Protective effects of fermentable dietary fiber and propionate in Dahl salt-sensitive hypertension and renal damage

The Dahl salt-sensitive (SS) rat is an established model of hypertensive kidney injury, where the gut microbiota has been shown to causally contribute to disease progression. Gut bacteria-derived metabolites serve as mechanistic links between the microbiota and disease, with dietary fiber providing a critical source of protective metabolites such as short-chain fatty acids (SCFAs). The current study hypothesized that the substitution of nonfermentable fiber cellulose with the fermentable fiber inulin would attenuate hypertension and renal damage in SS rats via increased circulating SCFAs. Male and female SS rats were placed on the 0.4% NaCl (low-salt, LS) inulin diet for 1 wk before the switch to a 4.0% NaCl (high-salt, HS) inulin diet for 4 wk. Controls were maintained on diets containing cellulose. Rats consuming inulin had a reduction in mean arterial pressure compared with cellulose, though the antihypertensive effect was more robust in females. The inulin diet significantly protected both sexes from albuminuria, medullary protein cast formation, and renal immune cell infiltration, and was associated with specific changes to the fecal microbiota. Assessed by mass spectrometry, inulin consumption resulted in increased circulating propionate and butyrate, and the administration of these SCFAs revealed a protective effect of propionate against salt-sensitive hypertension and kidney damage in males, which coincided with an expansion of renal T regulatory cells. In conclusion, substitution of cellulose for the fermentable fiber inulin lowered blood pressure and significantly attenuated salt-induced renal damage in both sexes, which may be attributed to greater production of the protective, anti-inflammatory SCFA propionate.<b>NEW & NOTEWORTHY</b> The dietary switch to inulin, a fermentable fiber, reduced salt-sensitive hypertension and kidney injury in male and female Dahl SS rats, and caused gut microbiota composition shifts and increases in SCFA production (propionate and butyrate). Direct administration of propionate ameliorated salt-sensitivity in males, which coincided with renal T regulatory cell expansion. These findings provide the mechanistic basis for leveraging the microbiota and its metabolites through dietary interventions as a therapeutic for hypertension and kidney disease.