Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension

Abstract

Rationale: High-salt diet is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt–induced hypertension (hSIH). However, the detailed roles of intestinal flora in hSIH pathogenesis have not yet been fully elucidated. Objective: To reveal the roles and mechanisms of intestinal flora in hSIH development. Methods and Results: The abovementioned issues were investigated using various techniques including 16S rRNA gene sequencing, untargeted metabolomics, selective bacterial culture, and fecal microbiota transplantation. We found that high-salt diet induced hypertension in Wistar rats. The fecal microbiota of healthy rats could dramatically lower blood pressure (BP) of hypertensive rats, whereas the fecal microbiota of hSIH rats had opposite effects. The composition, metabolism, and interrelationship of intestinal flora in hSIH rats were considerably reshaped, including the increased corticosterone level and reduced Bacteroides and arachidonic acid levels, which tightly correlated with BP. The serum corticosterone level was also significantly increased in rats with hSIH. Furthermore, the above abnormalities were confirmed in patients with hypertension. The intestinal Bacteroides fragilis could inhibit the production of intestinal-derived corticosterone induced by high-salt diet through its metabolite arachidonic acid. Conclusions: hSIH could be transferred by fecal microbiota transplantation, indicating the pivotal roles of intestinal flora in hSIH development. High-salt diet reduced the levels of B fragilis and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation. This study revealed a novel mechanism different from inflammation/immunity by which intestinal flora regulated BP, namely intestinal flora could modulate BP by affecting steroid hormone levels. These findings enriched the understanding of the function of intestinal flora and its effects on hypertension.

Implication of Gut Microbiota in Cardiovascular Diseases

“…More recently, a novel mechanism different from inflammation or immunity regulation has been presented. In high salt-induced hypertensive mice, elevated blood pressure is closely related to increased levels of intestinal-derived corticosterone [ 72 ].…”

Effect of Fecal Microbiota Transplantation on Primary Hypertension and the Underlying Mechanism of Gut Microbiome Restoration: Protocol of a Randomized, Double-Blinded, Placebo-Controlled Study

“…Our previous study firstly confirmed that transplants from hypertensive patient feces reshaped the gut microbiota of healthy GF mice and rendered significant BP elevation (9). Of note, modulating intestinal flora via transplantation from healthy rats could dramatically reduce BP in high salt-induced hypertensive animals (12). Oral antibiotics such as minocycline and vancomycin can assist on treatment of hypertension (13).…”

Rationale, protocol and baseline characteristics of the metabolome, microbiome, and dietary salt intervention study (MetaSalt)

“…Moreover, there is strong evidence that changes in the circulating metabolome and intestinal microbiota were closely associated with cardiovascular health status, and microbial and metabolomic profiling can be used to identify the crucial mechanisms responsible for the long-term outcomes [17, 18, 32]. Previous findings also suggested that high sodium intake could promote BP elevation by reducing the arachidonic acid and B fragilis levels in the intestine that could further increase the intestinal-derived corticosterone level in the serum and intestine [33]. However, previous Chinese epidemiologic studies were based on an observational design, which were not able to determine the causal relationship.…”