Dietary Nitrate influences Akkermansia-dependent Atherogenic Metabolites through the Enteral Microbiome – Results from a Randomized Controlled Trial

Background

Dietary nitrate, commonly found in leafy vegetables, offers cardiovascular benefits, often mediated by nitric oxide pathways. The enteral microbiome plays a critical role in cardiovascular health. However, the influence of nitrate on specific gut bacteria like Akkermansia, which is linked to cardioprotective and anti-inflammatory effects, is less understood. Akkermansia plays a role in regulating metabolites such as trimethylamine N-oxide (TMAO), a proatherogenic compound, yet its response to chronic nitrate intake remains largely unexplored.

Purpose

This study aimed to evaluate the effect of dietary nitrate intake on the composition of the enteral microbiome and levels of atherosclerosis-associated metabolites in a healthy population.

Methods

We recruited a group of 30 healthy patients who were divided into two cohorts. For 30 days, one cohort received dietary nitrate (0, 12 mmol/kg bodyweight) while the other cohort received equimolar dietary sodium chloride as a placebo.

We collected blood and stool samples at baseline and after 30 days. 16S-rRNA was sequenced from stool samples to analyse microbiome composition, with special regards to Akkermansia and Akkermansia-dependent metabolites such as SCFAs and TMAO in serum samples at baseline and follow-up.

Results

We detected a distinct regulation in enteral microbiome composition after dietary nitrate supplementation with increased abundance of the gram negative bacteria Akkermansia and Verrucomicrobia, which are associated with higher TMA levels. Notably, Akkermansia was more abundant in participants with elevated TMAO levels, suggesting a possible compensatory response. Microbiome diversity remained stable, while nitrate intake also reduced systolic blood pressure. There was no significant difference between the two groups after nitrate and placebo supplementation in the shannon diversity (p > 0.05).

Conclusions

These results suggest that dietary nitrate intake promotes Akkermansia growth, possibly influencing atherogenic metabolites like TMAO. Future research should explore Akkermansia's role in the nitrate-TMAO pathway to assess its therapeutic potential for cardiovascular health.