In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects according to the experimental context and the model disease tested. Previous highlighted either a positive or negative role played by IPA in the context of metabolic and cardiovascular diseases. Given the potential clinical implications of these experimental observations which may underline a role of IPA as biomarker or therapeutic agent we performed a study to delineate the main clinical and multiomics characteristics of human subjects characterized by low IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis revealed the enrichment of several signaling, regulatory and metabolic as well as oxidative phosphorylation and chemical carcinogenesis processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in high IPA group while in low IPA group Escherichia-Shigella, megasphera and Desulfovibrio genus were more abundant. Our results support the potential role of IPA as an agent useful to improve metabolic homeostasis or as a biomarker in human subjects.