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Volume 15 No. 10
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Obstructive Sleep Apnea and Systemic Hypertension: Gut Dysbiosis as the Mediator?

Saif Mashaqi, MD, FCCP1; David Gozal, MD, MBA2
1Division of Sleep Medicine, University of North Dakota School of Medicine – Sanford Health, Fargo, North Dakota; 2Department of Child Health and the Child Health Research Institute, University of Missouri School of Medicine, Columbia, Missouri

ABSTRACT

Introduction:

Obstructive sleep apnea (OSA) and systemic hypertension (SH) are common and interrelated diseases. It is estimated that approximately 75% of treatment-resistant hypertension cases have an underlying OSA. Exploration of the gut microbiome is a new advance in medicine that has been linked to many comorbid illnesses, including SH and OSA. Here, we will review the literature in SH and gut dysbiosis, OSA and gut dysbiosis, and whether gut dysbiosis is common in both conditions.

Methods:

We reviewed the National Center for Biotechnology Information database, including PubMed and PubMed Central. We identified a total of 230 articles. The literature search was conducted using the phrase “obstructive sleep apnea and gut dysbiosis.” Only original research articles were included. This yielded a total of 12 articles.

Results:

Most of the research conducted in this field was on animal models, and almost all trials confirmed that intermittent hypoxia models resulted in gut dysbiosis. Gut dysbiosis, however, can cause a state of low-grade inflammation through damage to the gut wall barrier resulting in “leaky gut.” Neuroinflammation is a hallmark of the pathophysiology of OSA-induced SH.

Conclusions:

Gut dysbiosis seems to be an important factor in the pathophysiology of OSA-induced hypertension. Reversing gut dysbiosis at an early stage through prebiotics and probiotics and fecal microbiota transplantation combined with positive airway pressure therapy may open new horizons of treatment to prevent SH. More studies are needed in humans to elicit the effect of positive airway pressure therapy on gut dysbiosis.

Citation:

Mashaqi S, Gozal D. Obstructive sleep apnea and systemic hypertension: gut dysbiosis as the mediator? J Clin Sleep Med. 2019;15(10):1517–1527.


INTRODUCTION

Sleep-related breathing disorders are common, with an estimated prevalence of 10% to 30%.1 In addition to symptoms of excessive daytime sleepiness and decline in cognitive functions, obstructive sleep apnea (OSA) is well known to be related to many comorbidities, including cardiovascular disorders (eg, coronary artery disease, systemic and pulmonary hypertension, atrial fibrillation and congestive heart failure), endocrinologic disorders (eg, diabetes mellitus and obesity), neurologic disorders (eg, ischemic stroke, epilepsy, multiple sclerosis, and neurodegenerative disorders), hematologic disorders (eg, hypercoagulable diseases), metabolic disorders, and cancer, leading to overall increased morbidity and mortality.14 It is currently assumed that most of the negative effect of sleep-disordered breathing (SDB) and its independent association with many of these comorbidities are secondary to the intermittent hypoxia and sleep fragmentation that characterize this disorder. However, it remains unclear whether there are additional mechanisms involved either directly or as an intermediate consequence of such sleep perturbations.

Systemic hypertension (SH) is a very common chronic disease that frequently coexists with SDB. It is estimated that at least 50% of general adult patients with OSA have underlying SH.5 Data from the Sleep Heart Health Study confirmed an increase in the risk of incident and prevalent SH in patients with OSA that is dose dependent (odds ratio of 1.37 in severe OSA compared to 1.07 in patients with no OSA).6,7 The pathophysiology that affects patients with OSA and their risk of the development or worsening of SH is not fully understood, but several mechanisms have been postulated, including sympathetic activation and nondipping blood pressure.8,9 An emerging concept that seems to be linked to many comorbidities is the gut microbiome (GM). Changes in the gut microbiota have been shown to play a critical role in the development of some chronic diseases (eg, systemic hypertension). At the same time, changes in GM are linked to OSA, which might lead to the conclusion that GM is a common player in both OSA and SH. In this critical review, we will review studies that examined OSA (or OSA models) effect on GM starting with animal models followed by human trials.

THE GUT MICROBIOME

Human microbiota refers to the comprehensive and exhaustive collection of microbes living in a specific organ of the human body (eg, skin, oral cavity, gut). These microbes include bacteria, viruses, fungi, and parasites, with bacteria being the most common microbes that have been identified. The gut harbors the largest proportion of the microbiota, with more than 100 trillion bacteria from more than 1,000 species.10 This ecosystem, which reflects the interaction between gut microbiota and the host, is influenced by the immune system, with 70% of the lymphoid tissues being found in the gut and forming the gut-associated lymphoid tissues.11 The five most common bacterial phyla that reside in the colon are Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Cerrucomicrobia.12 Bacteroidetes (gram-negative) and Firmicutes (gram-positive) form more than 90% of gut microbiota.13 The human body has its own microbiota and ecosystem generating a unique fingerprint of that individual, but rather than being one that is rigid and fixed; it is dynamic and modifiable.14 The gut microbiota profile starts to develop in utero, and rapidly evolves during infancy and early childhood to acquire its unique individual signature.15

This equilibrium and overall stability of the microbiota ecosystem are considered as a critical contributor to maintaining health, but many external factors can alter the gut microbiota and introduce more harmful species. This can start as early as the delivery period.13 Indeed, normal vaginal delivery has been shown to expose the fetus to Lactobacillus, which is very beneficial to the fetus.16 With the increasing numbers of cesarean sections being performed, there is a shift in the gut microbiota profile of neonates to an increased presence of Staphylococcus, Corynebacterium, and Propionibacterium (skin flora). The significance of these changes remains unclear.13,17,18 However, breastfeeding will enhance the presence of protective bacterial species, namely Bifidobacteria.19 Dietary characteristics are also major modulators of the gut microbiome and their persistent effects can start as early as 3 years after delivery.13 The accumulation of other external factors such as sedentary lifestyle, smoking, alcohol intake, and antibiotics will emerge and consolidate with more harmful species being detected and linked to a multitude of comorbidities and chronic diseases.20

