Increasing plant protein in the diet induces changes in the plasma metabolome that may be beneficial for metabolic health. A randomized crossover study in males

BACKGROUND & AIM: Dietary shifts replacing animal protein (AP) with plant protein (PP) sources have been associated with lowering cardiometabolic risk (CMR), but underlying mechanisms are poorly characterized. This nutritional intervention aims to characterize the metabolic changes induced by diets containing different proportions of AP and PP sources in males at CMR. DESIGN: This study is a 4-week, crossover, randomized, controlled-feeding trial in which 19 males with CMR followed two diets providing either 36 % for the control diet (CON-D) or 64 % for the flexitarian diet (FLEX-D) of total protein intake from PP sources. Plasma nontargeted metabolomes (LC-MS method) were measured in the fasted state and after a high-fat challenge meal at the end of each intervention arm. Lipogenesis and protein synthesis fluxes, flow-mediated dilatation (FMD) and gluco-lipidic responses were assessed after the challenge meal. Data were analyzed with mixed models, and univariate and multivariate models for metabolomics data. RESULTS: In both arms CMR improved with time, with decreased body weight (-0.9 %), insulin resistant (-34 %, HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) and low-density lipoproteins (LDL)-cholesterol (-11 %). Diet had no effect on FMD or metabolic fluxes, but a trend (0.05 <p ≤ 0.1) was observed for a stronger decrease in HOMA-IR and lower postprandial glucose after FLEX-D vs CON-D. The abundance of 21 and 37 metabolites differed between diets at fasted and fed states, respectively, including food intake biomarkers of AP (methylhistidine, eicosapentaenoic acid, hydroxyprolines) and PP sources (trigonelline, N-acetyl-ornithine). In fasted or fed states, indole acrylic acid and indole propionic acid, both products of tryptophan catabolism, were higher after FLEX-D vs CON-D, while the indispensable amino acids-related metabolites alpha-aminoadipic acid, hydroxymethylbutyric acids and propionylcarnitine were lower. In the postprandial state only, the ω-oxidation products dodecanedioic, tetradecanedioic and hexadecanedioic acids were higher after FLEX-D vs CON-D. CONCLUSIONS: Despite little changes in risk factors after 4 wk, this study evidenced subtle metabolic adaptations in amino acids and lipid metabolism and gut microbiota activity occurring after higher PP source intake that may be beneficial to CMR. GOV STUDY IDENTIFIER: NCT04236518. CLINICAL TRIAL REGISTRY: NCT04236518 on ClinicalTrials.gov.