The Dahl Salt-Sensitive (SS/MCW) rat develops elevated blood pressure, renal damage, and renal immune cell infiltration into the kidney in response to a high salt diet, which importantly parallels observations made in humans with SS hypertension. These rats are bred at the Medical College of Wisconsin (MCW) and are maintained on a purified, casein-based diet. Our recent studies indicate that non-sodium components of the diet, in particular the source of protein, can alter the severity of disease in SS rats. More specifically, SS rats fed a whole grain diet (SS/CRL) or a modified wheat gluten-based diet (SS/WG) have drastically reduced hypertension, renal damage, and renal immune cell infiltration compared to the SS/MCW. However, the precise mechanisms that link the diet to these changes in immunity, and ultimately hypertension, remain unknown. With the ability of the gut microbiota to regulate both nutrition processes and host physiology, the gut microbiota may serve as the potential link between the diet and SS hypertension. The present studies will test the hypothesis that dietary modulation of the Dahl SS gut microbiota profile alters the severity of salt-induced hypertension and renal damage. To test this, three specific aims are proposed. By utilizing 16S rRNA sequencing, AIM 1 will characterize the gut microbiota of Dahl SS rats fed different diets (SS/MCW, SS/CRL, and SS/WG) during low salt (LS, 0.4% NaCl) and after high salt challenge (HS, 4.0% NaCl). AIM 2 will determine causality by employing antibiotic treatment or FMT techniques to test whether gut bacteria directly contribute to the development of Dahl SS hypertension and renal disease. Finally, AIM 3 will explore mechanisms related to intestinal inflammation and the production of microbial secondary metabolites (i.e. short-chain fatty acids) as potential links between diet-induced gut dysbiosis and hypertension. Our exciting preliminary data shows that the gut microbiota drastically shifts in response to these different diets, and initial fecal microbiota transfer (FMT) studies as well as antibiotic therapy experiments suggest that bacteria are directly contributing to disease progression. The studies in this proposal can make new breakthroughs in defining key gut microbiome factors that may initiate the immune system in salt-sensitive hypertension, which may contribute to the development of new, more effective therapies.
|Program type||Career Development Award|
|Effective start/end date||04/01/2019 → 06/30/2022|