The hallmark of gut dysbiosis is an increase in the phylum Firmicutes compared to Bacteroidetes. Firmicutes are gram-positive bacteria and include some species at the family and genera levels, with harmful features locally (gut) and systematically. Examples include Prevotella and Desulfovibrio, which induce mucin degradation and subsequently alter gut wall permeability.21Desulfovibrio produces hydrogen sulfide, which had been linked to a higher risk of colon cancer.22,23Prevotella produces endotoxins (lipopolysaccharides) and encodes for superoxide reductase which may favor inflammation.24Lachnospiraceae and RC4-4 are shown to increase the risk of obesity.2426Akkermanisa had been reported in animal models with multiple sclerosis.27,28 However, Bacteroidetes are anaerobic bacteria that include different species involved in the fermentation of fibers in the colon to produce short-chain fatty acids (butyrate, acetate, and propionate) that serve as major nutrients to the epithelial cells of the gut. Examples include Lactobacillaceae, Bifidobacteriaceae, Erysipelotrichaceae, Ruminococcaceae, and Clostridiales.29,30

METHODS

We searched the literature (National Center for Biotechnology Information database) using the statement “Gut microbiome and obstructive sleep apnea.” The search yielded 15 articles in PubMed and 215 articles in PubMed Central (PMC). In PubMed, 6 articles were excluded (4 were not original research, 1 was an ongoing study for which the experimental protocol was published, and 1 did not meet the search criteria), such that a total of 9 original research articles were ultimately included.

In PMC, 199 articles did not meet the search criteria (6 articles were not original research, 7 were duplicate from PubMed). A total of additional 3 articles were included from PMC. Thus, the total number of original articles included in this review is 12. The exclusion criteria are (1) any none original research article (eg, review article); (2) duplicate articles in more than one database; (3) the gut microbiome and other sleep disorders (Not SDB).

OSA AND GM (ANIMAL MODELS)

The rapid evolution in the microbiome science prompted the initiation of a large number of studies attempting to identify the possible mechanisms through which gut dysbiosis can contribute to many comorbid medical conditions, and SDB is no exception. Chronic intermittent hypoxia during sleep (IH) elicits periodic decreases in the partial oxygen pressure (PO2) gradient in the gut lumen, which fosters changes in the relative abundance of aerobic bacteria along with the emergence of increased obligate and facultative anaerobes.31 Morenos-Indias et al showed that IH exposures in mice mimicking moderate OSA induced significant changes in the gut microbiome compared to control normoxic conditions. Mice were exposed to air with cyclic changes in partial oxygen pressure (normal air at 21% oxygen for 40 seconds followed by low PO2 air at 5% oxygen for 20 seconds). After 6 weeks, fecal samples from IH-exposed mice and corresponding controls were analyzed using 16S r RNA pyrosequencing. More Firmicutes, Prevotella, Paraprevotella, Desulfovibrio, and Lachnospiraceae species and less Bacteroidetes, Odoribacter, Turicibacter, Peptococcaceae and Erysipelotrichaceae species were found in patients with IH compared to control patients.21 Similar results were obtained when mice were exposed to experimental sleep fragmentation using intermittent tactile nonstressful stimulation every 2 minutes during the sleep period.32 Fecal microbiome changes were reversible when sleep fragmentation was discontinued, but surprisingly only partial reversibility was detected following cessation of IH for the same period of the IH exposure.33

Almost all animal studies using a similar model of IH exposures found an increase in the Firmicutes/Bacteroidetes (F/B) ratio. Some of the bacterial species noticed in the IH group (eg, Prevotella and Desulfovibrio) exhibited mucin degrading features, whereby the sulfate liberated during mucin degradation by Prevotella was removed by Desulfovibrio, and this process further enhanced mucin degradation.21,34 At the same time, fermentation of dietary fibers in the colon by “healthy” gut microbiota results in the production of short chain fatty acids (SCFA) that are very important nutrients and energy sources for the colon epithelium (especially butyrate, propionate, and acetate). Gut dysbiosis reduces butyrate and acetate levels, depriving the colonic epithelium of appropriate nutrients, which can lead to the dysfunctional epithelium.2,29,35 Furthermore, IH, which essentially represents recurrent hypoxia/reoxygenation cycles, induces injury to the epithelium as well.36 All these perturbations tend to disrupt the tight junctions between the colonic epithelial cells, resulting in “leaky gut,” as revealed by in vitro electrical cell impedance experiments, which showed reductions in trans-epithelial resistance across human colonic cell monolayers.32

