Impact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotonin

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dc.contributor.authorWalsh, Jacinta
dc.contributor.authorOlavarría-Ramírez, Loreto
dc.contributor.authorLach, Gilliard
dc.contributor.authorBoehme, Marcus
dc.contributor.authorDinan, Timothy G.
dc.contributor.authorCryan, John F.
dc.contributor.authorGriffin, Brendan T.
dc.contributor.authorHyland, Niall P.
dc.contributor.authorClarke, Gerard
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderYakult Bio-Science Foundationen
dc.contributor.funderNature Researchen
dc.contributor.funderDuPonten
dc.contributor.funderCremo SA, Switzerlanden
dc.contributor.funderMead Johnson Nutritionen
dc.contributor.funderDanoneen
dc.contributor.funder4D Pharmaen
dc.contributor.funderAlkermes Inc., Irelanden
dc.date.accessioned2020-03-24T10:17:00Z
dc.date.available2020-03-24T10:17:00Z
dc.date.issued2020-03-09
dc.date.updated2020-03-24T09:44:24Z
dc.description.abstractThe gastrointestinal tract houses a reservoir of bacterial-derived enzymes which can directly catalyze the metabolism of drugs, dietary elements, and endogenous molecules. Both host and environmental factors may influence this enzymatic activity, with the potential to dictate the availability of the biologically-active form of endogenous molecules in the gut and influence inter-individual variation in drug metabolism. We aimed to investigate the influence of the microbiota, and the modulation of its composition, on fecal enzymatic activity. Intrinsic factors related to the host, including age, sex, and genetic background, were explored. Fecalase, a cell-free extract of feces, was prepared and used in a colorimetric-based assay to quantify enzymatic activity. To demonstrate the functional effects of fecal enzymatic activity, we examined β-glucuronidase-mediated cleavage of serotonin β-D-glucuronide (5-HT-GLU) and the resultant production of free 5-HT by HPLC. As expected, β-glucuronidase and β-glucosidase activity were absent in germ-free mice. Enzymatic activity was significantly influenced by mouse strain and animal species. Sex and age significantly altered metabolic activity with implications for free 5-HT. β-glucuronidase and β-glucosidase activity remained at reduced levels for nearly two weeks after cessation of antibiotic administration. This effect on fecalase corresponded to significantly lower 5-HT levels as compared to incubation with pre-antibiotic fecalase from the same mice. Dietary targeting of the microbiota using prebiotics did not alter β-glucuronidase or β-glucosidase activity. Our data demonstrate that multiple factors influence the activity of bacterial-derived enzymes which may have potential clinical implications for drug metabolism and the deconjugation of host-produced glucuronides in the gut.en
dc.description.sponsorshipAPC Innovation Platform and in part by The Global Grants for Gut Health (Ref No. 626891 to NPH,). Science Foundation Ireland (Joint Programming Initiative-a healthy diet for a healthy life (JPI-HDHL)-investigating Nutrition and Cognitive Function (NutriCog); SFI Grant “A Menu for Brain Responses Opposing Stress-Induced Alternations in Cognition” (AMBROSIAC) 15/JPHDHL/3270)); Dupont (Dupont Nutrition Biosciences APS);en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid36en
dc.identifier.citationWalsh, J., Olavarria-Ramirez, L., Lach, G., Boehme, M., Dinan, T. G., Cryan, J. F., Griffin, B. T., Hyland, N. P. and Clarke, G. (2020) 'Impact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotonin', American Journal of Physiology - Gastrointestinal and Liver Physiology, 18(4), pp.G816-G826. https://doi.org/10.1152/ajpgi.00026.2020en
dc.identifier.doi10.1152/ajpgi.00026.2020en
dc.identifier.endpage826en
dc.identifier.issn1522-1547
dc.identifier.issued4
dc.identifier.journaltitleAmerican Journal of Physiology - Gastrointestinal and Liver Physiologyen
dc.identifier.startpage816en
dc.identifier.urihttps://hdl.handle.net/10468/9783
dc.identifier.volume18
dc.language.isoenen
dc.publisherAmerican Physiological Societyen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/en
dc.relation.urihttps://journals.physiology.org/doi/abs/10.1152/ajpgi.00026.2020
dc.rights© 2020, American Journal of Physiology-Gastrointestinal and Liver Physiologyen
dc.subjectMicrobiomeen
dc.subjectEnzyme activityen
dc.subjectGlucuronidationen
dc.subjectSerotoninen
dc.subjectBeta-glucuronidaseen
dc.subject~Pharmacy - Journal Articles~en
dc.subject~Anatomy and Neuroscience - Journal Articles~en
dc.subject~Physiology - Journal Articles~en
dc.subject~Psychiatry - Journal Articles~en
dc.titleImpact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotoninen
dc.typeArticle (peer-reviewed)en
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