Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes

Abstract

Characterizing the gut microbiota in terms of their capacity to interfere with drug metabolism is necessary to achieve drug efficacy and safety. Although examples of drug-microbiome interactions are well-documented, little has been reported about a computational pipeline for systematically identifying and characterizing bacterial enzymes that process particular classes of drugs. The goal of our study is to develop a computational approach that compiles drugs whose metabolism may be influenced by a particular class of microbial enzymes and that quantifies the variability in the collective level of those enzymes among individuals. The present paper describes this approach, with microbial β-glucuronidases as an example, which break down drug-glucuronide conjugates and reactivate the drugs or their metabolites. We identified 100 medications that may be metabolized by β-glucuronidases from the gut microbiome. These medications included morphine, estrogen, ibuprofen, midazolam, and their structural analogues. The analysis of metagenomic data available through the Sequence Read Archive (SRA) showed that the level of β-glucuronidase in the gut metagenomes was higher in males than in females, which provides a potential explanation for the sex-based differences in efficacy and toxicity for several drugs, reported in previous studies. Our analysis also showed that infant gut metagenomes at birth and 12 months of age have higher levels of β-glucuronidase than the metagenomes of their mothers and the implication of this observed variability was discussed in the context of breastfeeding as well as infant hyperbilirubinemia. Overall, despite important limitations discussed in this paper, our analysis provided useful insights on the role of the human gut metagenome in the variability in drug response among individuals. Importantly, this approach exploits drug and metagenome data available in public databases as well as open-source cheminformatics and bioinformatics tools to predict drug-metagenome interactions.

β-Glucuronidase Pattern Predicted From Gut Metagenomes Indicates Potentially Diversified Pharmacomicrobiomics

“…The microbial composition of intestinal microbiota impacts GUS abundance and diversity, with major effects on the metabolism of drugs and xenobiotics likely responsible for different individual responses ( Elmassry et al, 2021 ). This study wanted to determine the qualitative and quantitative differences of GUS-encoding genes among metagenomes of healthy subjects.…”

Comprehensive investigation of RNA‐sequencing dataset reveals the hub genes and molecular mechanisms of coronavirus disease 2019 acute respiratory distress syndrome

“…Small molecule drugs with a negative mean connective score and P < 0.05 were considered statistically significant and had inhibitory effects. The chemical structures of these small molecule compounds were obtained from the PubChem ( https://pubchem.ncbi.nlm.nih.gov ) database [ 29 , 30 , 31 , 32 , 33 ].…”

Metabolically-targeted dCas9 expression in bacteria

“…Gus operon expression is negatively regulated by binding of the TetR/lysR family GusR transcriptional regulator to operator sequences upstream of gusA , and induced by the presence of glucuronides that bind GusR to prevent DNA binding and relieve repression ( 38 , 39 , 39–45 ). Compounds that are substrates for GUS enzymes include xenobiotic medications that have been glucuronidated by mammalian UDP-glucuronosyltransferases ( 46 ). In particular, the anti-cancer drug irinotecan (CPT-11) that is activated by carboxylesterases to SN-38 and then glucuronidated to SN-38G is a substrate for GUS enzymes ( 47 ).…”