Individuals have unique microbiomes, which can lead to various responses to drug therapies. Consequently, these varied responses can be dangerous and costly due to unpredicted adverse side effects. Personalized medicine addresses this issue by focusing on an individual's genome and metagenome to provide tailored treatments. However, the molecular mechanisms by which gut microbes metabolize drugs have not received much attention. This problem is made more complicated due to the diversity of gut microbiomes. To address this problem, we have targeted several proteins expressed by human gut microbes <i>Eggerthella lenta, Clostridium scindens, and Bifidobacterium adolescentis, </i>that metabolize and alter drug structures. These enzymes include the 20-hydroxysteroid dehydrogenases (20-HSDHs) B0NC68 (a 20α-HSDH) and WP_008310233.1 (a 20β-HSDH), which change the structure of the host-produced steroid cortisol. Therefore, we hypothesized that these enzymes affect drug metabolism on corticosteroids, therapeutics structurally similar to cortisol. We have successfully cloned, purified, and tested two 20-HSDHs of opposite stereospecificity. Both enzymes were found to modify cortisol and other corticosteroids. Here we have found that the 20β-HSDH is more efficient and faster than the 20α-HSDH on all substrates, but each has a narrow substrate scope. This investigation serves as a springboard into the development of personalized medicine based on how a unique community of gut microbes modifies therapeutics, helping predict drug metabolism by knowing the makeup of an individual's microbiome.

Comparison of two human gut microbiome-derived drug-metabolizing dehydrogenases

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