The bacterial species Clostridioides difficile, or C. diff, which is well known for causing serious diarrheal infections, can also cause colorectal cancer, according to data collected by researchers at the Bloomberg Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Kimmel Cancer Center. Research reveal another troubling role for this microbe, which causes more than 500,000 infections a year in the United States, many of which are very difficult to treat.
“The increase in people under the age of 50 diagnosed with colorectal cancer in recent years is shocking. “We found that this bacterium appears to be a very unexpected contributor to colon malignancy, the process by which normal cells become cancerous,” says Cynthia Sears, M.D., Bloomberg~Kimmel Professor of Cancer Immunotherapy and Professor of Medicine at the Johns Hopkins University School of Medicine.
Researchers at the Sears Lab reported several years ago that more than half of colorectal cancer patients had bacterial biofilms—dense colonies of bacteria on the surface of the colon—while only 10% to 15% of healthy people without tumors had biofilms. However, one sample stood out to the researchers when they infected mice with biofilm samples from specific colorectal cancer patients because it significantly increased colorectal tumors in the mice. This slurry caused tumors in 85% of the mice, while most controls developed tumors of less than 5%.
In further work, the team identified a patient sample without biofilm that similarly increased colorectal tumors in mice. Although several bacterial species have been associated with colorectal cancer including the enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and a specific strain of Escherichia coli these microbes were either absent or present in the tumors of these two patients (B. fragilis and E. coli). do not successfully colonize mice (F. nucleatum), suggesting that other bacteria were responsible for promoting the colorectal cancer cascade.
To find out which bacteria can cause tumors in mice, Sears, along with study co-authors Julia Drewes, Ph.D., assistant professor of medicine, Jie (Angela) Chen, Ph.D., Jada Domingue, Ph.D. Johns Hopkins and colleagues conducted additional experiments to determine whether a single bacterial species or community of bacteria promotes tumor formation in mice.They noted that toxigenic C. difficile, the type of C. difficile that causes diarrhea, was not present in samples that did not cause tumors, but was present in samples that did cause tumors in mice. When researchers added this bacterium to samples that did not initially cause tumors, it induced colon tumors in mice. Further testing showed that C. difficile alone was sufficient to induce tumor formation in animal models.
Additional experiments led by co-author Nicholas Markham, M.D., Ph.D., assistant professor of medicine at Vanderbilt University Medical Center, and co-leaders Franck Housseau, Ph.D., associate professor of oncology at Johns Hopkins, and Ken Lau, Ph.D., associate professor of cell and developmental biology and surgery at Vanderbilt University School of Medicine, showed that C. difficile caused a series of changes in colon cells that made them vulnerable to cancer. 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 also triggered immune activity associated with harmful inflammation.
Most of this activity appears to be caused by a toxin produced by the bacterium – known as TcdB, the researchers say. When they used genetically engineered strains of C. difficile that contained inactivated toxin genes and/or released a related C. difficile toxin called TcdA, mice infected with microbes with inactivated TcdB produced far fewer tumors than those with active TcdB, whereas the TcdA produced by C. difficile was insufficient to causing tumors. Drewes says that to date there is limited epidemiological data linking C. difficile to colorectal cancer in humans, but if further research shows that the link exists, it could lead to screening for latent C.
Difficile infection or previous infection as a risk factor for cancer. Because long-term exposure to TcdB may increase the risk of colorectal cancer, important prevention efforts could include increased efforts to rapidly and effectively eradicate this pathogen, which recurs—often repeatedly—in 15-30% of infected patients after initial treatment , including pediatric patients.”While this association between C. difficile and colorectal cancer needs to be confirmed in prospective, longitudinal cohorts, the development of better strategies and treatments to reduce the risk of primary C. difficile infection and recurrence could spare patients the immediate consequences of severe diarrhea and potentially reduce the risk of colorectal cancer later,” says Drewes.
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