{"id":{"repo_id":"helsinki","oai_identifier":"oai:helda.helsinki.fi:10138/588010"},"canonical_url":"https://search.dev.ndltd.org/etd/helsinki/oai:helda.helsinki.fi:10138/588010","repository":{"repo_id":"helsinki","name":"University of Helsinki","base_url":"https://helda.helsinki.fi/server/oai/request"},"display":{"title":"Variability in fecal microbial drug deglucuronidation","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Neulasalmi, Oona Maria Helena"],"institution":"Helsingin yliopisto","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-11-15","date_published":"2024-11-15","updated_at":"2026-07-27T19:56:04Z","subjects":["fecal microbiota","deglucuronidation","β-glucuronidase activity","variability","individual variation","pharmacokinetics"],"languages":["eng"],"rights":["CC BY 4.0"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10138/588010","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Neulasalmi, Oona Maria Helena"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2024-11-15T07:12:03Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2024-11-15T07:12:03Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-11-15"]},{"key":"dc:publisher","label":"Institution","values":["Helsingin yliopisto","University of Helsinki","Helsingfors universitet"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["fecal microbiota","deglucuronidation","β-glucuronidase activity","variability","individual variation","pharmacokinetics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["CC BY 4.0"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10138/588010"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.","Suoliston mikrobisto on monimuotoinen kokonaisuus erilaisia mikrobeja, joilla on lukuisia tärkeitä tehtäviä ihmiselimistössä, mukaan lukien endogeenisten yhdisteiden ja vierasaineiden, kuten esimerkiksi lääkeaineiden, biotransformaatio. Useat suoliston bakteerit tuottavat erilaisia β-glukuronidaaseja, jotka katalysoivat UDP-glukuronosyylitransferaasi- eli UGT-entsyymivälitteisessä vaiheen II metaboliassa muodostuneiden glukuronidien deglukuronidaatiota. Deglukuronidaation seurauksena voi muodostua inaktiivinen, aktiivinen ja/tai toksinen yhdiste, joka voi takaisinimeytyä systeemiseen verenkiertoon osana enterohepaattista kiertoa, vaikuttaen näin ollen yhdisteen farmakokinetiikkaan. Tässä tutkimuksessa arvioitiin terveiltä yksilöiltä kerätyistä ulostenäytteistä eristettyjen 23:n bakteeri-isolaattien deglukuronidaatioaktiivisuutta kahden testiyhdisteen, 4-metyyliumbelliferyyli-β-D-glukuronidin (4-MUG) sekä 4-nitrofenoli-β-D-glukuronidin (PNPG), avulla. Niillä isolaateilla, joilla havaittiin deglukuronidaatioaktiivisuutta testiyhdisteillä tehdyissä kokeissa, deglukuronidaatiota tutkittiin myös indometasiinin, telmisartaanin, parasetamolin ja etsetimibin glukuronideilla. Lisäksi tutkimuksessa tarkasteltiin yksilöiden välistä ja yksilön sisäistä vaihtelua deglukuronidaatio-aktiivisuuksissa hyödyntämällä ulostenäytteitä, jotka oli kerätty kolmelta terveeltä luovuttajalta useissa eri aikapisteissä. Tutkituista isolaateista ainoastaan Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Lachnospira pectinoshiza sekä eräs Luoshenia-sukuun kuuluva laji havaittiin aktiiviseksi testiyhdisteillä tehdyissä kokeissa. Näiden isolaattien välillä oli havaittavissa vaihtelua reaktionopeuksissa sekä substraattispesifisyyksissä. Terveiltä luovuttajilta kerättyjen ulostenäytteiden 4-MUG deglukuronidaatioaktiivisuuksissa havaittiin sekä yksilöiden välistä, että yksilön sisäistä vaihtelua. Koska luovuttajan yksilöllinen mikrobikoostumus pysyi melko stabiilina näytteestä riippumatta, mikrobiston koostumus ei todennäköisesti yksinomaan selitä sen metabolista aktiivisuutta. Tutkimuksen tulokset osoittavat, että eri ulosteen mikrobeilla on hyvin vaihtelevat deglukuronidaatioaktiivisuudet. Tällainen vaihtelu voisi osittain selittää yksilöllisiä eroja lääkeaineiden farmakokinetiikassa, lääkeainealtistuksessa sekä kliinisessä vasteessa."]