The bacterium Clostridioides difficile (C. difficile), which causes severe diarrhea and an estimated 400,000 infections annually in the United States, may be a previously unrecognized contributor to colorectal cancer.
The findings from human colon cancer specimens, culturing, and mouse models were reported last month by researchers at Johns Hopkins University and Vanderbilt University Medical Center in the journal Cancer Discovery.
“These findings represent an initial glimpse into the tumorigenic potential of C. difficile,” Ken Lau, PhD, associate professor of Cell & Developmental Biology and Surgery at VUMC and the paper’s co-senior author. “Our work sheds light on the earliest epithelial response to this pathogen that may subsequently lead to cancer.”
“Researchers and providers studying C. difficile have been concerned about over-diagnosing patients who carry C. difficile but lack diarrhea or other symptoms,” added Nicholas Marham, MD, PhD, assistant professor of Medicine and of Pathology, Microbiology & Immunology at VUMC, and the paper’s co-first author.
“We need to perform more clinical studies to determine whether or not long-term carriage of C. difficile is a risk for cancer,” Markham said. “Perhaps clinicians might one day detect and treat certain bacteria to limit colon cancer risk.”
The research was led by Cynthia Sears, MD, Bloomberg~ Kimmel Professor of Cancer Immunotherapy at the Johns Hopkins University School of Medicine, Lau, and Franck Housseau, PhD, associate professor of oncology at Johns Hopkins.
Several years ago, researchers in Sears’ lab discovered that more than half of patients with colorectal cancer had bacterial biofilms — dense collections of bacteria on the colon surface — whereas 10% to 15% of healthy patients without tumors displayed biofilms.
When the researchers infected mice with biofilm samples derived from individual people with colorectal cancer, one sample markedly increased colorectal tumors in the mice.
Sears and colleagues performed additional experiments to see if a single bacterial species or a community of bacteria were promoting tumor formation in the mice. They noted that toxigenic C. difficile, the type of C. difficile that causes diarrhea, was absent in the samples that did not cause tumors, but present in the samples that caused tumors in mice.
When the researchers added this bacterium to the samples that originally did not cause tumors, it induced colon tumors in the mice. Further testing showed that C. difficile alone was sufficient to prompt tumor formation in the animal models.
Single-cell RNA-sequencing experiments led by Markham and Lau showed that C. difficile brought about a range of changes within colon cells that made the cells vulnerable to more rapid growth and carcinogenic mutations.
Cells exposed to this bacterium turned on genes that drive cancer and turned off genes that protect against cancer. These cells produced reactive oxygen species, unstable molecules that can damage DNA, and they also prompted immune activity associated with harmful inflammation.
A toxin produced by this bacterium — known as TcdB — appears to cause most of this activity. Mice infected with genetically engineered C. difficile strains in which the toxin gene had been inactivated produced far fewer tumors than those with TcdB-active ones.
To date, there is limited epidemiological data linking C. difficile with colorectal cancer in humans, but if further research shows that a connection exists, it could lead to screening for latent C. difficile infection and or previous infection as a risk factor for cancer, the researchers concluded.
