Drug Metabolism by the Gut Microbiota: A Potential Modifier of the Pharmacogenetic Phenotype

The human gut microbiome contains over a hundred times more unique genes than the human genome on which pharmacogenetics is based. The microbiota may influence the fate of drugs in a field referred to as pharmacomicrobiomics. In this review, we examine the impact of the microbiota on several classical pharmacogenetic polymorphisms, notably NAT2, CYP2D6, CYP2C19, CYP2C9, CYP3A4, and TPMT. We estimate that the microbiota can modify pharmacogenetic phenotypes associated with all six of these polymorphisms by three principal mechanisms that may lead to phenoconversion. First, the microbiome possesses both NAT2 and TPMT activity. Second, the microbiome produces secondary bile acids, which induce CYP3A4 by activating PXR. Third, released bacterial endotoxin (LPS) acts on immune cells via TLR4, initiating the intracellular NF-κB cascade leading to synthesis and release of the proinflammatory cytokines IL-1β, IL-6, and TNF-α, which attenuate expression of CYP2C19, CYP2C9, and CYP2D6, reducing their metabolic activity. There are therefore three primary mechanisms by which the microbiota modifies pharmacogenetic phenotype: direct microbial mimicry, inflammatory suppression, and secondary bile acid induction.