This Study Will Look at How Elevated Na+ Alters the Gut Microbiota, Particularly in Salt-sensitive Individuals, and is Associated With Inflammation, Metabolic Changes, and SSBP. The Study Will Examine 50 Individuals Using Randomized Crossover Trial Design.

Salt-sensitivity of blood pressure (SSBP), quantified as the change in 24-hour ambulatory mean arterial pressure (MAP) from one week of high-salt to one week of low-salt diet, is an independent predictor of death due to cardiovascular events. SSBP affects nearly 50% of the hypertensive and 25% of the normotensive population. Strong evidence indicates that reducing sodium (Na+) intake decreases blood pressure and cardiovascular events, however the precise mechanisms of how dietary Na+ contributes to BP elevation and cardiovascular disease remain unclear. The gut is the first and largest location for Na+ absorption. Studies from our group and others suggest that gut microbiota contribute to salt-induced inflammation and hypertension. In preliminary cross-sectional analyses, we found that elevated dietary Na+ alters the human and mouse gut microbiome, prompting an increase in Firmicutes and genus Prevotella bacteria. These alterations are associated with higher BP and altered metabolites in humans, and predispose mice to vascular inflammation and hypertension. However, there are limited data on the effect of Na+ intervention on gut microbiome composition and function, or on the contribution of microbiota to SSBP. Thus, we propose deep phenotyping of adult subjects (N=50) enrolled into a SSBP challenge study, coupled with extensive mechanistic interrogation. Briefly, we will quantify SSBP from 24-hour ambulatory BP monitoring in a randomized crossover design, using standardized one week low- and high-salt diets. We will collect repeated stool, urine and blood samples to determine the relationships between gut microbiota, SSBP, microbial and host metabolism, and inflammation in humans, and will conduct mechanistic research using human cells and mice. Our central hypothesis is that elevated Na+ alters the gut microbiota and is associated with altered metabolism, inflammation and SSBP. Our specific aims are to test the hypotheses that 1) SSBP correlates with Na+-induced changes in gut microbiome composition; 2) Na+-induced changes in the gut microbiome and SSBP are associated with altered metabolism and with immune cell activation; and 3) Microbiota from humans with SSBP induce inflammation and hypertension in germ-free mice. The proposed study examines novel hypotheses regarding the relationship between the gut microbiome and SSBP and will allow for comprehensive interrogation of multiple mechanistic pathways. Successful completion of the aims will delineate the role of gut microbiota in SSBP, identify microbiota, metabolite and immune cell markers of SSBP, and could lead to more feasible and cost-effective microbiome-based therapy for SSBP.

Inclusion criteria

• Age ≥ 50 years and ≤ 70 years.
• Omnivore.
• Willing to adhere to the study protocol.
• Able to provide written consent.

Exclusion criteria

• Unwilling to make dietary changes or otherwise adhere to the study protocol.
• Contraindications to high- or low-salt diet (e.g. heart, renal, or liver failure, postural orthostatic tachycardia syndrome)
• Use of salt tabs, fludricortisone, or midodrine.
• Contraindications to 24-hour ambulatory blood pressure monitoring, e.g. bilateral upper extremity lymphedema.
• Medical contraindications to foods, e.g. celiac disease, nut allergy, egg allergy, etc.
• Systolic blood pressure < 90 or > 160 mm Hg or diastolic blood pressure < 50 or > 100 mm Hg at screening
• Current use of anti-hypertensive medications
• Current use of oral steroids, daily NSAIDS, anti-inflammatory or immune modulating medications, probiotics, or antibiotics.
• Rheumatologic condition (e.g. Lupus, Rheumatoid Arthritis, Psoriatic arthritis, Inflammatory Bowel Disease, Multiple Sclerosis).
• Presence of acute or chronic medical conditions not generalizable to the general population (including eating disorders, cancer, severe mental illness, cognitive impairment, pregnancy or lactation).