Gut dysbiosis also increases toxin-producing bacteria, for example, endotoxins produced by Klebsiella and Prevotella. Lipopolysaccharides and lipopolysaccharide binding protein (LBP) which are a surrogate reporter of low-grade endotoxemia, can easily translocate through the “leaky” gut into the systemic circulation and induce a state of low-grade systemic inflammation. LBP levels in addition to other inflammatory mediators, such as interleukin 6 and tumor necrosis factor alpha were found to be elevated in the plasma of mice exposed to IH. In addition, Poroyko et al32 confirmed elevation of LBP circulating levels, inflammatory mediators, visceral white adipose tissue inflammation, and insulin resistance in mice who were exposed to sleep fragmentation but were not fed a high-fat diet (HFD), suggesting a nonobesity-related pathway for this inflammatory process. Tripathi et al37 used a different model consisting of combined intermittent hypoxia and hypercapnia (IHH) to mimic severe OSA, and showed alterations in the gut microbiome with increase in Mogibacteriaceae family, Oscillospira genus, Lachnospiraceae family, and Clotridiaceae family. These species have been shown to induce inflammatory changes in the host. The study also confirmed other systemic changes related to gut dysbiosis. There were significant alterations in bile acids, including both primary and secondary BAs, and changes in signals affecting the synthesis and secretion of bile acids from the liver. Because BAs are the transporters of cholesterol and fat-soluble substances, it can be inferred that alterations in BAs can increase cholesterol levels and enhance the processes underlying atherosclerosis. Some unsaturated fatty acids (eg, elaidic acid) play a role in reducing low-density lipoprotein (LDL) and increase high-density lipoprotein, through interactions with cholesteryl ester transfer protein (CETP). Gut dysbiosis has been shown to decrease the levels of elaidic acid, thereby making the host prone to atheroma formation.37 There is also evidence that IH is atherogenic and will accelerate and propagate atherosclerosis in some murine models.38 To expand on the importance of the IHH model that was described previously, Xue et al39 examined the effect of IHH compared to IH alone on atherosclerosis formation in apolipoprotein E (ApoE) and low-density lipoprotein receptor (Ldlr) deficient mice. They found significant atherosclerosis in the pulmonary artery and aortic arch in ApoE-deficient mice who were fed an HFD, suggesting that both HFD and IHH accelerate atherosclerosis in these rodents. The pathophysiologic processes that promote atherogenesis are multifactorial and include vascular inflammation, oxidative stress, and dyslipidemia. Gut microbiota also contributes to atherosclerosis by producing trimethylamine oxide (TMAO) through ingestion of trimethylamine (TMA)-containing dietary nutrients (eg, phosphatidylcholine and choline). TMAO has been shown to stimulate LDL uptake by macrophages, and the formation of foam cells. Blocking the TMA pathway through 3,3-dimethyl-1-butanol decreased atherosclerosis burden but did not completely eliminate it (Table 1, Figure 1).

Obstructive sleep apnea and gut dysbiosis (animal studies).

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Table 1

Obstructive sleep apnea and gut dysbiosis (animal studies).

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Obstructive sleep apnea may contribute to gut dysbiosis and subsequent increase in gut wall permeability, leading to release of inflammatory mediators causing a state of systemic low-grade inflammation.

This state enhances many metabolic changes in different organs and systems (cardiovascular, central nervous, hepatic, endocrine, and musculoskeletal) causing numerous chronic disorders. BA = bile acids, BCAA = branched chain amino acids, ET-1 = endothelin-1, HDL = high-density lipoprotein, IL-1 = interleukin 1, IL-6 = interleukin 6, Ile = isoleucine, LBP = lipopolysaccharide binding protein, NO = nitrous oxide, oxLDL = oxidized low-density lipoprotein, TMAO = trimethylamine-N-Oxide, TNFα = tumor necrosis factor alpha, Val = valine.

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Figure 1

Obstructive sleep apnea may contribute to gut dysbiosis and subsequent increase in gut wall permeability, leading to release of inflammatory mediators causing a state of systemic low-grade inflammation.

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In summary, OSA animal models confirmed that IH and sleep fragmentation, which are the major features of OSA, are associated with worsening gut microbiota profile with the emergence of species negatively influencing the gut through damage to the epithelial cells and producing endotoxins leading to a state of “low-grade systemic inflammation,” which may contribute to the pathophysiologic mechanisms for many chronic inflammatory, cardiovascular, and neoplastic disorders.

OSA AND GM (HUMAN STUDIES)

Kheirandish-Gozal et al reported elevations in LBP circulating levels in children with OSA, and further showed that the concurrent presence of obesity plays a synergistic effect leading to enhanced inflammation, further increases in LBP levels along with insulin resistance.40 Collado et al noticed an increased Firmicutes/Bacteroidetes ratios and reduced Actinobacteria/Proteobacteria ratios in snoring children at the age of 2 years, suggesting that the proinflammatory processes activated by OSA and increased upper airway resistance, that is, snoring, may be taking place early in life.41 Oral dysbiosis is reported in pediatric patients with OSA, but with no causal relationship. Using metabolomic analysis measures, some metabolites were shown as uniquely increased in the urine in pediatric patients with OSA compared to adults (metabolites associated with vitamins, bilirubin, and ornithine cycle). Although there is a tendency for a causal relation between OSA and urinary metabolites levels, more randomized controlled trials should be conducted to confirm such relation.42 Notwithstanding, the scarcity of translational research studies in this particular area makes it hard to confirm these findings in humans.

Other microbiota have been studied in addition to the gut microbiota. Lung microbiota was studied using bronchial lavage and elicit a significant change in the microbiome in patients with OSA compared to patients without OSA.43 Nasal microbiome revealed a change in microbiota profile in patients with severe OSA compared to control in addition to increase in inflammatory mediators. PAP therapy did not reverse nasal dysbiosis.44 A summary of human trials is illustrated in Table 2.

Obstructive sleep apnea and gut dysbiosis (human studies).

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Table 2

Obstructive sleep apnea and gut dysbiosis (human studies).

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SYSTEMIC HYPERTENSION AND GUT MICROBIOME

Systemic hypertension (SH) is a common disease. The prevalence of SH in the United States is 46% in the adult population corresponding to approximately 103 million adults,45 with a prevalence of 31% (approximately 1.39 billion people) worldwide.2 It is a leading cause of a multitude of organ dysfunction including coronary artery disease, end-stage renal disease, blindness, and central nervous system aneurysmal bleeding. SH is defined as a systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 80 mmHg, or any patient receiving antihypertensive treatment.45 Resistant hypertension is defined as SH that requires the use of three or more antihypertensive agents.46 The exact prevalence of resistant hypertension is unknown. In one study conducted in the United States, the prevalence of resistant hypertension was 9% among all hypertensive patients and 13% in patients treated with antihypertensive agents.47 One of the major risk factors for resistant hypertension is OSA. In three separate cohorts of patients with resistant hypertension, OSA was diagnosed in 71% to 85%.4850

Gut microbiota affects different systems in the host to maintain blood pressure under control, and gut dysbiosis has been shown to contribute to SH. In this section, we will review the mechanisms by which gut dysbiosis can lead to SH, and will also elaborate on the effect of treatment of gut dysbiosis on SH.

