Programming Indigenous Gut Bacteria to Prevent Colorectal Cancer Induced by Microbial Carcinogen
Abstract
This research project addresses the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Area of colorectal cancer (CRC), with the focus on gaps in cancer prevention. CRC is the second leading cause of cancer death among men and women combined in the United States. Our intestine is colonized by approximately 100 trillion bacteria of diverse strains. Among these are enteric bacteria that can produce a DNA-damaging small molecule named colibactin, which live in a large number of people in developed countries. Mechanistically, colibactin induces DNA damage by introducing many stable chemical crosslinks such that genomic DNA becomes entangled and/or susceptible to random gene mutations. As a result, clinical studies in CRC patients have linked the presence of colibactin and colibactin-positive bacteria to the high incidence rate of CRC. Despite efforts to understand the fundamental mechanisms underlying colibactin-induced CRC, a therapeutic strategy has yet to be developed against colibactin to address CRC. As a result, we will, for the first time, program an indigenous gut bacterium as live therapeutics that are highly safe and efficacious against colibactin-induced CRC in humans. Interestingly, colibactin-producing bacteria have developed a unique strategy to detoxify colibactin by synthesizing an enzyme, named ClbS, inside their own cells. Mechanistically, the enzyme ClbS acts as an antidote inside bacteria that can chop up colibactin and therefore, abolish its DNA-damaging activity to confer self-protection. Motivated by this finding, we propose to take advantage of the above-mentioned mechanism by engineering an indigenous intestinal bacterium, B. thetaiotaomicron, to secrete ClbS in the gut lumen, and further anchoring the enzyme within the mucus layer which separates intestinal cells from the inner space of the gut that contain fluids and digested food. ClbS’s ability to degrade colibactin can provide a highly effective strategy to dramatically reduce the level of colibactin in the gut. We propose that B. thetaiotaomicron can serve as a vessel for secreting ClbS into the human gut for several unique advantages: (1) It is both prevalent (present in 46% of humans) and abundant in the human gastrointestinal tract. (2) B. thetaiotaomicron has been shown to confer numerous health benefits and therefore, it can become a safe vehicle to deliver therapeutic enzymes. (3) B. thetaiotaomicron can be administered via the oral route and has demonstrated resistance against the gastric environment in preclinical animal models. (4) Unlike probiotics, B. thetaiotaomicron can establish long-term associations with human hosts and is not susceptible to rapid clearance by the host, making it particularly attractive for addressing the chronic nature of colibactin-induced CRC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110324
Entities
People
- Jiahe Li
Organizations
- Northeastern University
- United States Army