Harnessing Metabolomics to Advance Nutrition-Based Therapeutics for Inflammation: A Systematic Review of Randomized Clinical Trials

Abstract

Background/Objectives: The association between plasma metabolites derived from dietary substrates and inflammatory processes remains underexplored, despite its potential relevance in the prevention of non-communicable diseases. This systematic review aimed to examine the relationship between blood metabolites and the modulation of inflammatory biomarkers. Methods: A total of 25 randomized controlled trials, published between 2019 and 2024, were included from an initial pool of 111 records. These studies investigated the effects of dietary patterns, specific food groups, or nutritional supplements on the human metabolome and their potential links to inflammation. Results: Metabolomic analyses were predominantly performed using mass spectrometry (MS)-based platforms (17 out of 25), with liquid chromatography–mass spectrometry as the most frequently employed method. Both targeted (n = 14) and untargeted (n = 11) approaches were represented, and samples were drawn from plasma, urine, and feces. Across the interventions, 64 metabolites were modulated, including fatty acyls, glycerolipids, benzenoids, and organic acids, reflecting potential changes in pathways related to oxidative stress, lipid and carbohydrate metabolism, and inflammatory signaling. Several studies also assessed classical inflammatory biomarkers such as C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Interventions involving healthy traditional dietary patterns, improvements in dietary fat quality, or the use of specific probiotic strains were often associated with favorable immunometabolic outcomes. In contrast, some interventions, such as Mohana Choorna, elicited upregulation of immune-related gene expression in adipose tissue without improvements in glucose or lipid metabolism. Conclusions: While metabolomic responses varied across studies, the evidence highlights the value of dietary interventions in modulating systemic metabolism and inflammation. These findings support the integration of metabolomics into clinical nutrition to define more personalized and effective dietary strategies for inflammation-related chronic disease prevention.