Structural and Chemical Biology of the Human Microbiome
Drugs and the Gut Microbiome
We are unraveling how drugs affect the composition and activity of the gut microbiota. Drugs, or their metabolites, directed to the GI tract for excretion interact functionally in a variety of ways with factors unique to the gut microbiome. Preventing the reactivation of cancer drugs in the GI tract alleviates the toxicity these compounds cause, which limited their efficacy in humans. We have elucidated how the colon and pancreatic cancer drug irinotecan and the tyrosine kinase inhibitor regorafenib are reactivated by gut microbial enzymes. We have then provided effective and targeted small molecules that block this reactivation. Furthermore, we have demonstrated that NSAIDs, the most widely used drugs in the world, cause gut toxicity that leads to inflammation, bleeding and ulceration, and have been able to alleviate this damage in animal models. This is an active project with much more to do for the drugs listed above, and with many more drugs to examine in the future.
Hormones, Neurotransmitters, and the Gut Microbiome
We are examining how endobiotic hormones and neurotransmitters are metabolized by the gut microbiome. We have already shown that estrogens serve as substrates for a subset of gut microbial beta-glucuronidase enzymes. We are extending these studies to include a wide range of hormones and neurotransmitters. Local and systemic effects of gut reactivated hormones may drive several disease states that present in idiosyncratic ways due to variabilities in the gut microbiome. Indeed, our recent presentation of an activity-based probe-enabled proteomics pipeline effective for selecting individual proteins from the complexity of human feces is a key step toward understanding the functional roles gut proteins have on human physiology. This is an active project with many crucial compounds left to examine.
New Therapeutics Targeting the Gut Microbiome
We pioneered the development of drugs that specifically, potently and non-lethally control the impact of the gut microbiota on mammalian physiology. Starting with cancer drugs and extending into other indications, we have established gut microbial enzyme families as targets of novel inhibitors, and have advanced these inhibitors into animal studies and subsequent development. This is an active project that links structural and chemical biology to drug discovery and the gut microbiota.