The Immune System and the Autonomic Nervous System

The primary immune system (bone marrow) and secondary immune system (spleen, lymph node, and mucosa-associated lymphoid tissues) are the principal elements of the innate immune system responsible for continuous immunosurveillance. This process is under tight regulation from the autonomic nervous system (ANS) and encompasses the activities of both the sympathetic (SNS) and parasympathetic nervous systems (PNS). Norepinephrine is released by the postganglionic neurons of the SNS and mobilizes hematopoietic stem cells and progenitor cells in bone marrow in response to external stimuli.51 In the secondary immune tissues, the sympathetic nerves travel with blood vessels to control the release and differentiation of immune cells (T and B cell lymphocytes) from the gut-associated lymphoid tissues. Transient activations of the ANS maintain a delicate homeostatic balance between the immune system and the host.52 When this SNS stimulation is continuous, and particularly when such SNS stimulation is accompanied by PNS withdrawal (eg, OSA-induced hypertension), pathologic stimulation of the immune system ensues with resultant inflammation.5356 Conversely, PNS recruitment and targeted activation will lower blood pressure and heart rate, while concurrently enhancing both central and peripheral immune system anti-inflammatory responses.5760

Gut dysbiosis, through the production of specific metabolites that cross the blood-brain barrier (BBB) can stimulate the ANS and the immune system and participate in the process of neuroinflammation. Evidence from animal studies has demonstrated that some antibiotics with anti-inflammatory features that cross the BBB (eg, minocycline) can lower blood pressure.61,62 Some of the microbiota metabolites causing inflammation and disrupting the gut-brain axis are discussed as follows.

Short-Chain Fatty Acids

SCFAs are the result of anaerobic fermentation of dietary fibers (mainly polysaccharides) by gut microbiota.63 The three main SCFAs produced in the gut are butyrate, propionate, and acetate. In rodent models, SCFAs are direct vasodilators and elicit hypotension.64 In patients with ulcerative colitis and short bowel syndrome, there is an increase in lactate and underutilization of lactate to form SCFAs, suggesting that an imbalance between lactate and SCFAs plays a role in chronic inflammatory conditions (eg, hypertension).65,66 SCFAs induce intracellular signaling by binding to G-protein coupled receptors that are widely distributed in different organs, including the central nervous system and immune system. They contribute to homeostasis between the host immune system and gut microbiota.68,69 The most commonly studied SCFA is butyrate. It is produced mainly by Lachnospiraceae, Ruminococcaceae, and Acidaminococcaceae families.70 The anti-inflammatory effects of butyrate are mainly through the modulation of the immune system via suppression of inflammatory cytokines, stimulation of regulatory T-cells in vivo and modulation of the release of chemokines from neutrophils.35,71 Butyrate operates in mitochondria to modulate energy expenditure and repair ischemia-induced damage to neurons secondary to oxidative stress. At the metabolic level, butyrate increases insulin sensitivity in females with obesity.72 Propionate is mainly produced by Bacteroides, Salmonella, Dialister, and Veillonella species.73 It also induces dose-dependent hypotension in mice.67 Acetate is produced by Streptococcus, Prevotella, Bifidobacterium, and Clostridium species, and exerts vasoconstrictor activities.7476

Trimethylamine-N-Oxide

Gut dysbiosis can cause hypertension by metabolizing phosphatidylcholine and choline to trimethylamine (TMA), which is abundantly found in HFD containing choline and l-carnitine (eg, red meat and cheese). TMA is then transported to the liver where it is oxidized to TMAO. This had been proven in animal models only.35,77 In human models, TMAO has been linked to the risk of atherosclerosis and foam cell formation, but not hypertension.78 TMAO is mainly produced by Prevotella species linking them to a higher risk of atheroma formation.77

Oxidized LDL, Nitric Oxide, and Endothelin

Repeated oxidative stress associated with chronic inflammation can lead to a state of gut dysbiosis-oxidation of LDL. The oxidized form of LDL (oxLDL) can change the equilibrium between vasodilators and vasoconstrictors favoring enhanced vasoconstriction and elevation of blood pressure. The main mechanisms involved in this process are: (1) inhibition of nitric oxide synthase enzyme, which inhibits the conversion of arginine to nitric oxide; and (2) higher concentrations of oxLDL lead to high levels of endothelin-1, which acts as a potent vasoconstrictor.7981

Tryptophan and Its Metabolites

Tryptophol and kynurenine are two metabolites of tryptophan, and these amino acids protect gut epithelium and promote inflammation, respectively.82,83 The equilibrium of these metabolites is affected by gut microbiota. Serotonin (5-HT) is another metabolite of tryptophan that is produced mainly in the gut (approximately 90%).84 Gut dysbiosis is shown to alter 5-HT levels in the hippocampus, and the expression of 5-HT transporters in different parts of the circumventricular organs, which lack the BBB, allowing for a direct communication between their parenchyma and cerebrospinal fluid.85,86 5-HT also has a direct effect on gut motility favoring constipation, another factor that can alter the gut microbiota.87

Treatment Options Targeting Gut Dysbiosis and the Effect on Systemic Hypertension

Treating gut dysbiosis will decrease blood pressure in both animal models and human trials. Dietary approaches to stop hypertension combined with low sodium intake leads to a decrease in blood pressure, and its putative effects may be related to changes in gut microbiota.88,89 Lifestyle aspects such as physical activity contribute significantly to the ability to control underlying hypertension. Accordingly, athletes exhibit more diverse gut bacteria,90 and both exercise and high-protein diet alters gut microbiota. However, it is still not clear whether the physical activity effect on gut microbiome is independent of diet effects.91 Furthermore, probiotics (ie, microorganisms that are beneficial to the host, such as Enterococcus faecium, Streptococcus thermophiles, Lactobacillus casei)92 and prebiotics93 (ie, indigestible nutrients that escape digestion in the upper gastrointestinal tract and are digested by fermentation in the lower gut) will exert a positive effect on hypertension, obesity, and coronary artery disease.94,95

