The oncogenicity of E. coli depends on its ability to get close to the intestinal cells.
When we talk about mutations in DNA, the culprits usually include ultraviolet radiation, or ionizing radiation, or carcinogenic substances, or the cell’s own apparatus for doubling (replicating) DNA – it is known that replication proteins do not work with one hundred percent accuracy. But these are not the only causes of mutations. They can arise, for example, from the common E. coli, the most numerous and well-studied bacterium that lives in the intestines.
Some of its strains secrete a substance called colibactin – a special peptide that cross-links nitrogenous bases in DNA chains. Nitrogen bases (genetic letters) are usually held together by hydrogen bonds: the adenine base on one chain forms hydrogen bonds with the thymine base on the other chain, and the guanine base with the cytosine base. As a result, a double-stranded DNA molecule is stable enough that its chains do not diverge on their own, although special proteins that work with genetic information may well separate them. Colibactin connects the bases between both chains with a covalent bond, which cannot be broken so easily, and even if the bond is broken, the DNA in this place is not always restored correctly – in other words, mutations appear.
Colibactin strains of E. coli are more common in people with colon cancer or those who are about to develop a tumor. At the same time, not all such strains are equally dangerous. So, one of them is generally used as a probiotic, and it causes much less damage to DNA than in the case of other strains, although it produces the same amount of colibactin. Employees of Ghent University, together with colleagues from other scientific centers in Belgium, the USA and the UK, write in Nature about what determines the oncogenicity of colibactin Escherichia coli. The researchers noticed that the probiotic (safe) strain and another strain with colibactin, which is clearly associated with tumors, differ in a certain protein. This is a protein from the class of adhesins, on which the interaction of bacteria with the substrate, including host cells, depends. In the two strains it differed in only three amino acids, but as a result the bacteria behaved very differently.
The intestinal epithelium is covered with a layer of complex mucus, which protects it from various troubles, including bacteria. It is better for any bacteria, even symbiotic ones, not to come into direct contact with intestinal cells, and the probiotic strain of E. coli does not come into contact – these bacteria remain in the mucous layer. But the oncogenic strain in experiments with mice penetrated directly into the cells and even deeper, into the tissue itself. As a result, many more mutations appeared in the mouse cells, and their likelihood of tumors increased significantly. The researchers also showed that the problem was precisely in alternative versions of the adhesion protein: its gene was transplanted from a dangerous strain to a safe one and vice versa, after which the previously safe strain began to behave as dangerous, and the dangerous one as safe.
Obviously, if you treat the adhesion protein with some kind of drug that disables it, then the oncogenic strain will not be able to reach the intestinal cells. There is such a drug, it targets this particular protein, and it is currently being tested in clinical trials. In mice, it worked as expected: colibactin bacteria of the oncogenic strain could not penetrate the cells, and the mice developed intestinal tumors much less frequently. This drug may be worth clinical testing to see how it prevents colon cancer. But at the same time it would be worth studying the behavior of different colibactin strains in the human intestine.
The researchers observed that even in mice, the tumorigenicity of E. coli depended on the presence of other bacteria; By itself, it practically could not provoke a tumor. The microflora in mice and people is different, and in humans, dangerous strains of E. coli are likely to cooperate with other helpers. It cannot be ruled out that the adhesion protein gene, which allows bacteria to penetrate intestinal cells, is also present in other intestinal microbes (especially since bacteria can exchange genetic information due to horizontal gene transfer), and in their interaction with the intestinal mucosa and with its cells can be your own characteristics. Finally, when suppressing the work of the adhesion protein, it would be good to do it in such a way as not to harm beneficial symbiotic strains.
Source: www.nkj.ru
