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.