Metabolomic Biomarkers for the Human Diagnosis of Neglected Tropical Diseases: A Systematic Review.

Neglected tropical diseases (NTDs) affect more than 1.6 billion people worldwide and remain major contributors to morbidity, disability, stigma, and poverty. Metabolomics has emerged as a promising approach for investigating disease-associated biochemical alterations and identifying biomarkers for diagnosis, prognosis, and treatment monitoring. This systematic review evaluated the available evidence on metabolomic profiles in WHO-defined NTDs and their potential clinical applications. MEDLINE/PubMed, Web of Science, and Scopus were searched through March 2026. Observational studies investigating metabolomic profiles in human subjects with NTDs were included, and methodological quality was assessed using a modified QUADOMICS tool. Seventy-four studies met the inclusion criteria. Most were conducted in China and Brazil and focused on dengue, onchocerciasis, schistosomiasis, leprosy, and Chagas disease. Across diseases, metabolomic alterations were predominantly observed in amino acid, lipid, carbohydrate, and energy metabolism pathways. Several candidate biomarkers were identified, including N-acetyltyramine-O-β-glucuronide for onchocerciasis, bile acid derivatives for schistosomiasis, amino acids and peptides for Chagas disease, lipid mediators for leprosy, and lipid- and serotonin-related metabolites for dengue. However, most studies remained exploratory, and only two validated biomarkers in independent populations. Risk-of-bias assessment revealed frequent methodological limitations, including inadequate reporting of pre-analytical procedures, insufficient characterization of study populations, and lack of strategies to address overfitting. Human metabolomics studies were absent for several WHO-defined NTDs, highlighting major research gaps. Future research should prioritize standardized methodologies, multicenter validation studies, and greater inclusion of underrepresented diseases and endemic populations to translate metabolomic discoveries into clinically useful tools for NTD diagnosis, monitoring, and control.