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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Gut microbiota regulate the intestinal expression of drug-metabolizing enzymes, transporters, and barrier properties that determine oral drug absorption and disposition. This study compares germ-free Swiss Webster mice to mice colonized with fecal microbiota from a single human donor, evaluating microbiota-driven differences in colonic gene expression and P-gp protein expression, as well as small intestinal mucosal permeability. Transcriptomic analysis of colonic tissue revealed microbiota-induced upregulation of genes encoding P-gp and other drug transporters, including MCT1 and OCTN2. Immunofluorescence also indicated greater P-gp expression and apical localization in colonized mice. Gene expression of drug-metabolizing enzymes was also higher in colonized mice, including phase I enzymes (carboxylesterase 2 paralogs), phase II enzymes (UDP-glucuronosyltransferases and glutathione S-transferases), and enzymes responsible for synthesizing their co-substrates, UDP-glucuronic acid and glutathione. Small intestinal mucosal explants demonstrated lower permeability to 14C-labeled polyethylene glycol 4000 in colonized mice compared to germ-free mice. In the colon, transcriptomic analysis identified microbiota-dependent changes in genes regulating paracellular tight junctions and actomyosin contractility. These results show that human-derived gut microbiota alter gene expression in the mouse colon, identifying candidate microbiota-responsive genes relevant to oral drug absorption and disposition.<\/jats:p>","DOI":"10.3390\/ijms27177583","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:20:28Z","timestamp":1787592028000},"page":"7583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut Microbiota Alter Colonic Expression of Genes Encoding Drug Transporters and Drug-Metabolizing Enzymes in Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Douglas A.","family":"Nelson","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Veerareddy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojia","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purna C.","family":"Kashyap","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna R.","family":"Kalari","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7786-1915","authenticated-orcid":false,"given":"Karunya K.","family":"Kandimalla","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1208\/s12248-022-00687-0","article-title":"State of the Art and Uses for the Biopharmaceutics Drug Disposition Classification System (BDDCS): New Additions, Revisions, and Citation References","volume":"24","author":"Bocci","year":"2022","journal-title":"AAPS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/papr.12130","article-title":"Acetaminophen (Paracetamol) Oral Absorption and Clinical Influences","volume":"14","author":"Raffa","year":"2014","journal-title":"Pain Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1097\/FPC.0b013e3283559b22","article-title":"Metformin Pathways: Pharmacokinetics and Pharmacodynamics","volume":"22","author":"Gong","year":"2012","journal-title":"Pharmacogenet Genom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1021\/js980378j","article-title":"Role of P-glycoprotein-mediated Secretion in Absorptive Drug Permeabiity: An Approach Using Passive Membrane Permeability and Affinity to P-glycoprotein","volume":"88","author":"Doppenschmitt","year":"1999","journal-title":"J. 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