},{"key":"dc:title","label":"Title","values":["Variability in fecal microbial drug deglucuronidation"]}]}],"canonical_facts":{"dc:creator":["Neulasalmi, Oona Maria Helena"],"dc:date.accessioned":["2024-11-15T07:12:03Z"],"dc:date.available":["2024-11-15T07:12:03Z"],"dc:date.issued":["2024-11-15"],"dc:description.abstract":["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.","Suoliston mikrobisto on monimuotoinen kokonaisuus erilaisia mikrobeja, joilla on lukuisia tärkeitä tehtäviä ihmiselimistössä, mukaan lukien endogeenisten yhdisteiden ja vierasaineiden, kuten esimerkiksi lääkeaineiden, biotransformaatio. Useat suoliston bakteerit tuottavat erilaisia β-glukuronidaaseja, jotka katalysoivat UDP-glukuronosyylitransferaasi- eli UGT-entsyymivälitteisessä vaiheen II metaboliassa muodostuneiden glukuronidien deglukuronidaatiota. Deglukuronidaation seurauksena voi muodostua inaktiivinen, aktiivinen ja/tai toksinen yhdiste, joka voi takaisinimeytyä systeemiseen verenkiertoon osana enterohepaattista kiertoa, vaikuttaen näin ollen yhdisteen farmakokinetiikkaan. Tässä tutkimuksessa arvioitiin terveiltä yksilöiltä kerätyistä ulostenäytteistä eristettyjen 23:n bakteeri-isolaattien deglukuronidaatioaktiivisuutta kahden testiyhdisteen, 4-metyyliumbelliferyyli-β-D-glukuronidin (4-MUG) sekä 4-nitrofenoli-β-D-glukuronidin (PNPG), avulla. Niillä isolaateilla, joilla havaittiin deglukuronidaatioaktiivisuutta testiyhdisteillä tehdyissä kokeissa, deglukuronidaatiota tutkittiin myös indometasiinin, telmisartaanin, parasetamolin ja etsetimibin glukuronideilla. Lisäksi tutkimuksessa tarkasteltiin yksilöiden välistä ja yksilön sisäistä vaihtelua deglukuronidaatio-aktiivisuuksissa hyödyntämällä ulostenäytteitä, jotka oli kerätty kolmelta terveeltä luovuttajalta useissa eri aikapisteissä. Tutkituista isolaateista ainoastaan Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Lachnospira pectinoshiza sekä eräs Luoshenia-sukuun kuuluva laji havaittiin aktiiviseksi testiyhdisteillä tehdyissä kokeissa. Näiden isolaattien välillä oli havaittavissa vaihtelua reaktionopeuksissa sekä substraattispesifisyyksissä. Terveiltä luovuttajilta kerättyjen ulostenäytteiden 4-MUG deglukuronidaatioaktiivisuuksissa havaittiin sekä yksilöiden välistä, että yksilön sisäistä vaihtelua. Koska luovuttajan yksilöllinen mikrobikoostumus pysyi melko stabiilina näytteestä riippumatta, mikrobiston koostumus ei todennäköisesti yksinomaan selitä sen metabolista aktiivisuutta. Tutkimuksen tulokset osoittavat, että eri ulosteen mikrobeilla on hyvin vaihtelevat deglukuronidaatioaktiivisuudet. Tällainen vaihtelu voisi osittain selittää yksilöllisiä eroja lääkeaineiden farmakokinetiikassa, lääkeainealtistuksessa sekä kliinisessä vasteessa."],"dc:identifier.uri":["http://hdl.handle.net/10138/588010"],"dc:language.iso":["eng"],"dc:publisher":["Helsingin yliopisto","University of Helsinki","Helsingfors universitet"],"dc:rights":["CC BY 4.0"],"dc:subject":["fecal microbiota","deglucuronidation","β-glucuronidase activity","variability","individual variation","pharmacokinetics"],"dc:title":["Variability in fecal microbial drug deglucuronidation"]},"updated_at":"2026-07-27T19:56:04Z"}