Gut Microbiome, Metabolome, and SSBP

Salt‐sensitivity of blood pressure (SSBP), quantified as the change in 24‐hour ambulatorymean arterial pressure (MAP) from one week of high‐salt to one week of low‐salt diet, isan independent predictor of death due to cardiovascular events. SSBP affects nearly 50%of the hypertensive and 25% of the normotensive population. Strong evidence indicatesthat reducing sodium (Na+) intake decreases blood pressure and cardiovascular events,however the precise mechanisms of how dietary Na+ contributes to BP elevation andcardiovascular disease remain unclear. The gut is the first and largest location for Na+absorption. Studies from the investigator's group and others suggest that gut microbiotacontribute to salt‐induced inflammation and hypertension. In preliminary cross‐sectionalanalyses, the investigators found that elevated dietary Na+ alters the human and mousegut microbiome, prompting an increase in Firmicutes and genus Prevotella bacteria. Thesealterations are associated with higher BP and altered metabolites in humans, andpredispose mice to vascular inflammation and hypertension. However, there are limiteddata on the effect of Na+ intervention on gut microbiome composition and function, or onthe contribution of microbiota to SSBP. Thus, the investigators propose deep phenotypingof adult subjects (N=50) enrolled into a SSBP challenge study, coupled with extensivemechanistic interrogation. Briefly, the investigators will quantify SSBP from 24‐hourambulatory BP monitoring in a randomized crossover design, using standardized one weeklow‐ and high‐salt diets. The investigators will collect repeated stool, urine and bloodsamples to determine the relationships between gut microbiota, SSBP, microbial and hostmetabolism, and inflammation in humans, and will conduct mechanistic research using humancells and mice. The investigator's central hypothesis is that elevated Na+ alters the gutmicrobiota and is associated with altered metabolism, inflammation and SSBP. The specificaims are to test the hypotheses that 1) SSBP correlates with Na+‐induced changes in gutmicrobiome composition; 2) Na+‐induced changes in the gut microbiome and SSBP areassociated with altered metabolism and with immune cell activation; and 3) Microbiotafrom humans with SSBP induce inflammation and hypertension in germ‐free mice. Theproposed study examines novel hypotheses regarding the relationship between the gutmicrobiome and SSBP and will allow for comprehensive interrogation of multiplemechanistic pathways. Successful completion of the aims will delineate the role of gutmicrobiota in SSBP, identify microbiota, metabolite and immune cell markers of SSBP, andcould lead to more feasible and cost‐effective microbiome‐based therapy for SSBP.