Restructuring the Gut Microbiota by Intermittent Fasting Lowers Blood Pressure

Abstract

Rationale: In recent years, it has been demonstrated that a pathological change in the gut microbiota, termed gut dysbiosis, can be an underlying factor for the development of hypertension. Prevention of this dysbiosis can attenuate or abolish hypertension. Translational mechanisms to prevent gut dysbiosis as well as understanding of the mechanisms linking gut dysbiosis to hypertension are lacking. Objective: We first examined the efficacy of intermittent fasting (IF) in altering the gut microbiota and lowering blood pressure (BP). Next, we utilized a multi-omics approach to examine microbial influenced metabolites that may serve as the link between the gut microbiota and host BP regulation. Methods and Results: We demonstrate that IF significantly altered the makeup of the gut microbiota, cecal and plasma metabolome, and prevented the development of hypertension in the spontaneously hypertensive stroke-prone rat. The beneficial effects of IF were shown to be due to alterations of the gut microbiota through germ-free transplantation studies. Germ-free rats receiving microbiota from IF spontaneously hypertensive stroke-prone rat had significantly lower BP as compared with germ-free rats receiving microbiota from ad libitum fed spontaneously hypertensive stroke-prone rats. Through whole genome shotgun sequence analysis of the microbiota and untargeted metabolomics of cecal content and plasma, we identified bile acid metabolism as a potential mediator in BP regulation. Finally, we show supplementation with cholic acid, or activation of the G protein-coupled bile acid receptor (TGR5), significantly reduced BP of the spontaneously hypertensive stroke-prone rats. Conclusions: These studies demonstrate the BP-lowering effects of IF involves manipulation of the gut microbiota and metabolome and implicate disrupted bile acid signaling as novel mechanisms by which gut dysbiosis contributes to hypertension.