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      Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension

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          Abstract

          Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension (HTN) and their inhibition by minocycline, an anti-inflammatory antibiotic, produces beneficial effects. These observations led us to propose a dysfunctional brain-gut communication hypothesis for HTN. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in HTN. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3), a derivative of tetracycline that has potent anti-inflammatory activity, to address this question. Test the hypothesis that central administration of CMT-3 would inhibit microglial activation, attenuate neuroinflammation, alter selective gut microbial communities, protect the gut wall from developing HTN-associated pathology, and attenuate HTN. Rats were implanted with radio-telemetry devices for recording mean arterial pressure (MAP). Angiotensin II (AngII) was infused subcutaneously using osmotic mini-pumps to induce HTN. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly (ICV). ICV CMT- 3 infusion was also investigated in spontaneously hypertensive rats (SHR). Physiological, pathological, immuno-histological parameters, and fecal microbiota were analyzed. ICV CMT-3 significantly inhibited AngII-induced increases in number of microglia, their activation and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, ICV CMT-3 attenuated increased MAP, normalized sympathetic activity and left ventricular hypertrophy in AngII-rats as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by AngII and attenuated pathological alterations in gut wall. These observations demonstrate that inhibition of microglial activation alone was sufficient to induce significant antihypertensive effects. This was associated with unique changes in gut microbial communities and profound attenuation of gut pathology. They suggest, for the first time, a link between microglia and certain microbial communities that may have implications for treatment of HTN.

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          Most cited references28

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          The gut microbiota and inflammatory bowel disease

          Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut. Although the precise cause of IBD remains unknown, the most accepted hypothesis of IBD pathogenesis to date is that an aberrant immune response against the gut microbiota is triggered by environmental factors in a genetically susceptible host. The advancement of next-generation sequencing technology has enabled identification of various alterations of the gut microbiota composition in IBD. While some results related to dysbiosis in IBD are different between studies owing to variations of sample type, method of investigation, patient profiles, and medication, the most consistent observation in IBD is reduced bacterial diversity, a decrease of Firmicutes, and an increase of Proteobacteria. It has not yet been established how dysbiosis contributes to intestinal inflammation. Many of the known IBD susceptibility genes are associated with recognition and processing of bacteria, which is consistent with a role of the gut microbiota in the pathogenesis of IBD. A number of trials have shown that therapies correcting dysbiosis, including fecal microbiota transplantation and probiotics, are promising in IBD.
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            Alterations of the Gut Microbiome in Hypertension

            Introduction: Human gut microbiota is believed to be directly or indirectly involved in cardiovascular diseases and hypertension. However, the identification and functional status of the hypertension-related gut microbe(s) have not yet been surveyed in a comprehensive manner. Methods: Here we characterized the gut microbiome in hypertension status by comparing fecal samples of 60 patients with primary hypertension and 60 gender-, age-, and body weight-matched healthy controls based on whole-metagenome shotgun sequencing. Results: Hypertension implicated a remarkable gut dysbiosis with significant reduction in within-sample diversity and shift in microbial composition. Metagenome-wide association study (MGWAS) revealed 53,953 microbial genes that differ in distribution between the patients and healthy controls (false discovery rate, 0.05) and can be grouped into 68 clusters representing bacterial species. Opportunistic pathogenic taxa, such as, Klebsiella spp., Streptococcus spp., and Parabacteroides merdae were frequently distributed in hypertensive gut microbiome, whereas the short-chain fatty acid producer, such as, Roseburia spp. and Faecalibacterium prausnitzii, were higher in controls. The number of hypertension-associated species also showed stronger correlation to the severity of disease. Functionally, the hypertensive gut microbiome exhibited higher membrane transport, lipopolysaccharide biosynthesis and steroid degradation, while in controls the metabolism of amino acid, cofactors and vitamins was found to be higher. We further provided the microbial markers for disease discrimination and achieved an area under the receiver operator characteristic curve (AUC) of 0.78, demonstrating the potential of gut microbiota in prediction of hypertension. Conclusion: These findings represent specific alterations in microbial diversity, genes, species and functions of the hypertensive gut microbiome. Further studies on the causality relationship between hypertension and gut microbiota will offer new prospects for treating and preventing the hypertension and its associated diseases.
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              Oscillospira and related bacteria - From metagenomic species to metabolic features.

              Oscillospira is an under-studied anaerobic bacterial genus from Clostridial cluster IV that has resisted cultivation for over a century since the first time it was observed. In recent years its 16S rRNA gene was identified in several human gut microbiota studies where it was often associated with interesting traits, especially leanness. However, very little is known about its metabolism or physiology. Here we used nearly complete genomes derived from shot-gun metagenomic data from the human gut to analyze Oscillospira and related bacteria. We used sequence similarity, gene neighbourhood information and manual metabolic pathway curation to decipher key metabolic features of this intriguing bacterial genus. We infer that Oscillospira species are butyrate producers, and at least some of them have the ability to utilize glucuronate, a common animal-derived sugar that is both produced by the human host and consumed by that host in diets rich in animal products. These findings could help explain diet-related inter-individual variation in faecal Oscillospira levels as well as the observation that the presence of this genus is reduced in diseases that involve inflammation.
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                Author and article information

                Journal
                Circulation Research
                Circ Res
                Ovid Technologies (Wolters Kluwer Health)
                0009-7330
                1524-4571
                March 2019
                March 2019
                : 124
                : 5
                : 727-736
                Affiliations
                [1 ]From the Department of Physiology and Functional Genomics (R.K.S., T.Y., A.C.O., G.O.L., V.A., S.K., E.M.R., C.S., M.K.R.), College of Medicine, University of Florida, Gainesville.
                [2 ]Department of Medicine (C.J.P.), College of Medicine, University of Florida, Gainesville.
                Article
                10.1161/CIRCRESAHA.118.313882
                6395495
                30612527
                105e50ca-c1e0-4952-a5ed-83c500936c53
                © 2019
                History

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