Metabolomic patterns of dietary protein intake and their link to cardiometabolic risk: systematic review and meta-analysis

Dietary protein is a key macronutrient influencing cardiometabolic health, but metabolomic mechanisms linking protein quantity and source to cardiometabolic risk factors (CRFs) remain unclear. This study aimed to characterize metabolomic responses to dietary protein quantity and source and examine their associations with changes in CRFs. A systematic review and meta-analysis of human randomized controlled trials comparing higher versus lower protein intake, or animal versus plant protein consumption, was conducted. Metabolomic and CRF outcomes were synthesized using MetaboAnalyst 6.0 and amanida R package, with study quality assessed using Cochrane Risk of Bias 2. Eighty-seven studies were included, comprising 85 comparisons of higher versus lower protein intake and 17 comparisons of animal versus plant protein intake. Higher protein intake was associated with metabolomic profiles marked by increased concentrations of most amino acids, alongside alterations in nitrogen-related and gut microbiota-derived metabolites. Protein quantity also influenced phospholipid metabolism, which was associated with multiple CRFs, including lipid-lipoprotein panels. Differences between animal and plant protein intake were characterized by shifts in amino acid, bile acid, and microbial metabolite profiles, with links to CRFs through pathways in bile acid signaling and energy metabolism. Overall, dietary protein quantity and source shape distinct metabolomic signatures that may influence CRFs.