Gut Bacteria's DNA-Damaging Molecules May Explain IBD-Colon Cancer Link

For years, doctors have known that people with inflammatory bowel disease face a higher risk of developing colorectal cancer than the general population. The question has lingered: why? A team of researchers publishing in Science this week may have found a crucial piece of the answer, buried in the bacterial makeup of the gut.

The culprit is a molecule called indolimines—a previously unknown class of DNA-damaging compounds produced by a bacterium named Morganella morganii. This microbe thrives in the intestines of patients with IBD, the umbrella term for ulcerative colitis and Crohn's disease, as well as in those already diagnosed with colorectal cancer. In laboratory experiments, indolimines damaged DNA directly. In mice carrying colorectal tumors, the molecules accelerated cancer growth. When the researchers deleted the bacterial gene responsible for making indolimines, tumor growth stopped.

The discovery adds texture to a growing body of evidence linking the gut microbiome to cancer risk. Other bacteria have been implicated before—certain strains of E. coli, for instance, produce a genotoxin called colibactin that also damages DNA and promotes tumor development in mice. But indolimines represent a distinct mechanism, one that researchers had not previously identified. Cynthia Sears, a professor of medicine and oncology at Johns Hopkins University School of Medicine who was not involved in the study, described the finding as another thread in a much larger tapestry. "We have a vast array of data that links the microbiome to colon diseases and colon cancer," she said. "This is just one other piece that's been added to that."

To find indolimines, the research team screened more than 100 bacterial strains isolated from stool samples of eleven IBD patients. They grew each strain in a lab dish alongside DNA and identified eighteen that caused genetic damage. From those eighteen, they isolated individual molecules and tested which ones were responsible. The DNA damage pattern they observed was unlike anything colibactin produced, and the flagged bacteria could not make colibactin at all. This suggested the existence of genotoxins no one had recognized before. The team zeroed in on M. morganii because prior research had already flagged it as unusually common in both IBD and colon cancer patients. Through careful molecular work, they identified the indolimines and pinpointed the aspartate aminotransferase gene—the aat gene—that codes for the enzyme needed to produce them.

The mouse studies provided the most convincing evidence. When M. morganii carrying the functional aat gene was introduced into mice with colorectal tumors, cancer growth accelerated. When the researchers deleted the aat gene, indolimines could no longer be made, and tumor growth halted. Yet Sears cautioned that the mouse model has real limitations. The researchers used what are called gnotobiotic mice—animals engineered to contain only specific bacteria. They included M. morganii and seven other non-toxic bacterial species, a far simpler ecosystem than the thousands of species living in a human gut. This controlled setup allowed the scientists to isolate the cancer-driving effects of M. morganii, but it could not capture the full complexity of how bacteria interact in a real microbiome.

The implications, if the findings hold up in further research, could reshape how doctors approach colorectal cancer prevention. Stool samples could eventually become screening tools, allowing physicians to identify patients at elevated risk by detecting the presence of M. morganii or indolimines. Treatments might be developed to reduce the abundance of these cancer-linked bacteria, lowering disease risk before tumors form. But Sears emphasized that we are still in early territory. "We certainly know those clinical associations, but we don't know how to prevent them, or disrupt them, to decrease the risk of cancer," she said. "We need to figure out at a molecular level what the mediators are so we can bring something to the bedside, for patients." The next phase of research will need to establish how common M. morganii is across different types of IBD and colorectal cancer, how exactly indolimines damage DNA at the molecular level, and how influential these molecules are compared to other genotoxins in driving cancer development. For now, this study is a first step—one that opens a door but does not yet walk through it.