Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

TLDR

The study demonstrates that a person’s pre‑dose urinary metabolite profile predicts acetaminophen metabolism and proposes that microbiome activity should be integrated into drug development and personalized care, with the possibility of manipulating gut bacteria to improve efficacy and reduce adverse reactions. Using 1H NMR to obtain pre‑ and post‑dose urinary metabolite spectra, the authors statistically linked these profiles to drug metabolite excretion and identified a microbiome‑derived cometabolite predictor of acetaminophen fate. Individuals with high pre‑dose urinary p‑cresol sulfate exhibited a lower post‑dose acetaminophen sulfate/glucuronide ratio, indicating that bacterial p‑cresol competes for sulfonation and highlighting the microbiome’s significant impact on drug metabolism with implications for many other sulfonation reactions.

Abstract

We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by (1)H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.