One of the therapeutic options that can treat hypertension and at the same time support the notion that gut microbiota plays a critical role in blood pressure regulation is fecal microbiota transplantation. Adnan et al showed that transplantation of cecal gut microbiota of spontaneously hypertensive stroke-prone rats (SHRSP) to normotensive WKY rats increased systolic blood pressure readings in the latter, thereby reinforcing the concept that gut microbiota play a role in blood pressure regulation.96 Furthermore, Li et al examined the gut microbiota in patients who were either normotensive, prehypertensive, or hypertensive, and found that gut dysbiosis is not only found in patients with hypertension, but also in those with prehypertension, suggesting that gut dysbiosis is a prolonged process that exerts its effects on blood pressure over a period of many years. Notably, the hypertensive features of the gut microbiota were transferrable through transplantation of cecal microbiota from human donors with hypertension into germ-free normotensive mice.97

Finally, having reviewed the effect of OSA models on GM followed by the effect of GM on SH, we will review OSA-induced hypertension and its effect on GM.

OSA-INDUCED HYPERTENSION AND GM

Because both OSA and hypertension have been shown as being linked to gut dysbiosis and chronic inflammation, examination of an animal model of OSA and hypertension is necessary to evaluate whether gut dysbiosis in the context of OSA can cause hypertension or explain treatment-resistant hypertension. The concept of chronic intermittent hypoxia (CIH) seen in OSA has been challenged. We know that aberrancy in the cardiorespiratory physiology in response to CIH is mediated through the autonomic nervous system and carotid bodies, which are the main sensors for PO2. Afferent nerve fibers (transmitting signals to carotid bodies) and efferent fibers to the cardiorespiratory system cause hyperventilation, increase ventilatory response to hypoxia, and increase the ventilatory drive to compensate for hypoxia. Sympathetic-induced and parasympathetic blunted signals cause tachycardia and hypertension. Lucking et al examined this concept in guinea pigs in which the carotid bodies are “insensitive” to hypoxia. The CIH model they used was modest in severity and for 12 days only. It did not result in tachycardia or hypertension as expected.98 However, with more severe degree of hypoxia (30 cycles per hour for 8 hours per day) for a longer period of time (30 days), there was evidence of hypertension, tachycardia, and sympathetic overstimulation as shown by increased norepinephrine peripherally in the blood and urine and centrally in the pons and medulla,99 suggesting that more intense CIH for a longer period of time is capable of causing sympathetic-induced cardiovascular changes via carotid “independent” sites, most likely the gut microbiota.

Liu et al concluded that OSA model (CIH) synergized with a high salt diet in worsening hypertension in rats by increasing TMAO levels and CD4+ T cell-induced type-I inflammation. Inflammatory cytokines (interferon gamma and interleukin 4) are increased on the surface of CD4+ cells in the spleen. They also noted depletion in Lactobacillus rhamnosus in the fecal microbiome. To confirm this, rats with hypertension with OSA were treated with probiotic Lactobacillus rhamnosus, which resulted in a reduction in TMAO levels, inflammatory cytokines, and ultimately reduced hypertension severity.100 Durgan et al implemented a model of OSA in rats consisting of implanting an inflatable device in the trachea that was periodically activated, causing tracheal obstruction, and thus mimicking OSA as seen in humans. In this model, hypertension occurred only when OSA was combined with an HFD. OSA alone did not induce significant changes in the microbial richness and diversity. In fact, HFD alone was associated with the highest F/B ratio, microbial richness, and diversity. However, fecal microbiota transplantation from OSA-HFD rats to normal chow-fed recipient rats exposed to OSA for 7 to 14 days resulted in hypertensive changes.101 To further study this model, Ganesh et al examined the effects of replacing SCFAs by the administration of a combination of both pre- and probiotic supplementation, and confirmed that: (1) OSA-HFD caused damage to the gut epithelium by goblet cells loss in the cecal epithelium and that probiotics and prebiotics prevented goblet cells loss. (2) OSA-HFD induced thinning of the mucus barrier and such changes were prevented by probiotic and prebiotics supplementation; (3) OSA-HFD elicited increases in the gut barrier permeability, and that prebiotic supplementation was preventive; (4) OSA-HFD reduced cecal acetate levels compared to butyrate and propionate, which did not occur when prebiotic and probiotic supplements were given; (5) continuous infusion of acetate for 2 weeks in OSA-HFD exposed rats prevented the development of hypertension; and (6) OSA-HFD exposures led to activation of microglia in the central nervous system suggesting neuroinflammation, which was prevented by prebiotics and probiotics supplementation.102

CONCLUSIONS

We have attempted to bring together the evidence linking hypertension to alterations in the gut microbiota, and that exposure to the prototypic physiologic perturbations that characterize OSA, namely IH and fragmented sleep, also leads to major changes in gut microbiota. From these two separate lines of evidence, we have reviewed the existing studies showing that OSA-induced hypertension is linked to gut dysbiosis. In this setting, it appears that SCFAs in general, and more particularly reduction in gut acetate levels, play a critical role in facilitating the emergence of hypertension and neuroinflammation in rodent models of OSA.

A large number of gaps in this concept linking OSA to hypertension via the gut microbiome will need to be explored, particularly in humans. For example, it will be critical to examine the effect of positive airway pressure (PAP) therapy on gut dysbiosis and the changes in blood pressure in patients with OSA. In other words, could PAP therapy reverse gut dysbiosis and could the extent of individual changes in gut microbiota account for changes in blood pressure associated with PAP therapy? As we move toward a more personalized approach to OSA management,103 the potential mining of the individual OSA-gut-vascular axis may not only offer predictive biomarkers of PAP response but also incorporate the leveraging of gut microbiota-targeted interventions into the armamentarium of current OSA treatment.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. Work for this study was performed at Sanford Research, University of North Dakota School of Medicine and University of Missouri School of Medicine, Columbia. The authors report no conflicts of interest.

