Metabolite Biomarkers Linking a High-Fiber Rye Intervention with Cardiometabolic Risk Factors: The RyeWeight Study

Wholegrain rye, considered one of the cereals with the highest content of dietary fiber and bioactive compounds, has been linked with reduced risk of cardiometabolic diseases. Thus, biomarkers reflecting its intake and/or the metabolic effect after consumption are essential to better elucidate its health effects. Our aim was to identify plasma metabolite biomarkers associated with a high-fiber rye intervention and to assess the associations between these metabolites, gut microbiota composition, and cardiometabolic risk factors in a 12-week randomized controlled trial comparing a hypocaloric diet with high-fiber rye (n = 108) or refined wheat (n = 99) in participants with obesity. Rye intervention increased plasma concentrations of benzoxazinoids (DIBOA-S) and phenylacetamides (2-HPA-S and 2-HHPA-S), gut microbial metabolites (indolepropionic acid, 2-aminophenol, enterolactone sulfate, and enterolactone glucuronide), betainized compounds (pipecolic-betaine), phenolic acids (2,6-DHBA and gallic acid-4-sulfate), and diverse endogenous metabolites. Microbiota composition changes were increased Eubacterium xylanophilum and Agathobacter and decreased Ruminococcus torques and Romboutsia. Moreover, the intervention effect was mostly captured by changes in metabolites and gut microbiota compared to clinical variables. Gallic acid-4-sulfate and phenylacetamides were associated with reductions in weight, fat mass, BMI, or fasting insulin levels even after adjusting for plasma alkylresorcinols, used as markers for rye intake compliance. Altogether, these metabolites may constitute biomarkers of wholegrain rye cardiometabolic effects.