Time-Dependent Changes in Urinary Metabolome Before and After Intensive Phase Tuberculosis Therapy: A Pharmacometabolomics Study

Abstract

Pharmacometabolomics is a rapidly emerging omics science signaling the convergence of clinical pharmacology, metabolomics, precision medicine, and biomarker research. Tuberculosis (TB) treatment outcomes have complex biological, environmental, and social determinants and thus, represent a promising application of pharmacometabolomics. In samples of 23 patients undergoing intensive phase TB therapy for 4 weeks, we identified drug-induced host-metabolome variations before and at repeated time intervals post-treatment: (1) an overall reduction in the oxidative stress levels over the course of TB treatment; (2) a time-dependent induction and inhibition of several enzymes in response to the drugs (CYP2E1, CYP3A4, alcohol dehydrogenase, and aminocarboxymuconate-semialdehyde decarboxylase), and altered oxidative stress levels (aconitase, formylglycine-generating enzyme, α-ketoglutarate dehydrogenase, and succinate-semialdehyde dehydrogenase); (3) an upregulated urea cycle; and (4) altered insulin production. This is the first study of its kind to indicate changes to the host metabolome in response to intensive TB treatment, at different time intervals during the course of treatment. These results provide new insights into the mechanisms of TB drug metabolism, drug action, and drug-related side effects, thereby paving the way for the development of improved therapeutic approaches for the disease, and perhaps more importantly, also for monitoring treatment progression.