Study Results Suggest C. Difficile Drives Some Colorectal Cancers

Clostridioides difficile, a bacterial species well known for causing diarrheal infections, could also drive colorectal cancer, according to data from the Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Kimmel Cancer Center.

“The uptick of individuals under age 50 being diagnosed with colorectal cancer in recent years has been shocking. We found that this bacterium appears to be a very unexpected contributor to colon malignancy, the process by which normal cells become cancer,” Cynthia Sears, MD, professor of cancer immunotherapy at Bloomberg~Kimmel and professor of medicine at the Johns Hopkins University School of Medicine, said in a statement.

Several years ago, investigators discovered that more than half of individuals with colorectal cancer had bacterial biofilms compared with approximately 10% to 15% of those without tumors who had biofilms.

However, when the investigations infected mice with biofilm samples derived from the individuals with colorectal cancer, 1 sample increased the colorectal tumors in the mice. In the controls, less than 5% developed tumors, whereas those with biofilms induced tumors in about 85% of mice.

In additional work, the investigators identified a patient without a biofilm that similarly increased colorectal tumors in mice. Several other bacterial species have been linked with colorectal cancer, including enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and a specific strain of Escherichia coli. However, these microbes were either absent in the tumors of the 2 individuals or did not successfully colonize the mice.

This suggests that other bacteria were responsible for inducing colorectal cancer.

To determine which bacteria could be causing the tumors, investigators performed additional experiments to see if a community of bacteria or a single bacterial species induced the tumor formation.

Investigators found that toxigenic C. difficile was absent in the samples that did not cause tumors but present in the samples that did have tumors. When they added to the bacterium those who did not originally have tumors, it induced colon tumors in those mice.

After further testing, investigators concluded that C. difficile alone was sufficient to promote tumor formation in animal models.

Additional experiments showed that C. difficile brought about a range of changes within colon cells that made them vulnerable to cancer.

Investigators found that cells exposed to the bacterium turned on genes that drive cancer and turned off genes that protect against cancer. The cells also produced reactive oxygen species and prompted immune activity that was associated with harmful inflammation.

Furthermore, a toxin produced by the bacterium appeared to cause the activity. When investigators used genetically engineered C. difficile strains that contained inactive toxin genes and/or released a C. difficile toxin called TcdA, mice infected with the TcdB-inactive microbes produced far fewer tumors than TcdB-active once.

“While this link between C. difficile and colorectal cancer needs to be confirmed in prospective, longitudinal cohorts, developing better strategies and therapeutics to reduce the risk of C. difficile primary infection and recurrence could both spare patients the immediate consequences of severe diarrhea and potentially limit colorectal cancer risk later on,” Julia Drewes, PhD, assistant professor of medicine at Johns Hopkins, said in the statement.

The findings were published in Cancer Discovery.

Reference

Study suggests that c. difficile drives some colorectal cancers. EurekAlert. News release. July 14, 2022. Accessed July 15, 2022. https://www.eurekalert.org/news-releases/958680