Human gut bacterial β-glucuronidase inhibition: An emerging approach to manage medication therapy

Abstract

Bacterial β-glucuronidase enzymes (BGUSs) are at the interface of host-microbial metabolic symbiosis, playing an important role in health and disease as well as medication outcomes (efficacy or toxicity) by deconjugating a large number of endogenous and exogenous glucuronides. In recent years, BGUSs inhibition has emerged as a new approach to manage diseases and medication therapy and attracted an increasing research interest. However, a growing body of evidence underlines great genetic diversity, functional promiscuity and varied inhibition propensity of BGUSs, which have posed big challenges to identifying BGUSs involved in a specific pathophysiological or pharmacological process and developing effective inhibition. In this article, we offered a general introduction of the function, in particular the physiological, pathological and pharmacological roles, of BGUSs and their taxonomic distribution in human gut microbiota, highlighting the structural features (active sites and adjacent loop structures) that affecting the protein-substrate (inhibitor) interactions. Recent advances in BGUSs-mediated deconjugation of drugs and carcinogens and the discovery and applications of BGUS inhibitors in management of medication therapy, typically, irinotecan-induced diarrhea and non-steroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy, were also reviewed. At the end, we discussed the perspectives and the challenges of tailoring BGUS inhibition towards precision medicine.

Keywords: Bacterial β-glucuronidases; Drug metabolism; Efficacy/toxicity; Inhibition.