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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.

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
Hypertension ; 72(5): 1125-1132, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354811


G-protein-coupled estrogen receptor, Gper1, has been implicated in cardiovascular disease, but its mechanistic role in blood pressure control is poorly understood. Here, we demonstrate that genetically salt-sensitive hypertensive rats with complete genomic excision of Gper1 by a multiplexed guide RNA CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated proteins) approach present with lower blood pressure, which was accompanied by altered microbiota, different levels of circulating short chain fatty acids, and improved vascular relaxation. Microbiotal transplantation from hypertensive Gper1+/+ rats reversed the cardiovascular protective effect exerted by the genomic deletion of Gper1. Thus, this study reveals a role for Gper1 in promoting microbiotal alterations that contribute to cardiovascular pathology. However, the exact mechanism by which Gper1 regulates blood pressure is still unknown. Our results indicate that the function of Gper1 is contextually dependent on the microbiome, whereby, contemplation of using Gper1 as a target for therapy of cardiovascular disease requires caution.

Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Hipertensão/fisiopatologia , Receptores Acoplados a Proteínas-G/genética , Animais , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , RNA Guia , 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