Exploiting Microbiota Metabolism for Colorectal Cancer Prevention
Abstract
Microorganisms living in the human intestinal tract, termed the human gut microbiota, have been linked to the initiation of colorectal cancer. Certain strains of E. coli produce a toxin called “colibactin,” and our team established that colibactin causes colorectal cancer using mouse models. The colibactin pathway is found in up to 67% of colorectal cancer patients, and the specific DNA mutations caused by colibactin can be observed in cancer patients’ genomes. Our team also characterized the structure and function of this important toxin at a detailed level. These advancements have now opened the door to developing new strategies to prevent colorectal cancer in a sizable number of patients. Soldiers may be exposed to higher levels of toxins and pathogens during active duty, which would put them at even higher risk of developing colorectal cancer. In contrast to the human genome, which derives from hereditary origins, we can readily change and influence our microbiome in defined ways to better prevent cancer formation, augment cancer treatments, and promote human health. We discovered an antibiotic that is only activated inside colibactin-producing cells. Consequently, we propose to use this antibiotic to eliminate the colorectal cancer factor without affecting the rest of the “healthy” microbiome. Because we have the genetic instructions for the production of these antibiotics, we will add these instructions to probiotics currently used in human health. We call these probiotics “Colirette,” which is analogous to “Nicorette.” While Nicorette can be used to mitigate lung cancer risk associated with voluntary smoking, Colirette could be the first safe, non-toxic, and affordable probiotic to protect humans from a more potent cancer risk factor involuntarily found in our intestinal tracts. To reach these human goals, we first have to develop the best Colirette probiotics and test them in colorectal cancer mouse models, which is the primary goal of this research program. One of our control strains is already available for use in humans, and if this control has any positive effect in our studies, these probiotics could be available immediately. However, our engineered variants are expected to have much higher efficacy. If the 3-year project is successful, then our team would be poised to initiate human clinical trials on these optimal probiotics. In sum, our project could ultimately lead to safe, affordable, and accessible colorectal cancer prevention strategies and substantially reduce the burden of the third-leading cause of cancer deaths in the United States.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110547
Entities
People
- Jason Crawford
Organizations
- United States Army
- Yale University