Gut Microbial Enzymes and Human Disease

PROJECT SUMMARY Although it has been established that the gut microbiota influence normal physiology and transitions to disease, the roles played by microbial proteins in these complex molecular processes are still poorly understood. Through this project, we will examine the structures and functions of diverse gut microbial enzymes, modulate their activities with targeted small molecules, and unravel their roles in human disease. Over the last five years, we have elucidated the structures and functions of key microbial protein families, created gut bacterial enzyme inhibitors, and developed novel multi-omics approaches to examine gut microbial processes. Here we will focus on pathways that are unique to the gut microbiome, concentrating specifically on bile salt hydrolases, tryptophan-indole lyases, and -glucuronidases. Bile salt hydrolases convert amino acid-conjugated bile salts to free bile acids with direct effects on the host and the microbiota. We will unravel the diversity in structures and functions of bile salt hydrolases in the gut microbiome and pinpoint the roles these enzymes play in recurrent Clostridioides difficile infection. Gut microbial tryptophan-indole lyases, or tryptophanases, are the only source indole in humans. Indole is converted to the uremic toxin indoxyl-sulfate, which exacerbates kidney and heart diseases. We will characterize tryptophan-indole lyases in the human gut microbiome and will target these enzymes with novel, potent and selective inhibitors to block indoxyl-sulfate formation in animal models. Finally, -glucuronidases reactivate previously inactivated endobiotics in the gut including serotonin, dopamine, and estrogen. We will define the roles that gut microbial -glucuronidases play in the antenatal depression experienced by one in seven expectant mothers by evaluating their impacts on neurotransmitter and steroid hormone levels. Overall, this interdisciplinary project will employ the tools of structural and chemical biology, biochemistry, and multi-omics and will take advantage of human clinical samples and select mouse models. In summary, the proposed research program will define how gut microbial enzymes influence human disease toward the development of novel diagnostic and therapeutic paradigms.