Effect of Novel Interactions Between Gut Microbiome and PBDEs on the Regulation of Intestinal Drug‐Processing Genes Expression
Authors: Lee SooWan , Li Cindy Yanfei , Cui Julia Yue 
Published: November 2023

Following ingestion xenobiotic biotransformation first occurs in intestine. We have previously demonstrated that lack of gut microbiota markedly alters basal gene expression and enzyme activities of various cytochrome P450s (Cyps) in liver. However, very little is known regarding to what extent gut microbiota is necessary for modulating the xenobiotic‐mediated regulation of important drug‐processing genes (DPGs) in intestine. Polybrominated diphenyl ethers (PBDEs) are persistent environmental toxicants previously used as flame‐retardants and cause a wide spectrum of adverse health effects. A major exposure route to BDE‐47 and BDE‐99 congeners is through oral ingestion of seafood and breast milk and is converted to more toxic metabolites via distinct Cyp isoforms. The goal of this study was to investigate the interaction between gut microbiota and effect of PBDEs on intestinal DPG expression in mice. Three‐month‐old male C57BL/6J conventional (CV) or germ‐free (GF) mice were orally administered corn oil, BDE‐47, or BDE‐99 (both 100μmol/kg) once daily for four days and intestinal sections were collected on the fifth day (n=5/group). RT‐qPCR demonstrated the lack of gut microbiota alters the basal expression of many DPGs. Notably, the mRNAs of the luminal efflux transporters multidrug resistance related protein 2 (Mrp2) and ATP‐binding cassette g8 (Abcg8) were absent in colon of control CV mice, but both were markedly increased to the highest expressed level among all sections of intestine in control GF mice. Control GF mice had lower basal levels of several Cyp isoforms and the bile acid efflux transporter organic solute transporter β (Ostβ), but higher basal levels of Cyp2s1 and sulfotransferases (Sult1b1, Sult1d1, and Sult2b1) in certain sections of small intestine (SI). Two distinct regulatory patterns were associated with lack of gut microbiota following treatment: 1) Potentiation effect due to GF conditions. For example, Cyp1a1 mRNA was substantially increased in colon of GF mice by BDE‐47 and BDE‐99, but was minimally altered in any intestinal sections of CV mice. Lack of gut microbiota potentiated the PBDE‐mediated mRNA increase of many Phase‐II glutathione S‐transferases in SI of GF mice. 2) Gut microbiota‐dependent regulations. For example, BDE‐99 mediated up‐regulation of the cholesterol efflux dimer transporters (Abcg5/Abcg8) and the xenobiotic uptake transporter organic anion transporting polypeptide 2a1 were only observed in SI of CV mice, and Mrp4 mRNA in all sections of intestine in CV mice, but not in GF mice. Gut microbiota‐dependent up‐regulation by BDE‐99 was observed for many other DPGs as well as the xenobiotic‐sensors PXR, CAR, and PPARα. BDE‐47 was less potent in modulating the DPG expression and less responsive to lack of gut microbiota than BDE‐99. In conclusion, the present study has demonstrated that gut microbiota plays an essential role in regulating the basal as well as PBDE‐mediated transcriptional changes in various drug metabolizing enzymes and transporters in the host intestine. Understanding the interactions between gut microbiota and orally exposed environmental chemicals is essential for more accurate risk assessment in vulnerable populations.