Variability in fecal microbial drug deglucuronidation

The gut microbiota is a diverse community of various microorganisms that are responsible of numerous essential functions within the human body, including the biotransformation of endogenous compounds and xenobiotics, such as drugs. Several intestinal bacteria produce various β-glucuronidase enzymes, which catalyze deglucuronidation of compounds formed during UDP-glucuronosyltransferase (UGT) mediated phase II metabolism. Deglucuronidation can result in the formation of an inactive, active, and/or toxic compound, which may be reabsorbed into systemic circulation as part of enterohepatic recycling, thereby influencing the pharmacokinetics of these compounds. In this study, the deglucuronidation activity of 23 bacterial isolates, extracted from fecal samples collected from healthy individuals, was evaluated using two test substrates: 4-methylumbelliferyl-β-D-glucuronide (4-MUG) and 4-nitrophenol-β-D-glucuronide (PNPG). For isolates demonstrating deglucuronidation activity with these test compounds, further analysis was conducted using the glucuronides of indomethacin, telmisartan, paracetamol, and ezetimibe. Additionally, inter- and intraindividual variability in deglucuronidation activities was assessed by utilizing multiple fecal samples collected at different time points from each of the three healthy donors. Only the isolates Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Lachnospira pectinoshiza, and a species from the Luoshenia genus were found to have deglucuronidation activity in the 4-MUG and PNPG assays. Variability in reaction rates and substrate specificities was observed among these isolates. Fecal lysates from the healthy donors demonstrated both inter- and intraindividual variability in 4-MUG deglucuronidation activity. Since the individual microbial composition of the donor remained relatively stable regardless of the sample, the composition of the microbiota alone is unlikely to fully explain its metabolic activity. The results of this study demonstrate that different gut microbes exhibit highly variable deglucuronidation activities. This variability may partly explain individual differences in drug pharmacokinetics, drug exposure, and clinical response.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2024

Author dc:creator

• Neulasalmi, Oona Maria Helena

• fecal microbiota
• deglucuronidation
• β-glucuronidase activity
• variability
• individual variation
• pharmacokinetics

Statement dc:rights

• CC BY 4.0

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/588010

OAI identifier oai:identifier

oai:helda.helsinki.fi:10138/588010