Salt-Responsive Gut Microbiota Induces Sex-Specific Blood Pressure Changes

Area of Science:

• Microbiology
• Physiology
• Genetics

Background:

• Tryptophan metabolism, particularly the tryptophan-indole pathway, is crucial for blood pressure regulation and is mediated by gut microbiota.
• Angiotensin-converting enzyme 2 (ACE2) influences tryptophan absorption and gut microbiota composition, with ACE2 deficiency altering microbial communities.
• Sex differences in gut microbiota are known, but their impact on blood pressure via the tryptophan-indole pathway remains unclear.

Purpose of the Study:

• To investigate the sex-specific mechanisms by which gut microbiota-mediated tryptophan-indole pathway influences hypertension.
• To establish a novel rat model for studying these sex-specific effects.

Main Methods:

• Generated a novel rat model using CRISPR-Cas9 to delete Ace2 in Dahl salt-sensitive rats.
• Performed cecal microbiota transfers from donors of both sexes to female recipients.
• Administered indole orally to rats of both sexes to assess blood pressure response.

Main Results:

• Female gut microbiota showed greater resilience to tryptophan, Ace2 deficiency, and salt compared to male gut microbiota.
• Female rats receiving male cecal microbiota exhibited a greater blood pressure increase in response to salt.
• Indole elevated blood pressure in males but not females; salt altered host tryptophan metabolism, reducing serotonin and increasing kynurenine derivatives in females.

Conclusions:

• A novel sex-specific mechanism in gut microbiota-mediated tryptophan metabolism impacts blood pressure regulation.
• Salt differentially affects host-gut microbiota tryptophan metabolism in a sex-dependent manner.
• Gut microbiota and its metabolism play distinct sex-specific roles in the development of salt-sensitive hypertension.