Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A

SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2009; 106(34):14728-33. DOI: 10.1073/pnas.0904489106
Source: PubMed


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.

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Available from: Jeremy K Nicholson, Jul 21, 2014
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    • "Multiple omics platforms integrating metabolic changes in the host, including the metabolism of drugs and environmental toxins, with microbiota diversity have highlighted the necessity of personalized medicine. Gut microbial enzymes for the metabolism of commonlyprescribed drugs, such as acetaminophen and cholesterollowering agent simvastatin, were identified [65] [66]. In addition, microbiota plays a critical role in the generation of more-(e.g., sulfasalazine) or less-active (e.g., digoxin) drug metabolites [58]. "
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    ABSTRACT: Gut microbiota of higher vertebrates is host-specific. The number and diversity of the organisms residing within the gut ecosystem are defined by physiological and environmental factors, such as host genotype, habitat, and diet. Recently, culture-independent sequencing techniques have added a new dimension to the study of gut microbiota and the challenge to analyze the large volume of sequencing data is increasingly addressed by the development of novel computational tools and methods. Interestingly, gut microbiota maintains a constant relative abundance at operational taxonomic unit (OTU) levels and altered bacterial abundance has been associated with complex diseases such as symptomatic atherosclerosis, type 2 diabetes, obesity, and colorectal cancer. Therefore, the study of gut microbial population has emerged as an important field of research in order to ultimately achieve better health. In addition, there is a spontaneous, non-linear, and dynamic interaction among different bacterial species residing in the gut. Thus, predicting the influence of perturbed microbe-microbe interaction network on health can aid in developing novel therapeutics. Here, we summarize the population abundance of gut microbiota and its variation in different clinical states, computational tools available to analyze the pyrosequencing data, and gut microbe-microbe interaction networks. Copyright © 2015. Production and hosting by Elsevier Ltd.
    Full-text · Article · Jul 2015
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    • "It is best to test new biomarkers under multiple different scenarios to determine the domain of applicability of the biomarker (Altar et al. 2008; Matheis et al. 2011). This review will cover biomarkers of APAP-induced liver injury that were discovered in omics nonclinical studies (Chen et al. 2008; Clayton et al. 2009; Coen et al. 2003; Reilly et al. 2001; Stamper et al. 2011; Sun et al. 2009; van Swelm et al. 2012; Yang et al. 2012b) or multiple omics nonclinical studies (Coen et al. 2004; Prot et al. 2011; Ruepp et al. 2002; Sun et al. 2012), whether these biomarkers went through analytical biomarker verification and whether these biomarkers have been observed in clinical studies (Bhattacharyya et al. 2014a, b; Fannin et al. 2010; Yang et al. 2015). This review will provide the status of APAP protein adducts and systems biology omics biomarkers (miRNAs, protein biomarkers and metabolite biomarkers ) of APAP liver injury in the clinical setting. "
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    ABSTRACT: Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.
    Full-text · Article · May 2015 · Archives of Toxicology
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    • "The gut microbiome (the collective genomes of the gut microbes) encodes 3.3 million non-redundant genes and is 150 times larger than the human gene complement, with most of these genes having unknown functions (Qin et al., 2010). Recent evidences suggested that gut microbiota affect many aspects of host physiology, including the diet, vitamin production, drug metabolism, disease pathogenesis, and the regulation of the immune system (Xu et al., 2013), as well as the metabolism of pharmaceuticals, heavy metals, and organic chemicals (Breton et al., 2013; Clayton et al., 2009). The composition of the gut microbiota and the number of microorganisms differed in dependence on local environmental conditions (Frick and Autenrieth, 2013). "
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    ABSTRACT: Neochamaejasmin A, isolated from Stellera chamaejasme L., has been widely used in China. Gut microbiota represent the first barrier against xenobiotics. This study aimed to evaluate the effects of subchronic exposure to neochamaejasmin A on the composition of gut microbiota. We found that neochamaejasmin A altered 21 OTUs in female rats and 46 OTUs in male rats. Among these OTUs, OTU86, OTU338 and OTU482 were shared in neochamaejasmin A-fed groups in both genders, implying that neochamaejasmin A might promote the growth of these three genera. In contrast, little or no effect on 226 OTUs was observed at all doses in both genders, suggesting their resistance to neochamaejasmin A. These findings could help improve our understanding of the health effects of neochamaejasmin A and provide an example of the risk assessment of pharmaceuticals or food contaminants on the gut microbiota composition. Copyright © 2015 Elsevier B.V. All rights reserved.
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