MSACL 2019 EU Abstract

Investigation of Bacterial β-Glucuronidase Inhibition on the Metabolic Profile of Mice Using a Combined Platform of NMR and LCMS-based Untargeted Metabolomics

Marine P. M. Letertre(1), Aadra P. Bhatt(2), Matthew R. Redinbo(2), Jeremy K. Nicholson(3), Jonathan R. Swann(1), & Ian D. Wilson(1).
(1)Imperial College London, London, UK. (2)University of North Carolina, Chapel Hill, USA. (3)Murdoch University, Murdoch, Australia.

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Marine Letertre (Presenter) Imperial College London

Presenter Bio: I am a third year PhD student within the Computational and Systems Medicine division at ICL, studying the interactions between gut microbiota and drug metabolism. I am using targeted and untargeted LCMS as well as NMR metabolic profiling and amplicon sequencing. I have graduated in 2015 from the University of Nantes (France), with a Master’s Degree (Hons), specialized in the use of Natural Active Ingredients for a pharmaceutical application. Although I am a chemist by training, I have always worked at the interface of Chemistry and Biology, allowing me to work on diverse projects such as understanding the toxicity of Bisphenol A on human testicular explants by MALDI-Imaging Mass Spectrometry (Rennes, France) or developing a novel class of irreversible kinase inhibitors using organic chemistry technics as well as enzyme assays and molecular modelling (Auckland, New Zealand).

Relevant Financial Disclosures (within past 24 months) Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

Irinotecan is a drug used as a chemotherapy agent mainly to treat colorectal cancer. Despite its remarkable efficacy, the gastrointestinal toxicity induced by the drug is life-threatening and often lead to an interruption of the treatment. Indeed, irinotecan is a pro-drug from which the active form is SN-38. Once reaching the liver, SN-38 is conjugated with glucuronic acid to then be excreted. However, once SN-38-G reaches the gut, a bacterial enzyme β-glucuronidase cleaves the glucuronic acid, releasing the aglycone SN-38 back into the GI tract, which is inducing the gastrointestinal toxicity. Even if inhibition of β-glucuronidase had proved to remove the ADRs from SN-38 in mice, it is logical to think that if this bacterial enzyme, which is present in more than 43% of the Human Microbiome Project Database species, might be affecting other metabolic pathways. In a project aiming to explore the potential to target the microbiome by selectively inhibit the bacterial β-glucuronidase, a 1H NMR spectroscopy and UPLC-MS metabolomics platform was used in order to assess the effect of this inhibitor on the metabolic profile of mice, particularly on the liver, gall bladder, colon tissues, plasma, urine, faeces and colon contents. A metabolic shift was observed only for the colon contents, faeces and urine samples, as well as a very slight one for the colon tissues. The metabolites significantly affected by the treatment seem to be mainly microbial metabolites, although metabolite identification process is still on-going. In another study where mice were treated with both the inhibitor and SN-38, the targeted UPLC-MS analysis of intestinal contents and plasma revealed the presence of different SN-38-G forms, potentially explained by a ring-opening mechanism leading to the carboxylate form of the molecule. Structural elucidation of these SN-38-G forms will be performed with high-resolution ion mobility mass spectrometry. Overall, even if further studies are needed to confirm preliminary findings, the inhibition of bacterial β-glucuronidase seems promising.