Microbial DNA Enrichment Promotes Adrenomedullary Inflammation, Catecholamine Secretion, and Hypertension in Obese Mice.
Hong GaoZhongmou JinKechun TangYudong JiJorge SuarezJorge A SuarezKarina Cunha E RochaDinghong ZhangWolfgang H DillmannSushil K MahataWei YingPublished in: Journal of the American Heart Association (2022)
Background Obesity is an established risk factor for hypertension. Although obesity-induced gut barrier breach leads to the leakage of various microbiota-derived products into host circulation and distal organs, the roles of microbiota in mediating the development of obesity-associated adrenomedullary disorders and hypertension have not been elucidated. We seek to explore the impacts of microbial DNA enrichment on inducing obesity-related adrenomedullary abnormalities and hypertension. Methods and Results Obesity was accompanied by remarkable bacterial DNA accumulation and elevated inflammation in the adrenal glands. Gut microbial DNA containing extracellular vesicles (mEVs) were readily leaked into the bloodstream and infiltrated into the adrenal glands in obese mice, causing microbial DNA enrichment. In lean wild-type mice, adrenal macrophages expressed CRIg (complement receptor of the immunoglobulin superfamily) that efficiently blocks the infiltration of gut mEVs. In contrast, the adrenal CRIg+ cell population was greatly decreased in obese mice. In lean CRIg -/- or C3 -/- (complement component 3) mice intravenously injected with gut mEVs, adrenal microbial DNA accumulation elevated adrenal inflammation and norepinephrine secretion, concomitant with hypertension. In addition, microbial DNA promoted inflammatory responses and norepinephrine production in rat pheochromocytoma PC12 cells treated with gut mEVs. Depletion of microbial DNA cargo markedly blunted the effects of gut mEVs. We also validated that activation of cGAS (cyclic GMP-AMP synthase)/STING (cyclic GMP-AMP receptor stimulator of interferon genes) signaling is required for the ability of microbial DNA to trigger adrenomedullary dysfunctions in both in vivo and in vitro experiments. Restoring CRIg+ cells in obese mice decreased microbial DNA abundance, inflammation, and hypertension. Conclusions The leakage of gut mEVs leads to adrenal enrichment of microbial DNA that are pathogenic to induce obesity-associated adrenomedullary abnormalities and hypertension. Recovering the CRIg+ macrophage population attenuates obesity-induced adrenomedullary disorders.
Keyphrases
- circulating tumor
- cell free
- microbial community
- blood pressure
- single molecule
- insulin resistance
- high fat diet induced
- metabolic syndrome
- weight loss
- type diabetes
- oxidative stress
- weight gain
- adipose tissue
- stem cells
- magnetic resonance
- skeletal muscle
- body mass index
- circulating tumor cells
- multidrug resistant
- immune response
- signaling pathway
- dendritic cells
- staphylococcus aureus
- wild type
- physical activity
- cell death
- cell therapy
- high glucose
- mesenchymal stem cells
- computed tomography
- escherichia coli
- induced apoptosis
- gram negative
- protein kinase
- biofilm formation
- klebsiella pneumoniae
- genome wide analysis
- stress induced