of obesity and type 2 diabetes. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Transmission of atherosclerosis susceptibility with gut microbial transplantation.

            Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.
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              Age‐related changes in the gut microbiota influence systemic inflammation and stroke outcome

              Objective Chronic systemic inflammation contributes to the pathogenesis of many age‐related diseases. Although not well understood, alterations in the gut microbiota, or dysbiosis, may be responsible for age‐related inflammation. Methods Using stroke as a disease model, we tested the hypothesis that a youthful microbiota, when established in aged mice, produces positive outcomes following ischemic stroke. Conversely, an aged microbiota, when established in young mice, produces negative outcomes after stroke. Young and aged male mice had either a young or an aged microbiota established by fecal transplant gavage (FTG). Mice were subjected to ischemic stroke (middle cerebral artery occlusion; MCAO) or sham surgery. During the subsequent weeks, mice underwent behavioral testing and fecal samples were collected for 16S ribosomal RNA analysis of bacterial content. Results We found that the microbiota is altered after experimental stroke in young mice and resembles the biome of uninjured aged mice. In aged mice, the ratio of Firmicutes to Bacteroidetes (F:B), two main bacterial phyla in gut microbiota, increased ∼9‐fold (p < 0.001) compared to young. This increased F:B ratio in aged mice is indicative of dysbiosis. Altering the microbiota in young by fecal gavage to resemble that of aged mice (∼6‐fold increase in F:B ratio, p < 0.001) increased mortality following MCAO, decreased performance in behavioral testing, and increased cytokine levels. Conversely, altering the microbiota in aged to resemble that of young (∼9‐fold decrease in F:B ratio, p < 0.001) increased survival and improved recovery following MCAO. Interpretation Aged biome increased the levels of systemic proinflammatory cytokines. We conclude that the gut microbiota can be modified to positively impact outcomes from age‐related diseases. Ann Neurol 2018;83:23–36
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                Author and article information

                Journal
                Hypertension
                Hypertension
                Ovid Technologies (Wolters Kluwer Health)
                0194-911X
                1524-4563
                November 2018
                November 2018
                : 72
                : 5
                : 1141-1150
                Affiliations
                [1 ]From the Department of Neurology, University of Texas Health Sciences Center, Houston (B.P.G.)
                [2 ]Department of Anesthesiology, Baylor College of Medicine, Houston TX (J.W.N., A.G., R.M.B., D.J.D.)
                [3 ]Mercer University School of Medicine, Macon, GA (J.R.E.).
                [4 ]Department of Molecular Virology and Microbiology, The Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston TX (N.J.A., J.F.P.)
                [5 ]Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston TX (R.M.B., D.J.D.)
                Article
                10.1161/HYPERTENSIONAHA.118.11695
                6209125
                30354816
                9c1c1ace-2f25-4cde-8d43-be6e9a9d3b7a
                © 2018
                History

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