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J Am Heart Assoc ; 9(2): e014373, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31928175


Background Pediatric hypertension is recognized as an emerging global health concern. Although new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. Genetics and environmental factors do not fully account for the growing incidence of pediatric hypertension. Because stable bacterial flora in early life are linked with health outcomes later in life, we hypothesized that reshaping of gut microbiota in early life affects blood pressure (BP) of pediatric subjects. Methods and Results To test this hypothesis, we administered amoxicillin, the most commonly prescribed pediatric antibiotic, to alter gut microbiota of young, genetically hypertensive rats (study 1) and dams during gestation and lactation (study 2) and recorded their BP. Reshaping of microbiota with reductions in Firmicutes/Bacteriodetes ratio were observed. Amoxicillin treated rats had lower BP compared with untreated rats. In young rats treated with amoxicillin, the lowering effect on BP persisted even after antibiotics were discontinued. Similarly, offspring from dams treated with amoxicillin showed lower systolic BP compared with control rats. Remarkably, in all cases, a decrease in BP was associated with lowering of Veillonellaceae, which are succinate-producing bacteria. Elevated plasma succinate is reported in hypertension. Accordingly, serum succinate was measured and found lower in animals treated with amoxicillin. Conclusions Our results demonstrate a direct correlation between succinate-producing gut microbiota and early development of hypertension and indicate that reshaping gut microbiota, especially by depleting succinate-producing microbiota early in life, may have long-term benefits for hypertension-prone individuals.

Vascul Pharmacol ; 125-126: 106633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31843471


Commensal microbiota within a holobiont contribute to the overall health of the host via mutualistic symbiosis. Disturbances in such symbiosis is prominently correlated with a variety of diseases affecting the modern society of humans including cardiovascular diseases, which are the number one contributors to human mortality. Given that a hallmark of all cardiovascular diseases is changes in vascular function, we hypothesized that depleting microbiota from a holobiont would induce vascular dysfunction. To test this hypothesis, young mice of both sexes raised in germ-free conditions were examined vascular contractility and structure. Here we observed that male and female germ-free mice presented a decrease in contraction of resistance arteries. These changes were more pronounced in germ-free males than in germ-free females mice. Furthermore, there was a distinct change in vascular remodeling between males and females germ-free mice. Resistance arteries from male germ-free mice demonstrated increased vascular stiffness, as shown by the leftward shift in the stress-strain curve and inward hypotrophic remodeling, a characteristic of chronic reduction in blood flow. On the other hand, resistance arteries from germ-free female mice were similar in the stress-strain curves to that of conventionally raised mice, but were distinctly different and showed outward hypertrophic remodeling, a characteristic seen in aging. Interestingly, we observed that reactive oxygen species (ROS) generation from bone marrow derived neutrophils is blunted in female germ-free mice, but it is exacerbated in male germ-free mice. In conclusion, these observations indicate that commensal microbiota of a holobiont are central to maintain proper vascular function and structure homeostasis, especially in males.

Cell Rep ; 25(3): 677-689.e4, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332647


Dietary salt reduction and exercise are lifestyle modifications for salt-sensitive hypertensives. While exercise has prominent metabolic effects, salt has an adverse effect on metabolic syndrome, of which hypertension is a hallmark. We hypothesized that dietary salt impacts metabolism in a salt-sensitive model of hypertension. An untargeted metabolomic approach demonstrates lower circulating levels of the ketone body, beta-hydroxybutyrate (ßOHB), in high salt-fed hypertensive rats. Despite the high salt intake, specific rescue of ßOHB levels by nutritional supplementation of its precursor, 1,3-butanediol, attenuates hypertension and protects kidney function. This beneficial effect of ßOHB was likely independent of gut-microbiotal and Th17-mediated effects of salt and instead facilitated by ßOHB inhibiting the renal Nlrp3 inflammasome. The juxtaposed effects of dietary salt and exercise on salt-sensitive hypertension, which decrease and increase ßOHB respectively, indicate that nutritional supplementation of a precursor of ßOHB provides a similar benefit to salt-sensitive hypertension as exercise.

Ácido 3-Hidroxibutírico/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hipertensão/prevenção & controle , Inflamassomos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cloreto de Sódio na Dieta/toxicidade , Ácido 3-Hidroxibutírico/administração & dosagem , Animais , Pressão Sanguínea , Aromatizantes/toxicidade , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Masculino , Ratos , Ratos Endogâmicos Dahl
Physiology (Bethesda) ; 32(3): 224-233, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28404738


Hypertension, or elevated blood pressure (BP), has been extensively researched over decades and clearly demonstrated to be caused due to a combination of host genetic and environmental factors. Although much research remains to be conducted to pin-point the precise genetic elements on the host genome that control BP, new lines of evidence are emerging to indicate that, besides the host genome, the genomes of all indigenous commensal micro-organisms, collectively referred to as the microbial metagenome or microbiome, are important, but largely understudied, determinants of BP. Unlike the rigid host genome, the microbiome or the "second genome" can be altered by diet or microbiotal transplantation in the host. This possibility is attractive from the perspective of exploiting the microbiotal composition for clinical management of inherited hypertension. Thus, focusing on the limited current literature supporting a role for the microbiome in BP regulation, this review highlights the need to further explore the role of the co-existence of host and the microbiota as an organized biological unit called the "holobiont" in the context of BP regulation.

Hipertensão/genética , Hipertensão/microbiologia , Metagenoma , Microbiota , Animais , Humanos , Camundongos