With over 10 trillion bacteria living in our gut, the human digestive system is more of an ecosystem than a series of organs. As human hosts, we hold crucial symbiotic relationships with many of our bacterial residents. In return for much needed nutrients and a protected living environment, much our healthy flora provides necessary digestive and immune functions. However, much of the activity of the estimated 500-1000 species of bacterial inhabitants of our gut is largely unknown.
With efforts such as the Human Microbiome Project, which was launched by the National Institute of Health in 2008, with a goal of identifying and genetically sequencing the myriad of microbial species found in our various organ systems, science has begun to amass a body of knowledge that has catalyzed research in the field.
Developments from researchers at the Wistar Institute in Philadelphia represent some of the latest advances spawned by this initiative. At the 2014 annual meeting of the association for cancer research in San Diego, Frank Rauscher, III, a researcher at the Wistar Institute, and other members of his research team will present findings that they believe implicate certain species of intestinal E. coli with increased risks of colon cancer. If their research is supported, it could lead to a significant step forward in the treatment of colon cancer.
Thanks to increased public awareness, the incidence rates of colon cancer have actually declined in the United States over the past few years. However, this decrease in incidence has not been accompanied by an increase in survival rates. Although scientists have identified genetic mutations related to the disease, they have not been able to translate their new knowledge to patient survival. This new research from the Wistar Institute represents a new avenue for potential treatment of the disease.
The link between the E. coli bacterial strain and colon cancer was discovered while Rauscher and his colleagues were studying the anti-inflammatory properties of pathogenic E. coli. Both healthy and unhealthy strains are known to actively reduce inflammation of surrounding human tissue. This is often interpreted as a survival mechanism, as the human inflammatory response is activated by the body to promote healing as well as the spread of bacteria.
The Wistar researchers identified several proteins produced by E. coli that they believed to be the active agents of this process. One such enzyme, referred to as NLEE, is an enzyme that targets a downstream effector in the NF-kB pathway, a pathway known to be involved in inflammatory response.
While looking for other potential targets of the NLEE enzyme, Rauscher and colleagues discovered that NLEE was capable of binding and subsequently deactivating certain proteins involved in DNA repair. Through collaboration with Fen Shao, a researcher at the National Institute of Biological Science in Beijing, China, the team determined that NLEE targets a common protein structural motif known as the zinc finger. This motif allows many proteins, including those involved DNA repair, to bind DNA and RNA. Biochemical analysis revealed that by adding a single methyl group to the zinc finger of DNA repair proteins, NLEE was able destabilize these proteins causing them to unfold and unable to perform their regulatory function. Such failure of the gene repair mechanisms is a known hallmark of both cell death and cancer cell development. Thus, the researchers were able to connect this E. coli-supported activity to cancer.
This research may lead to a significant advance in the treatment of colon cancer. With this information, pharmaceutical companies could develop drugs that more directly treat colon cancer risk factors. However, more research needs to be done before this becomes a viable approach.
