Influence of Gut Microbiota on Oral Drug Absorption and Metabolism

Abstract

Gut bacteria influence host intestinal phenotype in ways that impact drug absorption and metabolism. By comparing colonic tissue from germ-free mice to those colonized with human microbiota, this study evaluates microbiota-driven differences in gene expression and P-gp efflux capacity. Transcriptomic analysis revealed upregulation of genes coding ATP-binding cassette drug transporters P-gp (Abcb1a, Abcb1b), BCRP (Abcg2), and MRP3 (Abcc3), along with increased expression of solute carriers MCT1 (Slc16a1) and OCTN2 (Slc22a5). Immunohistochemistry indicated greater P-gp expression and apical localization in humanized mice. No relevant gene expression changes were observed in human homologs of drug-metabolizing Cytochrome P450 enzymes, though cytochrome P450 oxidoreductase (Por) upregulation suggests increased cytochrome activity. Other phase I drug-metabolizing enzymes, including multiple homologs of human carboxylesterase 2 (CES2) and several reductases, were upregulated with high significance. Regarding phase II metabolism, genes encoding most UDP-glucuronosyltransferases and glutathione S-transferases were upregulated, along with all the enzymes responsible for synthesizing their corresponding co-substrates, UDP-glucuronic acid and glutathione. Ussing chamber experiments with small intestinal tissue demonstrated higher permeability of ¹⁴C-labeled polyethylene glycol (PEG) 4000 in germ-free mice, while expression changes in claudins, zonula occludens, and myosin II-related genes suggest a molecular basis for these differences.

Competing Interest Statement

The authors have declared no competing interest.