ABBREVIATIONS

ANS

autonomic nervous system

BBB

blood-brain barrier

CIH

chronic intermittent hypoxia

HFD

high-fat diet

IH

intermittent hypoxia

IHH

intermittent hypoxia and hypercapnia

LBP

lipopolysaccharide binding protein

LDL

low-density lipoprotein

OSA

obstructive sleep apnea

oxLDL

oxidized low-density lipoprotein

PAP

positive airway pressure

PNS

parasympathetic nervous system

PO2

partial oxygen pressure

SCFA

short-chain fatty acids

SDB

sleep-disordered breathing

SH

systemic hypertension

SNS

sympathetic nervous system

TMAO

Trimethylamine-N-Oxide

REFERENCES

1 

Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ. 2009;108(5):246–249. [PubMed Central][PubMed]

2 

Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension. 1995;26(1):60–69. [PubMed]

3 

Marshall NS, Wong KK, Phillips CL, Liu PY, Knuiman MW, Grunstein RR. Is sleep apnea an independent risk factor for prevalent and incident diabetes in the Busselton Health Study? J Clin Sleep Med. 2009;5(1):15–20. [PubMed Central][PubMed]

4 

Brunetti V, Ferilli MAN, Vollono C, Della Marca G. Sleep apneas trigger epilepsy. Sleep Med. 2017;39:23–24. [PubMed]

5 

Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378–1384. [PubMed]

6 

Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA. 2000;283(14):1829–1836. [PubMed]

7 

Cano-Pumarega I, Duran-Cantolla J, Aizpuru F, et al. Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria Sleep Cohort. Am J Respir Crit Care Med. 2011;184(11):1299–1304. [PubMed]

8 

Elmasry A, Lindberg E, Hedner J, Janson C, Boman G. Obstructive sleep apnoea and urine catecholamines in hypertensive males: a population-based study. Eur Respir J. 2002;19(3):511–517. [PubMed]

9 

Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VK. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation. 1999;100(23):2332–2335. [PubMed]

10 

Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–335. [PubMed]

11 

Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clin Exp. Immunol. 2008;153(Suppl 1):3–6. [PubMed Central]

12 

Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65. [PubMed Central][PubMed]

13 

Dominguez-Bello MG, Blaser MJ, Ley RE, Knight R. Development of the human gastrointestinal microbiota and insights from high-throughput sequencing. Gastroenterology. 2011;140(6):1713–1719. [PubMed]

14 

Ursell LK, Clemente JC, Rideout JR, Gevers D, Caporaso JG, Knight R. The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J Allergy Clin Immunol. 2012;129(5):1204–1208. [PubMed Central][PubMed]

15 

Hansen R, Scott KP, Khan S, et al. First-pass meconium samples from healthy term vaginally-delivered neonates: an analysis of the microbiota. PLoS One. 2015;10(7):e0133320[PubMed Central][PubMed]

16 

Butel MJ, Waligora-Dupriet AJ, Wydau-Dematteis S. The developing gut microbiota and its consequences for health. J Dev Orig Health Dis. 2018;9(6):590–597. [PubMed]

17 

James L, Gorwitz RJ, Jones RC, et al. Methicillin-resistant Staphylococcus aureus infections among healthy full-term newborns. Arch Dis Child Fetal Neonatal Ed. 2008;93(1):F40–F44. [PubMed]

18 

Arboleya S, Suarez M, Fernandez N, et al. C-section and the neonatal gut microbiome acquisition: consequences for future health. Ann Nutr Metab. 2018;73(Suppl 3):17–23

19 

Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4653–4658

20 

Farré N, Farré R, Gozal D. Sleep apnea morbidity: a consequence of microbial-immune cross-talk? Chest. 2018;154(4):754–759. [PubMed]

21 

Moreno-Indias I, Torres M, Montserrat JM, et al. Intermittent hypoxia alters gut microbiota diversity in a mouse model of sleep apnoea. Eur Respir J. 2015;45(4):1055–1065. [PubMed]

22 

Huycke MM, Gaskins HR. Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models. Exp Biol Med (Maywood). 2004;229(7):586–597

23 

Muyzer G, Stams AJ. The ecology and biotechnology of sulphate-reducing bacteria. Nat Rev Microbiol. 2008;6(6):441–454. [PubMed]

24 

Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife. 2013;2:e01202[PubMed Central][PubMed]

25 

Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature. 2012;488(7413):621–626. [PubMed Central][PubMed]

26 

Ziętak M, Kovatcheva-Datchary P, Markiewicz LH, Stahlman M, Kozak LP, Backhed F. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 2016;23(6):1216–1223. [PubMed Central][PubMed]

27 

Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017;114(40):10719–10724. [PubMed Central][PubMed]

28 

Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7(1):12015

29 

Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17(12):1519–1528. [PubMed Central][PubMed]

30 

Berni Canani R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics. 2012;4(1):4[PubMed Central][PubMed]

31 

Albenberg L, Esipova TV, Judge CP, et al. Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology. 2014;147(5):1055–1063.. [PubMed Central][PubMed]

32 

Poroyko VA, Carreras A, Khalyfa A, et al. Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice. Sci Rep. 2016;6(1):35405

33 

Moreno-Indias I, Torres M, Sanchez-Alcoholado L, et al. Normoxic recovery mimicking treatment of sleep apnea does not reverse intermittent hypoxia-induced bacterial dysbiosis and low-grade endotoxemia in mice. Sleep. 2016;39(10):1891–1897. [PubMed Central][PubMed]

34 

Payne AN, Chassard C, Lacroix C. Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host-microbe interactions contributing to obesity. Obes Rev. 2012;13(9):799–809. [PubMed]

35 

Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858–876. [PubMed Central][PubMed]

