Identifying and Quantifying Drug Metabolism by the Human Gut Microbiome

INVESTIGATOR: Tyler Stack, Providence College
MENTOR: Karen Allen, Boston University

SCIENTIFIC THEME: Environmental Health Sciences

ABSTRACT: A growing field of research is identifying the myriad of ways that gut bacteria affect human health. Among many known roles, these microbes can aid digestion, prevent infections of virulent bacteria, and impact mood by altering hormones. One growing area of research is identifying how gut bacteria can modify drugs, which affects the efficacy and safety of therapeutics. As one example, the side effects of the chemotherapeutic irinotecan have been recently shown to depend upon the specific gut bacteria present during drug administration. A significant challenge to this field is associating genomic and metagenomics studies and any enzyme-encoding genes with their functions and the chemistries they catalyze. This work is further complicated by the diversity in the human gut and the uniqueness of an individual’s gut bacterial community. The long-term goal of our research is to predict the bacterial xenometabolism of drugs given a sequenced genome or metagenome by studying enzyme families abundant in gut bacteria. In this proposed research, we will build off published research using whole-cell studies that identified esterases from PF13472 from Bacteroides thetaiotaomicron and other gut microbes to demonstrate the feasibility of our method. We will quantify the efficiency and promiscuity of enzymes in the protein family to determine the full potential of these enzymes to modify drugs. Following reports that gut bacteria can modify the naturally produced cortisol and the structurally similar anti-inflammatory drug dexamethasone, we expect that the known bacterial enzymes that metabolize cortisol are likely to alter the structure of corticosteroids like dexamethasone and others. This research also proposes to study the genes capable of catabolizing cortisol and characterize any modification of corticosteroids. Drug metabolism affects the pharmacokinetics and pharmacodynamics of therapeutics. Personalized medicine could one day account for an individual’s microbiome when considering the best therapy to treat human diseases and cancers, but this requires a genetic link to a drug transformation and to score the ability of the encoded enzyme to lead to drug metabolism.

HUMAN HEALTH RELEVANCE: The human intestines are host to trillions of microbes that aid the digestion of foods, but these microbes also digest the drugs meant to improve human health. These modifications can change the effectiveness and safety of pharmaceuticals. This proposed research is expected to identify how drugs change and the rate common intestinal bacteria digest these drugs.