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Recently, four studies on the potential value of small-molecule metabolites by highthroughput functional metabolomics were published in Nature Medicine (Buergel et al., 2022; Chen et al., 2022; Kachroo et al., 2022; Surendran et al., 2022). These studies have shown that metabolic profiling of small molecules offers invaluable insights into the function of candidate metabolites, leading to better diagnosis, prognosis, and therapeutic effects. These four publications have elucidated how the metabolite biosignatures as attractive biomarkers from human biofluids provide a link between the genotype, environment, and phenotype. Metabolic abnormalities lead to the accumulation or deficiency of small-molecule metabolites, which are related to phenotypic variation, can reveal the pathological mechanisms of various diseases and decipher therapeutic potential (Bar et al., 2020). Functional metabolomics is defined as a research strategy for discovering differential metabolites from large metabolome that comprehensively uses molecular and cell biology, bioinformatics, metagenome, and transcriptome to explore the biological functions of metabolites and related physiological as well as pathological significance (Figure 1). It provides an innovative approach to answering phenotype-related questions distinctly altered in diseases, elucidating the biochemical functions, and delineating the associated mechanisms implicated in the dysregulated metabolism in patients within clinical settings. High-throughput metabolomics technology has been used to identify phenotypic variation arising in the human plasma metabolome that is influenced by dietary, genetic, and microbial factors. Chen et al. (2022) first evaluated a total of 1,183 plasma metabolites in the Dutch cohort and then conducted an interaction analysis to assess the critical effect of diet, intestinal microbiome, and genetics on human metabolism regulation and showed that 610, 85, and 38 metabolites were significantly related to each type of factors (diet, genetics, or microbiome), respectively. These metabolites show key links between the genotype and environment and provide a closer image of the final phenotype. The authors then used the plasma metabolome to explore and predict diet quality and illustrated the relationship between humanmetabolism and diet. Notably, they observed a significant correlation between 1-methylhistidine and meat and fish intake, as well as lower levels of 1-methylhistamine in vegetarians. They combined plasma metabolites and genetic association to provide functional insight into disease etiology and found that 5-acetamido-6-formylamino-3-methyluracil has the strongest association with the N-acetyltransferase 2 gene, which is linked to the risk of bladder cancer. Since small-molecule metabolites are closely linked to the phenotype, they govern the modulation of its function, thus reflecting the interactions with the environment. The gut microbiota generates active metabolites which enter into the circulation system and regulate host metabolism responses and metabolic disorders in vivo that affect systemic health. The authors further observed the potential causal relationship to assess the contribution of the microbiome to the plasma metabolome and found that the increased level of adenosylcobalamin biosynthesis was related to the reduced level of 5-hydroxytryptophan OPEN ACCESS