UC San Diego

Obesity is an established risk factor for hypertension. Building upon the known fact that obesity-induced gut barrier breach leads to the leakage of various microbiota-derived products into host circulation and distal organs, this study seeks to explore impacts of microbial DNA enrichment on inducing obesity-related adrenomedullary abnormalities and hypertension. CRIg (Complement receptor of the immunoglobulin superfamily) abundance is identified as a major factor in blocking the infiltration of gut mEVs (microbial DNAcontaining extracellular vesicles) into the bloodstream and adrenal glands. In lean CRIg-/- or C3-/- mice intravenously injected with gut mEVs, adrenal microbial DNA accumulation elevated adrenal inflammation and norepinephrine secretion, concomitant with hypertension. In addition, microbial DNAs promoted inflammatory responses and norepinephrine production in PC12 cells treated with gut mEVs. Depletion of microbial DNA cargos markedly blunted the effects of gut mEVs. We also validated that activation of cGAS/STING signaling is required for the ability of microbial DNAs 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. The leakage of gut mEVs leads to adrenal enrichment of microbial DNAs that are pathogenic to induce obesityassociated adrenomedullary abnormalities and hypertension. Recovering CRIg+ macrophage population attenuate obesity-induced adrenomedullary disorders.