The intestinal microbiota encode millions of genes that represent unique pharmaceutical targets for human diseases from neurological disorders to drug toxicity. We are interested in the role the intestinal microbiota play in reactivating compounds that have been inactivated through glucuronidation in the liver. In particular, the chemotherapy drug CPT-11, or irinotecan, is inactivated by UGTs in the liver and then reactivated by bacterial b-glucuronidase (GUS) enzymes in the large intestine resulting in dose-limiting diarrhea. However, the numbers, types, and diversity of these proteins in the human GI microbiome remain undefined. Using the Human Microbiome Project GI database, we identify 3,013 total and 279 unique microbiome-encoded GUS proteins clustered into six unique structural categories. A representative in vitro panel of the most common GUS proteins by read abundances highlights structural and functional variabilities within the family, including their differential processing of smaller glucuronides and larger carbohydrates. We have developed, using chemical biology, novel inhibitors that potently and non-lethally inhibit GUS enzymes from one of the six structural categories. These data provide a sequencing-to-molecular roadmap for examining microbiome-encoded enzymes and establish that the microbiome contains targets for non-lethal pharmacology to address acute problems of human health.
Sponsored by the Host Microbiome Initiative