Metabolites

Overview

Metabolites are the small-molecule products and intermediates of cellular metabolism. They include compounds generated by endogenous biochemical pathways as well as molecules derived from diet, drugs, and the microbiome. In biomedical research, metabolites are central readouts of physiological state because they reflect enzyme activity, nutrient availability, host-microbe interactions, and disease-related metabolic reprogramming.

Because metabolites can act as substrates, cofactors, signaling molecules, and bioactive effectors, they are increasingly studied not only as biomarkers but also as mechanistic mediators in conditions such as type 1 diabetes, osteoporosis, sepsis-associated acute kidney injury, pulmonary hypertension, insomnia, cancer immunotherapy response, and altered vaccine responsiveness. Their roles are often interpreted alongside microbiota, lipidome, transcriptome, and immune phenotypes, making them a key component of multi-omics biomedical research.

Focus of Latest Publications

Recent studies have used metabolites as both analytical targets and mechanistic intermediates across diverse disease and physiology settings. In preterm infants exposed to antibiotics, investigators proposed that antibiotic-driven changes in the microbiome and metabolome may sustain suppressive innate immune cell populations, potentially weakening adaptive vaccine responses. This places metabolites within a host-microbiota-immune axis relevant to early-life immune development and sex-specific differences.

In pediatric type 1 diabetes, multi-omics profiling integrated microbiome, metabolome, lipidome, and transcriptome data from newly diagnosed patients and healthy controls to define age-related endotypes. Here, metabolites were part of a broader heterogeneity analysis aimed at distinguishing biological subgroups rather than serving as isolated biomarkers. Similarly, in studies of cancer immunotherapy, microbiota-derived metabolites were described as modulators of both innate and adaptive immunity and as direct regulators of tumour cells, highlighting their potential to influence anti-tumour immunity and treatment response.

Several studies focused on identifying disease-associated metabolite signatures. In pulmonary hypertension, researchers aimed to identify metabolites and pathways associated with right ventricular systolic function and to determine whether associations differed by pulmonary vascular resistance, group 1 pulmonary hypertension status, and sex. In sepsis-associated acute kidney injury, differentially expressed metabolites were investigated to uncover biomarkers and pathophysiological mechanisms. In osteoporosis research, a metabolomics-driven machine learning model was developed to identify novel metabolites associated with risk and assess predictive utility, with performance evaluated using the Area Under the Receiver Operating Curve and related clinical metrics such as hip bone mineral density.

Metabolites were also examined in relation to neurobehavioral and cardiometabolic phenotypes. A Mendelian randomization study with mouse experimental validation explored the two-way relationship between metabolites and insomnia, indicating that causal directionality remains incompletely understood. In another study, fecal and plasma metabolite correlations were compared after nutrition or exercise interventions, reinforcing the idea that metabolites are focal players in host-microbiota crosstalk. Related work on latent cytomegalovirus infection among people living with HIV included plasma metabolites as one of five omics layers, supporting their use in systems-level causal analyses.

Microbial and dietary contexts were prominent in several reports. In colorectal cancer, trace elements, metabolites such as 5-Hydroxytryptophol, and host bacteria were modeled as factors exerting negative effects on most plasmids, suggesting that metabolites can participate in ecological interactions within the gut. In ulcerative colitis-related work, metabolic profiling of Gegen-Qinlian Decoction and its modified formula in gut microbiota from healthy individuals and patients with different syndromes characterized metabolized prototype constituents, metabolites, pathways, and metabolic rates. Another study profiled metabolites of Ficus natalensis fruit and annotated 160 metabolites across multiple phytochemical classes, illustrating the breadth of metabolite discovery in natural products research.

Drug metabolism and xenobiotic biotransformation were also represented. Zongertinib pharmacokinetics and metabolism were studied in rats, with metabolites in rat plasma investigated by LC-Orbitrap-HRMS. Likewise, constituents of the stem of Bauhinia championii and their metabolites in rat plasma were characterized to support quality evaluation and mechanism research. These studies emphasize that metabolites are essential endpoints in pharmacokinetic and biotransformation analyses.

