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Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension.

ABSTRACT: Individuals suffering from obstructive sleep apnea (OSA) are at increased risk for systemic hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We tested the hypothesis that gut dysbiosis contributes to hypertension observed with OSA. OSA was modeled in rats by inflating a tracheal balloon during the sleep cycle (10-s inflations, 60 per hour). On normal chow diet, OSA had no effect on blood pressure; however, in rats fed a high-fat diet, blood pressure increased 24 and 29 mm Hg after 7 and 14 days of OSA, respectively (P<0.05 each). Bacterial community characterization was performed on fecal pellets isolated before and after 14 days of OSA in chow and high-fat fed rats. High-fat diet and OSA led to significant alterations of the gut microbiota, including decreases in bacterial taxa known to produce the short chain fatty acid butyrate (P<0.05). Finally, transplant of dysbiotic cecal contents from hypertensive OSA rats on high-fat diet into OSA recipient rats on normal chow diet (shown to be normotensive) resulted in hypertension similar to that of the donor (increased 14 and 32 mm Hg after 7 and 14 days of OSA, respectively; P<0.05). These studies demonstrate a causal relationship between gut dysbiosis and hypertension, and suggest that manipulation of the microbiota may be a viable treatment for OSA-induced, and possibly other forms of, hypertension.

SUBMITTER: Durgan DJ

PROVIDER: S-EPMC4713369 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension.

Durgan David J DJ Ganesh Bhanu P BP Cope Julia L JL Ajami Nadim J NJ Phillips Sharon C SC Petrosino Joseph F JF Hollister Emily B EB Bryan Robert M RM

Hypertension (Dallas, Tex. : 1979) 20151228 2

Individuals suffering from obstructive sleep apnea (OSA) are at increased risk for systemic hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We tested the hypothesis that gut dysbiosis contributes to hypertension observed with OSA. OSA was modeled in rats by inflating a tracheal balloon during the sleep cycle (10-s inflations, 60 per hour). On normal chow diet, OSA had no effect on blood pressu ...[more]

PMID: 26711739

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Project description:Due to its effects, like an exaggerated negative intrathoracic pressure, sympathetic activation, systemic inflammation, oxidative stress, and endothelial dysfunction, obstructive sleep apnea (OSA) has been involved as a cause in multiple cardiovascular diseases. These diseases include coronary artery disease, hypertension, heart failure, and pulmonary hypertension (PH). Furthermore, OSA often coexists with chronic thromboembolic pulmonary hypertension (CTEPH) in clinical practice. However, few studies focus on OSA and its relationship with CTEPH. This study aims to determine whether OSA has an influence on the clinic status of patients with CTEPH, and to identify what possible factors are associated with OSA in CTEPH. Patients who were newly diagnosed with CTEPH and received overnight polysomnography (PSG) monitoring from September 2015 to December 2017 were enrolled. OSA was defined as apnea-hypopnea index (AHI) of ?5/h and the obstructive events at ?50%. Baseline clinical characteristics and parameters were collected and compared between CTEPH patients with and without OSA. In addition, logistic regression analysis was performed to identify possible factors associated with OSA in CTEPH. Fifty-seven patients with CTEPH were eventually enrolled. Among them, 32 patients were diagnosed with OSA by PSG. CTEPH patients with OSA showed an older age, a higher body mass index (BMI), a higher hemoglobin level, a lower oxygen saturation and a worse World Health Organization functional class (WHO FC) (all P<0.05) when compared to CTEPH patients without OSA. In addition, sleep data including AHI, oxygen desaturation index and minimum oxygen saturation were also statistically different between two groups (all P<0.05). Adjusted for age, sex and BMI, hemoglobin [odd ratio (OR) =1.057, 95% confidence interval (CI): 1.001-1.117, P=0.046], oxygen saturation (OR =0.718, 95% CI: 0.554-0.929, P=0.012), N-terminal pro-brain natriuretic peptide (OR =1.001, 95% CI: 1.000-1.002, P=0.016), mean right atrium pressure (OR =1.284, 95% CI: 1.030-1.600, P=0.026), mean pulmonary arterial pressure (mPAP) (OR =1.087, 95% CI: 1.001-1.180, P=0.048), cardiac index (CI) (OR =0.058, 95% CI: 0.008-0.433, P=0.037), pulmonary vascular resistance (OR =1.004, 95% CI: 1.001-1.007, P=0.014) and WHO FC III-IV (OR =18.550, 95% CI: 2.363-144.128, P=0.005) were associated with OSA in CTEPH. Multivariate logistic regression analysis demonstrated CI (OR =0.051, 95% CI: 0.003-0.868, P=0.040) was independently associated with OSA in CTEPH in addition to age, sex and BMI. OSA may aggravate the clinical status of CTEPH patients to some degree. In turn, a worse hemodynamics, oxygenation state and cardiac function are associated with OSA in CTEPH after being adjusted for age, sex and BMI. Among them, CI is the most important parameter in indicating the coexistence of OSA and CTEPH.