36 

Taylor CT, Colgan SP. Hypoxia and gastrointestinal disease. J Mol Med (Berl). 2007;85(12):1295–1300

37 

Tripathi A, Melnik AV, Xue J, et al. Intermittent hypoxia and hypercapnia, a hallmark of obstructive sleep apnea, alters the gut microbiome and metabolome. mSystems. 2018;3(3):e00020-18[PubMed Central][PubMed]

38 

Song D, Fang G, Mao SZ, et al. Selective inhibition of endothelial NF-kappaB signaling attenuates chronic intermittent hypoxia-induced atherosclerosis in mice. Atherosclerosis. 2018;270:68–75. [PubMed]

39 

Xue J, Zhou D, Poulsen O, et al. Intermittent hypoxia and hypercapnia accelerate atherosclerosis, partially via trimethylamine-oxide. Am J Respir Cell Mol Biol. 2017;57(5):581–588. [PubMed Central][PubMed]

40 

Kheirandish-Gozal L, Peris E, Wang Y, et al. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab. 2014;99(2):656–663. [PubMed]

41 

Collado MC, Katila MK, Vuorela NM, Saarenpää-Heikkilä O, Salminen S, Isolauri E. Dysbiosis in snoring children: an interlink to comorbidities? J Pediatr Gastroenterol Nutr. 2019;68(2):272–277. [PubMed]

42 

Xu H, Li X, Zheng X, et al. Pediatric obstructive sleep apnea is associated with changes in the oral microbiome and urinary metabolomics profile: a pilot study. J Clin Sleep Med. 2018;14(9):1559–1567. [PubMed Central][PubMed]

43 

Lu D, Yao X, Abulimiti A, et al. Profiling of lung microbiota in the patients with obstructive sleep apnea. Medicine (Baltimore). 2018;97(26):e11175

44 

Wu BG, Sulaiman I, Wang J, et al. Severe obstructive sleep apnea is associated with alterations in the nasal microbiome and increase in inflammation. Am J Respir Crit Care Med. 2019;199(1):99–109.. [PubMed]

45 

Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. Circulation. 2018;137(2):109–118. [PubMed]

46 

Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72(5):e53–e90. [PubMed Central][PubMed]

47 

Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011;57(6):1076–1080. [PubMed]

48 

Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;19(12):2271–2277. [PubMed]

49 

Gonçalves SC, Martinez D, Gus M, et al. Obstructive sleep apnea and resistant hypertension: a case-control study. Chest. 2007;132(6):1858–1862. [PubMed]

50 

Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, Calhoun DA. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest. 2007;131(2):453–459. [PubMed]

51 

Hanoun M, Maryanovich M, Arnal-Estape A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron. 2015;86(2):360–373. [PubMed Central][PubMed]

52 

Bellinger DL, Lorton D. Autonomic regulation of cellular immune function. Auton Neurosci. 2014;182:15–41. [PubMed]

53 

Zubcevic J, Jun JY, Kim S, et al. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat. Hypertension. 2014;63(3):542–550. [PubMed]

54 

Lin M, Ai J, Li L, et al. Structural remodeling of nucleus ambiguus projections to cardiac ganglia following chronic intermittent hypoxia in C57BL/6J mice. J Comp Neurol. 2008;509(1):103–117. [PubMed]

55 

Yan B, Soukhova-O’Hare GK, Li L, et al. Attenuation of heart rate control and neural degeneration in nucleus ambiguus following chronic intermittent hypoxia in young adult Fischer 344 rats. Neuroscience. 2008;153(3):709–720. [PubMed]

56 

Yan B, Li L, Harden SW, et al. Chronic intermittent hypoxia impairs heart rate responses to AMPA and NMDA and induces loss of glutamate receptor neurons in nucleus ambiguous of F344 rats. Am J Physiol Regull Integr Comp Physiol. 2009;296(2):R299–R308

57 

Popper P, Mantyh CR, Vigna SR, Maggio JE, Mantyh PW. The localization of sensory nerve fibers and receptor binding sites for sensory neuropeptides in canine mesenteric lymph nodes. Peptides. 1988;9(2):257–267. [PubMed]

58 

Matteoli G, Boeckxstaens GE. The vagal innervation of the gut and immune homeostasis. Gut. 2013;62(8):1214–1222. [PubMed]

59 

Gierthmuehlen M, Plachta DT. Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication. Hypertens Res. 2016;39(2):79–87. [PubMed]

60 

Grabauskas G, Owyang C. Plasticity of vagal afferent signaling in the gut. Medicina (Kaunas). 2017;53(2):73–84

61 

Yang T, Santisteban MM, Rodriguez V, et al. Gut dysbiosis is linked to hypertension. Hypertension. 2015;65(6):1331–1340. [PubMed Central][PubMed]

62 

Qi Y, Aranda JM, Rodriguez V, Raizada MK, Pepine CJ. Impact of antibiotics on arterial blood pressure in a patient with resistant hypertension - a case report. Int J Cardiol. 2015;201:157–158. [PubMed Central][PubMed]

63 

El Kaoutari A, Armougom F, Gordon JI, Raoult D, Henrissat B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat Rev Microbiol. 2013;11(7):497–504. [PubMed]

64 

Nutting CW, Islam S, Daugirdas JT. Vasorelaxant effects of short chain fatty acid salts in rat caudal artery. Am J Physiol. 1991;261(2 Pt 2):H561–H567. [PubMed]

65 

Iraporda C, Errea A, Romanin DE, et al. Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. Immunobiology. 2015;220(10):1161–1169. [PubMed]

66 

Vernia P, Caprilli R, Latella G, Barbetti F, Magliocca FM, Cittadini M. Fecal lactate and ulcerative colitis. Gastroenterology. 1988;95(6):1564–1568. [PubMed]

67 

Pluznick JL, Protzko RJ, Gevorgyan H, et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci U S A. 2013;110(11):4410–4415. [PubMed Central][PubMed]

