Bacterial Extracellular Vesicles Mediate Microbiota-Host Communication to Regulate Blood Pressure in Male Rats.

Abstract

BACKGROUND: Altered gut microbiota composition has been implicated in the development of hypertension. Evidence suggests bacterial products and metabolites can enter circulation, act on peripheral tissues, and modulate blood pressure (BP). We identified extracellular vesicles (EVs) of bacterial origin (bacterial extracellular vesicles [bEVs]) in the circulation of spontaneously hypertensive stroke-prone rats (SHRSP). We hypothesized that bEVs mediate communication between microbiota and the host, and that bEVs from SHRSP microbiota contain unique cargo that promotes hypertension. METHODS: EVs were isolated from plasma and cecal content of SHRSP and Wistar-Kyoto (WKY) rats. Multiomics analysis, including 16S rRNA sequencing, small RNA sequencing, lipidomics, and proteomics were performed to assess the cargo of bEVs. BEVs from WKY and SHRSP were transplanted by oral gavage to WKY and SHRSP recipients, and the effects on BP and sympathetic activity were monitored. The potential role of bEVs on BP was also evaluated in Dahl salt sensitive (S) and obstructive sleep apnea models of hypertension. RESULTS: Significant differences were observed in WKY and SHRSP bEV cargo, including small RNAs, proteins, and PAMPs (pathogen-associated molecular patterns). Transplantation of SHRSP bEVs to WKY rats increased renal sympathetic nerve activity and elevated BP. Moreover, we showed that bEVs influence BP regulation in Dahl S and obstructive sleep apnea-induced hypertension. CONCLUSIONS: Our findings position bEVs as critical mediators of microbiota-host communication in BP regulation and demonstrate that bEVs from the altered SHRSP microbiota promote hypertension. Our findings shed new light on the role of bEVs in hypertension pathogenesis and offer new perspectives for diagnostics and therapeutic interventions.