Dataset Information

Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction.

ABSTRACT:

Background

The gut microbiome is essential for physiological host responses and development of immune functions. The impact of gut microbiota on blood pressure and systemic vascular function, processes that are determined by immune cell function, is unknown.

Methods and results

Unchallenged germ-free mice (GF) had a dampened systemic T helper cell type 1 skewing compared to conventionally raised (CONV-R) mice. Colonization of GF mice with regular gut microbiota induced lymphoid mRNA transcription of T-box expression in T cells and resulted in mild endothelial dysfunction. Compared to CONV-R mice, angiotensin II (AngII; 1 mg/kg per day for 7 days) infused GF mice showed reduced reactive oxygen species formation in the vasculature, attenuated vascular mRNA expression of monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS) and NADPH oxidase subunit Nox2, as well as a reduced upregulation of retinoic-acid receptor-related orphan receptor gamma t (Ror?t), the signature transcription factor for interleukin (IL)-17 synthesis. This resulted in an attenuated vascular leukocyte adhesion, less infiltration of Ly6G(+) neutrophils and Ly6C(+) monocytes into the aortic vessel wall, protection from kidney inflammation, as well as endothelial dysfunction and attenuation of blood pressure increase in response to AngII. Importantly, cardiac inflammation, fibrosis and systolic dysfunction were attenuated in GF mice, indicating systemic protection from cardiovascular inflammatory stress induced by AngII.

Conclusion

Gut microbiota facilitate AngII-induced vascular dysfunction and hypertension, at least in part, by supporting an MCP-1/IL-17 driven vascular immune cell infiltration and inflammation.

SUBMITTER: Karbach SH

PROVIDER: S-EPMC5079031 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction.

Karbach Susanne H SH Schönfelder Tanja T Brandão Ines I Wilms Eivor E Hörmann Nives N Jäckel Sven S Schüler Rebecca R Finger Stefanie S Knorr Maike M Lagrange Jeremy J Brandt Moritz M Waisman Ari A Kossmann Sabine S Schäfer Katrin K Münzel Thomas T Reinhardt Christoph C Wenzel Philip P

Journal of the American Heart Association 20160830 9

<h4>Background</h4>The gut microbiome is essential for physiological host responses and development of immune functions. The impact of gut microbiota on blood pressure and systemic vascular function, processes that are determined by immune cell function, is unknown.<h4>Methods and results</h4>Unchallenged germ-free mice (GF) had a dampened systemic T helper cell type 1 skewing compared to conventionally raised (CONV-R) mice. Colonization of GF mice with regular gut microbiota induced lymphoid mR ...[more]

PMID: 27577581

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Project description:RATIONALE:Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension, 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 hypertension. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in hypertension. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3)-a derivative of tetracycline that has potent anti-inflammatory activity-to address this question. OBJECTIVE: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 hypertension-associated pathology, and attenuate hypertension. METHODS AND RESULTS:Rats were implanted with radiotelemetry devices for recording mean arterial pressure. Ang II (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also investigated in SHR (spontaneously hypertensive rats). Physiological, pathological, immunohistological parameters, and fecal microbiota were analyzed. Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in number of microglia, their activation, and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 attenuated increased mean arterial pressure, normalized sympathetic activity, and left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by Ang II and attenuated pathological alterations in gut wall. CONCLUSIONS: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 hypertension.

Dataset Information

Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction.

Background

Methods and results

Conclusion

Publications

Gut Microbiota Promote Angiotensin II-Induced Arterial Hypertension and Vascular Dysfunction.

Similar Datasets

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