Scientists have discovered molecules that damage DNA from gut bacteria that may explain why people with inflammatory bowel disease (IBD) have higher rates of colon cancer than those without the condition.
In a new study, published Thursday (Oct. 27) in the journal Sciencethe researchers identified a previously unknown class of DNA-damaging molecules, or genotoxins, which they named “indolimines.”
These molecules are produced by Morganella morganiia bacterium that multiplies in the intestines of IBD patients and those with colon cancer.
Indolimines damaged DNA in laboratory dish experiments and also led to the development of cancer in mice with colon tumors.
And by blocking the production of indolimines from M. morganiiscientists found that they could prevent tumor growth in mice.
Other gut bugs have been linked to IBD and colon cancer in the past, said Cynthia Sears, a professor of medicine and oncology at Johns Hopkins University School of Medicine in Baltimore, who was not involved in the study.
For example, select strains of Escherichia coli are linked to IBD and produce a genotoxin called colibactin, which damages DNA and leads to tumor growth in mice.
The new study adds to our understanding of how other bacteria may contribute to these diseases.
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“We have a huge body of data – and this is just another piece added to it – that links the microbiome to colon disease and colon cancer,” Sears said.
In the long term, this line of research could lead to screening tools that help doctors identify patients at high risk of colon cancer simply by taking a stool sample.
It could also lead to preventative treatments that reduce the abundance of cancer-linked bacteria in patients’ guts and thus reduce the risk of disease.
At this point, “we certainly know these clinical associations, but we don’t know how to prevent or interrupt them to reduce cancer risk,” Sears said.
“We need to understand at the molecular level what the mediators are so we can bring something to the bedside, for patients.”
To identify the mysterious DNA-damaging molecules, the researchers first examined more than 100 types of gut bacteria from stool samples of 11 IBD patients. (IBD is a term that includes ulcerative colitis, which causes inflammation and sores in the lining of the large intestine and rectum, and Crohn’s disease, which causes inflammation of all or part of the digestive tract, most commonly in the small intestine.)
The team grew each of these bacterial strains in a laboratory dish with DNA and identified 18 strains that destroyed the genetic molecule.
From these strains, the scientists identified individual molecules produced by the bacteria and examined which of them caused DNA damage.
Interestingly, the DNA damage the researchers observed did not match that caused by colibactin, and the labeled bacteria were unable to produce colibactin.
“These data thus suggested the existence of previously unrecognized microbe-derived genotoxins,” the researchers wrote in their report.
To characterize some of the unknown genotoxins, the researchers zoomed in M. morganiiwhich was previously reported to be prevalent in both bowel and colon cancer patients.
Through this work, they not only discovered indolimines, but also identified a bacterial gene required for their production: the so-called aspartate aminotransferase (aat) gene, which encodes an enzyme.
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In a mouse model of colon cancer, M. morganii strains with the aat gene exacerbated tumor growth.
But by deleting this gene from the bacteria, the team stopped the production of indolimines and thus stopped the cancer from growing.
“The best evidence they show is the mouse studies — that convinced me,” Sears said.
However, the mouse model has its limitations. The researchers used “gnotobiotic” mice, meaning they chose exactly which bacteria to grow in the rodents. they only included M. morganii and seven other bacteria that were not genotoxic.
This allowed scientists to observe the cancer-causing effects M. morganiibut it didn’t capture the complexity of a natural gut microbiome, Sears said.
More work is needed to understand how widespread it is M. morganii are in different types of IBD and colon cancer.
Follow-up studies should also identify exactly how indolimines cause DNA damage and how much these molecules affect cancer development, compared to other genotoxins, Sears said.
“This is a first step,” he said of the new paper.
This article was originally published by Live Science. Read the original article here.