SCOPE: The plasma metabolomics profiles of protein intake have been rarely investigated. The aim is to identify the distinct plasma metabolomics profiles associated with overall intakes of protein as well as with intakes from animal and plant protein sources.

METHODS AND RESULTS: A cross-sectional analysis using data from 1833 participants at high risk of cardiovascular disease is conducted. Associations between 385 identified metabolites and the intake of total, animal protein (AP), and plant protein (PP), and plant-to-animal ratio (PR) are assessed using elastic net continuous regression analyses. A double 10-cross-validation (CV) procedure is used and Pearson correlations coefficients between multi-metabolite weighted models and reported protein intake in each pair of training-validation datasets are calculated. A wide set of metabolites is consistently associated with each protein source evaluated. These metabolites mainly consisted of amino acids and their derivatives, acylcarnitines, different organic acids, and lipid species. Few metabolites overlapped among protein sources (i.e., C14:0 SM, C20:4 carnitine, GABA, and allantoin) but none of them toward the same direction. Regarding AP and PP approaches, C20:4 carnitine and dimethylglycine are positively associated with PP but negatively associated with AP. However, allantoin, C14:0 SM, C38:7 PE plasmalogen, GABA, metronidazole, and trigonelline (N-methylnicotinate) behave contrarily. Ten-CV Pearson correlation coefficients between self-reported protein intake and plasma metabolomics profiles range from 0.21 for PR to 0.32 for total protein.

CONCLUSIONS: Different sets of metabolites are associated with total, animal, and plant protein intake. Further studies are needed to assess the contribution of these metabolites in protein biomarkers' discovery and prediction of cardiometabolic alterations.