68 

Li G, Su H, Zhou Z, Yao W. Identification of the porcine G protein-coupled receptor 41 and 43 genes and their expression pattern in different tissues and development stages. PLoS One. 2014;9(5):e97342[PubMed Central][PubMed]

69 

Nohr MK, Egerod KL, Christiansen SH, et al. Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience. 2015;290:126–137. [PubMed]

70 

Duncan SH, Barcenilla A, Stewart CS, Pryde SE, Flint HJ. Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl Environ Microbiol. 2002;68(10):5186–5190. [PubMed Central][PubMed]

71 

Vieira EL, Leonel AJ, Sad AP, et al. Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J Nutr Biochem. 2012;23(5):430–436. [PubMed]

72 

Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58(7):1509–1517. [PubMed Central][PubMed]

73 

Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):29–41. [PubMed]

74 

Rey FE, Faith JJ, Bain J, et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J Biol Chem. 2010;285(29):22082–22090. [PubMed Central][PubMed]

75 

Marques FZ, Nelson E, Chu PY, et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation. 2017;135(10):964–977. [PubMed]

76 

Natarajan N, Hori D, Flavahan S, et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol Genomics. 2016;48(11):826–834. [PubMed Central][PubMed]

77 

Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–585. [PubMed Central][PubMed]

78 

Stremmel W, Schmidt KV, Schuhmann V, et al. Blood trimethylamine-N-oxide originates from microbiota mediated breakdown of phosphatidylcholine and absorption from small intestine. PLoS One. 2017;12(1):e0170742[PubMed Central][PubMed]

79 

Boulanger CM. Secondary endothelial dysfunction: hypertension and heart failure. J Mol Cell Cardiol. 1999;31(1):39–49. [PubMed]

80 

Ma FX, Zhou B, Chen Z, et al. Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase. J Lipid Res. 2006;47(6):1227–1237. [PubMed]

81 

Peluso I, Morabito G, Urban L, Ioannone F, Serafini M. Oxidative stress in atherosclerosis development: the central role of LDL and oxidative burst. Endocr Metab Immune Disord Drug Targets. 2012;12(4):351–360. [PubMed]

82 

Schirmer M, Smeekens SP, Vlamakis H, et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell. 2016;167(7):1897

83 

Lanis JM, Alexeev EE, Curtis VF, et al. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. Mucosal Immunol. 2017;10(5):1133–1144. [PubMed Central][PubMed]

84 

Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev. 2012;64(2):359–388. [PubMed Central][PubMed]

85 

Takeuchi Y, Sano Y. Serotonin distribution in the circumventricular organs of the rat. An immunohistochemical study. Anat Embryol (Berl). 1983;167(3):311–319

86 

Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047–3052. [PubMed Central][PubMed]

87 

El Aidy S, Ramsteijn AS, Dini-Andreote F, et al. Serotonin transporter genotype modulates the gut microbiota composition in young rats, an effect augmented by early life stress. Front Cell Neurosci. 2017;11:222[PubMed Central][PubMed]

88 

Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344(1):3–10. [PubMed]

89 

Bray GA, Vollmer WM, Sacks FM, Obarzanek E, Svetkey LP, Appel LJ. A further subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: results of the DASH-Sodium Trial. Am J Cardiol. 2004;94(2):222–227. [PubMed]

90 

O’Sullivan O, Cronin O, Clarke SF, et al. Exercise and the microbiota. Gut Microbes. 2015;6(2):131–136. [PubMed Central][PubMed]

91 

Clarke SF, Murphy EF, O’Sullivan O, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014;63(12):1913–1920. [PubMed]

92 

Hutkins RW, Krumbeck JA, Bindels LB, et al. Prebiotics: why definitions matter. Curr Opin Biotechnol. 2016;37:1–7. [PubMed]

93 

Sanders ME. Probiotics: definition, sources, selection, and uses. Clin Infect Dis. 2008;46(Suppl 2):S58–S61. , discussion S144-S151.

94 

Kawase M, Hashimoto H, Hosoda M, Morita H, Hosono A. Effect of administration of fermented milk containing whey protein concentrate to rats and healthy men on serum lipids and blood pressure. J Dairy Sci. 2000;83(2):255–263. [PubMed]

95 

Ferrier KE, Muhlmann MH, Baguet JP, et al. Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol. 2002;39(6):1020–1025. [PubMed]

96 

Adnan S, Nelson JW, Ajami NJ, et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genomics. 2017;49(2):96–104. [PubMed]

97 

Li J, Zhao F, Wang Y, et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017;5(1):14[PubMed]

98 

Lucking EF, O’Connor KM, Strain CR, et al. Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs. EBioMedicine. 2018;38:191–205. [PubMed Central][PubMed]

99 

Morgan BJ, Adrian R, Wang ZY, Bates ML, Dopp JM. Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats. J Appl Physiol. 2016;120(10):1186–1195. [PubMed Central][PubMed]

100 

Liu J, Li T, Wu H, et al. Lactobacillus rhamnosus GG strain mitigated the development of obstructive sleep apnea-induced hypertension in a high salt diet via regulating TMAO level and CD4(+) T cell induced-type I inflammation. Biomed Pharmacother. 2019;112:108580[PubMed]

101 

Durgan DJ, Ganesh BP, Cope JL, et al. Role of the gut microbiome in obstructive sleep apnea-induced hypertension. Hypertension. 2016;67(2):469–474. [PubMed]

102 

Ganesh BP, Nelson JW, Eskew JR, et al. Prebiotics, probiotics, and acetate supplementation prevent hypertension in a model of obstructive sleep apnea. Hypertension. 2018;72(5):1141–1150. [PubMed]

103 

Sanchez-de-la-Torre M, Khalyfa A, Sanchez-de-la-Torre A, et al. Precision medicine in patients with resistant hypertension and obstructive sleep apnea: blood pressure response to continuous positive airway pressure treatment. J Am Coll Cardiol. 2015;66(9):1023–1032. [PubMed]