Scientists have uncovered the mechanism of communication between intestinal bacteria and colorectal cancer

There are billions of bacteria in the human gut, most of which pose no health risk. However, some microorganisms are capable of producing substances that damage tissues and disrupt the functioning of organs. Scientists have been studying the connection of one of these bacteria with the development of colorectal cancer for almost two decades, but could not determine how its toxin attacks intestinal cells. Now, researchers have discovered a protein that helps it attach to tissues. About how the bacterium disrupts the protection of the intestine and why it can contribute to the formation of tumors — in the material "Izvestia".

A bacterium associated with the development of tumors

Researchers from Johns Hopkins University and Harvard Medical School studied the bacterium Bacteroides fragili. It can be present in the intestines of about 20% of healthy people. By itself, its detection does not mean that a person will develop cancer: certain strains that produce the BFT toxin are dangerous.

Scientists have known about the connection of this substance with damage to the mucous membrane of the colon and the formation of tumors since 2009. In previous experiments, the researchers found that the toxin destroys the protein E-cadherin, which helps neighboring cells hold together. Because of this, the integrity of the protective barrier of the intestine is disrupted, and harmful substances and bacteria can enter the surrounding tissues.

However, the question remained open: if the toxin affects E-cadherin, why does it not bind to it directly? A research team led by Cynthia Sears has found the answer in a new paper published in the journal Nature.

A protein that helps the toxin attack cells

To find the missing link, scientists used CRISPR technology. With its help, they sequentially disabled different genes in the cells of the colon epithelium and checked which of them were necessary for the toxin to attach and damage tissues.

The researchers paid special attention to the gene responsible for the production of the protein claudin-4. It participates in the formation of tight contacts between neighboring cells and helps maintain the integrity of the intestinal barrier. When the scientists turned off this gene, the BFT toxin stopped binding to cells and could no longer attack E-cadherin.

Thus, claudin-4 turned out to be a kind of attachment point for the bacterial toxin. First, BFT binds to this protein, and then it gets the opportunity to act on E-cadherin. In laboratory experiments, the researchers also confirmed that the toxin and claudin-4 molecules interact directly with each other and form a stable complex.

An unusual Bacterial Toxin strategy

Claudin-4 surprised the researchers because they expected to find among the possible receptors a protein associated with signaling inside the cell. Such molecules help cells respond to environmental changes. However, the found protein performs another task — it supports physical connections between neighboring cells.

To confirm the interaction of the molecules, the Johns Hopkins team collaborated with structural biology specialists from the Institute of Molecular Biology in Barcelona. Using methods for measuring molecular interactions, they showed that BFT and claudine-4 form a closely related complex. In this case, one molecule of the protein receptor accounts for one molecule of the toxin.

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How is intestinal damage related to cancer

When the toxin destroys E-cadherin, the cells lose some of their connections with each other, and the protective barrier of the intestine becomes less stable. This can promote the penetration of bacteria and other substances into the surrounding tissues and support inflammatory processes. Prolonged inflammation, in turn, can create conditions favorable for the formation of tumors.

However, the presence of Bacteroides fragilis in the intestine does not mean that a person will necessarily encounter cancer. The specific strain of the bacterium and its ability to produce BFT toxin are important. In addition, the development of colorectal cancer depends on many factors, so the discovered mechanism cannot be considered the sole cause of the disease.

The authors note that the discovery helped explain an important stage in the interaction of bacterial toxin with intestinal cells. However, scientists have yet to figure out the exact three-dimensional structure of the BFT and claudine-4 complex. The researchers also emphasize that the laboratory results reveal a biological mechanism, but by themselves do not allow us to establish how often it leads to the development of tumors in humans.