Bacteria can promote our health, but they can also harm it. For example, this is the case with certain strains of Escherichia coli. As a study with miniature intestines in the petri dish now shows, these toxin-producing microbes can trigger mutations that can potentially cause illness. They leave a characteristic signature in the genome of intestinal cells. The researchers found exactly such mutation patterns in the DNA of colon cancer patients. For the first time, they demonstrate a direct connection between our microbial roommates and cancer-promoting mutations in the intestine.
Our digestive tract is populated by trillions of tiny organisms: the bacteria in the intestinal flora. These microbes have a decisive influence on our health – also on the health of the intestine itself, as is increasingly shown. But what role do our microbial roommates play in digestive organ cancer? While the gastric germ Helicobacter pylori is known to promote gastric carcinoma, the question of microbial triggers in colon cancer has so far been less clear. However, evidence of bacterial involvement has increased recently: Studies show that patients often have characteristic abnormalities with regard to the composition of their intestinal flora. Among other things, bacteria are particularly common among them, which can produce carcinogenic substances.
These microbes also include certain strains of Escherichia coli. These bacteria produce colibactin – a toxic substance that can damage DNA and thus promote mutations that cause illness. However, a direct connection between these bacteria called pks + E. coli and the occurrence of cancer-causing changes in the genetic material has not yet been demonstrated. This is exactly what Cayetano Pleguezuelos-Manzano from the Hubrecht Institute in Utrecht and his colleagues have now made up for: To find out how an infection with these microbes affects DNA, they first cultivated intestinal organoids in the Petri dish. They then repeatedly exposed these miniature replicas of the digestive organ to pks + E. coli over a period of five months. Before and after treatment, they sequenced the organoid genome.
Characteristic signature
Would the bacterial infection change the genetic makeup? In fact, the evaluations revealed that the epithelial cells of the mini-intestines had twice as much DNA damage as control organoids that had been treated with harmless E. coli germs. But not only that: The scientists also identified two characteristic patterns in the DNA of these cells – a mutation signature that the colibactin toxin had left behind like a fingerprint. Specifically, it was an exchange of the DNA base adenine to one of the other three possible bases in the code of the DNA and the loss of a single adenine in long sections of successive copies of this base. From these results, the researchers conclude that colibactin-producing bacteria can cause mutations in intestinal cells that potentially cause disease. But can these genetic changes actually be found increasingly in colon cancer patients? The researchers examined this on samples from two independent patient groups. Overall, they analyzed the genomes of 5,876 tumors from various types of cancer – including many intestinal tumors.
The result was clear: “The mutagenic footprint could be clearly detected in more than five percent of the intestinal tumors, while it was found in less than 0.1 percent of the other cancers,” reports Pleguezuelos-Manzano’s colleague Jens Puschhof. The few other tumors that also showed the characteristic mutation signature belong to cancers that are also associated with Escherichia coli – for example tumors of the oral cavity or bladder. “It is known that E. coli can also infect these organs,” explains Puschhof. For the first time, the scientists have demonstrated a direct connection between bacterial toxins and genetic changes that promote cancer. “Even carcinogenic influences such as tobacco or UV radiation leave specific mutation patterns in the DNA. But never before have we discovered patterns in colorectal cancer that can be traced back to bacteria that live in our bodies, ”stated group leader Hans Clevers.
Dangerous probiotics?
“The study provides clear evidence of the causal role of pks + E. coli bacteria in the development of some types of colon cancer and, together with many previous studies, suggests that a better understanding of bacterial processes in cancer development will also open up new possibilities for prevention and therapy “Comments Georg Zeller from the European Molecular Biology Laboratory (EMBL) in Heidelberg. In fact, the results could have a direct impact on health care. Because it is known that around 20 percent of all people harbor the harmful E. coli bacteria in their intestines. Identifying these in the context of screenings could help to identify risk persons in the future.
In the future, the cancer-promoting germs may also be removed in a targeted manner with the help of antibiotics or other measures, as the researchers suggest – however, this has not yet been possible without further ado. The new findings are also relevant for the production of probiotics: “Probiotics are marketed that contain genotoxic strains of E. coli,” says Clevers. “These strains should be critically re-evaluated in the laboratory. As probiotics, they may provide relief for some short-term symptoms. However, decades after treatment, they could lead to cancer. “
More research needed
In the future, further research will have to show the conditions under which colonization with colibactin-producing E. coli germs really leads to colorectal cancer and the overall role of the bacteria in cancer risk. Because: Not all people who have these bacteria in them get sick. And not all colon cancer patients colonized with this germ carry the mutation signature now identified in their genome, as Erik Thiele Orberg from the Technical University of Munich comments. “We therefore need a better understanding of how colonization can lead to colon cancer in some patients and which genetic or immunological predispositions may have to exist in those affected,” concluded the doctor.
Source: Cayetano Pleguezuelos-Manzano (Hubrecht Institute Utrecht, The Netherlands) et al., Nature, doi: 10.1038 / s41586-020-2080-8