Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 318, Issue 4, Pages G816-G826Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00026.2020
Keywords
enzyme activity; glucuronidation; microbiome; serotonin; beta-glucuronidase
Categories
Funding
- APC Innovation Platform
- Global Grants for Gut Health [626891]
- Science Foundation Ireland (SFI) through the Irish Governments National Development Plan [SFI/12/RC/2273]
- Science Foundation Ireland (SFI) through Joint Programming Initiative-a healthy diet for a healthy life (JPI-HDHL)-investigating Nutrition and Cognitive Function (NutriCog) by an SFI Grant A Menu for Brain Responses Opposing Stress-Induced Alternations in [15/JPHDHL/3270]
- Dupont Nutrition Biosciences APS
- Alkermes Inc.
- Cremo SA
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The gastrointestinal tract houses a reservoir of bacterial-derived enzymes that 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 also 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 beta-glucuronidase-mediated cleavage of serotonin beta-D-glucuronide (5HT-GLU) and the resultant production of free 5-HT by HPLC. As expected, beta-glucuronidase and beta-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. beta-Glucuronidase and beta-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 with incubation with pre-antibiotic fecalase from the same mice. Dietary targeting of the microbiota using prebiotics did not alter beta-glucuronidase or beta-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. NEW & NOTEWORTHY This article explores a comprehensive range of host and environmental factors that introduce variability in the expression of bacterial-derived metabolic enzymes. Our results demonstrate that altered beta-glucuronidase activity has implications for the bioavailability of luminal serotonin. The experimental approach employed, fecalase, provides a mechanistic basis and translational platform to further delineate the functional outputs of altered metabolic activity, and the associated physiological effects of microbiotatargeted interventions on host response to drugs and host-produced glucuronides.
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