A mechanistic example linking a microbiota-derived metabolite to host lipid handling came from work on Akkermansia muciniphila-derived L-norleucine. Using FABP1 protein-based metabolite enrichment coupled with untargeted metabolomics, investigators identified L-norleucine as a competitive FABP1 inhibitor despite its smaller molecular size relative to long-chain fatty acids. This connects metabolites to fatty acid transport and suggests a route by which microbial products can influence host metabolism through FABP1-dependent pathways.

Other studies used metabolite profiling for tissue biology and reproductive phenotyping. In Sophora flavescens root and stem tissues, differential metabolite analysis identified metabolites enriched or depleted between organs. In bull sperm, metabolic profiling retained 547 metabolites for downstream analysis after normalization and filtration, supporting the use of metabolite signatures in fertility marker discovery. Dried blood spot profiling also detected proteins and metabolites previously implicated in type 2 diabetes pathophysiology, showing feasibility for clinical trial sample workflows.

Across these studies, metabolites were consistently treated as biologically informative molecules that integrate host genetics, microbiota composition, immune state, and environmental exposures such as antibiotic therapy, nutrition, and exercise. Their study spans biomarker discovery, causal inference, mechanistic biochemistry, and translational pharmacology.

Key Publications

• Jun Early antibiotic exposure and vaccine immune responses in preterm infants: potential sex-specific differences. (Gut microbes, 2026, PMID 42363866): "Antibiotic-driven changes in the microbiome and metabolome may sustain suppressive innate immune cell populations, which may in turn weaken adaptive responses to vaccination."
• Jun Multi-omics reveals microbiota, metabolite, and immunological heterogeneity of age-related endotypes in type 1 diabetes. (Signal transduction and targeted therapy, 2026, PMID 42297781): "Here, we integrate microbiome, metabolome, lipidome, and transcriptome profiling from 108 newly diagnosed pediatric patients with T1D, along with 56 healthy controls, to investigate age-related endotypes."
• Jun Akkermansia muciniphila-derived L-norleucine modulates FABP1-dependent fatty acid transport. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42207914): "Through FABP1 protein-based metabolite enrichment coupled with untargeted metabolomics, we identified L-norleucine as a competitive FABP1 inhibitor despite its smaller molecular size relative to long-chain fatty acids."
• Jun Metabolomics data of root and stem tissues in five-year-old Sophora flavescens. (Data in brief, 2026, PMID 42125596): "Differential metabolite analysis was conducted to determine the metabolites that were more enriched and depleted in roots and stems."
• May Comparison of fecal and plasma metabolite correlations following nutrition or exercise interventions. (Metabolomics : Official journal of the Metabolomic Society, 2026, PMID 42177687): "Metabolites are focal players in the host-microbiota crosstalk."
• May Causal relationships between insomnia and blood metabolome: a Mendelian randomization study with mouse experimental validation. (Metabolomics : Official journal of the Metabolomic Society, 2026, PMID 42177678): "The two-way relationship between metabolites and insomnia is not yet fully understood."
• May Metabolomics of Right Ventricular Function in Pulmonary Hypertension. (Circulation research, 2026, PMID 41983297): "We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex."
• May BLOG: Bayesian longitudinal omics with group constraints. (Statistical applications in genetics and molecular biology, 2026, PMID 42155008): "Bayes factors are used to rank metabolites by evidence, and their mapping to posterior model probabilities under prior odds can provide local posterior null probabilities whose average over the rejection set defines a Bayesian analogue of the global FDR."
• May Decoding the human gut bacterial plasmids in colorectal cancer. (Communications biology, 2026, PMID 42141123): "SEM revealed that trace elements (e.g., Ni), metabolites (e.g., 5-Hydroxytryptophol), and host bacteria (e.g., Campylobacterales, Enterobacterales) predominantly exerted negative effects on most plasmids."
• May Metabolic profiling of Gegen-Qinlian Decoction and its modified formula in gut microbiota from healthy individuals and ulcerative colitis patients with different syndromes using UHPLC-QTOF-MS/MS and an in vitro incubation model. (Journal of pharmaceutical and biomedical analysis, 2026, PMID 41605091): "The profiles comprised metabolized prototype constituents, metabolites, pathways, and metabolic rates."