Restructuring the Gut Microbiota by Intermittent Fasting Lowers Blood Pressure

Abstract

Studies have demonstrated that disruption of the gut microbiota, termed gut dysbiosis, plays a causal role in the development of hypertension (HT) in animal models and patients. Prevention of this dysbiosis can attenuate or abolish HT. Translational mechanisms to prevent gut dysbiosis as well as an understanding of the mechanisms linking gut dysbiosis to HT are lacking. Recent studies revealed that intermittent fasting alters the gut microbiota and the production of microbial metabolites. Thus, we hypothesized that every-other-day-fasting (EODF) would prevent elevations of blood pressure (BP) in the spontaneously hypertensive stroke prone rat (SHRSP) by maintaining a healthy gut microbiota. Five-week old SHRSP rats and normotensive Wistar Kyoto (WKY) rats were randomized to be fed ad lib or on EODF for 10 weeks. BP was measured weekly, and cecal content and plasma were collected at the end of the study. To examine the roles of gut microbiota and microbial metabolites in HT, we performed whole-genome shotgun sequencing on cecal samples and non-targeted metabolomics on cecal contents and plasma. We found that ten-weeks EODF was able to prevent elevations of systolic BP (SBP) in SHRSP compared to ad lib fed SHRSP (~220 vs. ~170 mmHg; n=6-8, p<0.05). Principle coordinate analysis showed that EODF significantly altered the overall composition of both WKY and SHRSP microbiota (WKY p<0.01, SHRSP p<0.009). Multi-omics analysis indicates distinct microbiome and metabolome in SHRSP compared to WKY, and significant alterations to each induced by EODF. To examine the direct effects of the EODF altered microbiota on BP regulation and eliminate the confounding variable of fasting, pooled cecal contents of SHRSP and WKY animals fed ad lib or EODF were given to germ-free (GF) rats by oral gavage. GF rats transplanted with SHRSP ad lib microbiota had a significantly higher SBP as compared to those transplanted with SHRSP EODF microbiota (~152 vs. ~140 mmHg; n=6-7, p<0.01), indicating that microbiota and their metabolites are accountable for the effects of EODF. These findings suggest that EODF is able to prevent HT in SHRSP, and this involves altering the gut microbiota and metabolome.