Project description:Obstructive sleep apnea (OSA) is a common disorder characterized by episodic obstruction to breathing due to upper airway collapse during sleep. Because of the episodic airway obstruction, intermittently low O2 (hypoxia) and high CO2 (hypercapnia) ensue. OSA has been associated with adverse cardiovascular and metabolic outcomes, although data regarding potential causal pathways are still evolving. As changes in inspired O2 and CO2 can affect the ecology of the gut microbiota and the microbiota has been shown to contribute to various cardiometabolic disorders, we hypothesized that OSA alters the gut ecosystem, which, in turn, exacerbates the downstream physiological consequences. Here, we model human OSA and its cardiovascular consequence using Ldlr-/- mice fed a high-fat diet and exposed to intermittent hypoxia and hypercapnia (IHH). The gut microbiome and metabolome were characterized longitudinally (using 16S rRNA amplicon sequencing and untargeted liquid chromatography-tandem mass spectrometry [LC-MS/MS]) and seen to covary during IHH. Joint analysis of microbiome and metabolome data revealed marked compositional changes in both microbial (>10%, most remarkably in Clostridia) and molecular (>22%) species in the gut. Moreover, molecules that altered in abundance included microbe-dependent bile acids, enterolignans, and fatty acids, highlighting the impact of IHH on host-commensal organism cometabolism in the gut. Thus, we present the first evidence that IHH perturbs the gut microbiome functionally, setting the stage for understanding its involvement in cardiometabolic disorders. IMPORTANCE Intestinal dysbiosis mediates various cardiovascular diseases comorbid with OSA. To understand the role of dysbiosis in cardiovascular and metabolic disease caused by OSA, we systematically study the effect of intermittent hypoxic/hypercapnic stress (IHH, mimicking OSA) on gut microbes in an animal model. We take advantage of a longitudinal study design and paired omics to investigate the microbial and molecular dynamics in the gut to ascertain the contribution of microbes on intestinal metabolism in IHH. We observe microbe-dependent changes in the gut metabolome that will guide future research on unrecognized mechanistic links between gut microbes and comorbidities of OSA. Additionally, we highlight novel and noninvasive biomarkers for OSA-linked cardiovascular and metabolic disorders.

Project description:Study objectivesTo explore and analyze diversity and abundance of oropharyngeal microbiota in patients with obstructive sleep apnea (OSA).MethodsThis was a cross-sectional study. Middle-aged men, suspected to have OSA, referred to full-night polysomnography, and willing to provide oropharyngeal swab samples, were consecutively enrolled. OSA severity was assessed by apnea-hypopnea index (AHI) as non-OSA (AHI < 5 events/h) and OSA (AHI ≥ 15 events/h). Bacterial DNA of oropharyngeal samples was extracted and quality test performed. Oropharyngeal microbiota was analyzed using 16S ribosomal DNA (rDNA) sequencing, and bioinformatic analysis carried out after sequencing.ResultsSamples from 51 men (25 in the non-OSA group and 26 in the OSA group) were sent for examination. Of these, 40 samples were found to have sufficient concentration of DNA and were analyzed for bioinformatics. In alpha diversity analysis, the OSA group exhibited significantly lower sobs (198.33 ± 21.71 versus 216.57 ± 26.21, P = .022), chao (221.30 ± 26.62 versus 243.86 ± 26.20, P = .014), ace (222.17 ± 27.15 versus 242.42 ± 25.81, P = .028) and shannon index (3.14 ± 0.23 versus 3.31 ± 0.26, P = .035), suggesting a reduction in microbial species diversity. We further divided participants into non-OSA, moderate OSA, and severe OSA groups and observed a significant decrease in the bacterial biodiversity of OSA groups compared with the non-OSA group, with the most significant decrease occurring in the moderate OSA group. Principal coordinate analysis showed two extremely different oropharyngeal microbial communities in non-OSA and OSA groups. More interestingly, proportion of Neisseria was slightly higher in the severe OSA group (20.64%), followed by the moderate OSA and non-OSA groups (12.57% and 9.69%, respectively). Glaciecola was not detected in the OSA groups compared to the non-OSA group (0 versus 0.772 ± 0.4754, P < .001).ConclusionsMiddle-aged men with OSA showed less oropharyngeal species diversity and altered abundance, on which further confirmation is warranted.

Dataset Information

Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension.

Publications

Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension.

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