Pro-inflammatory immune cells in the gut discovered and reprogrammed

Researchers at the Bosch Health Campus and the Mayo Clinic in Rochester (USA) have identified a previously unknown subgroup of immune cells that have a pro-inflammatory effect in Crohn's disease. They have also developed a method to successfully reprogram these cells. As inflammatory bowel diseases increase the risk of colorectal cancer, the findings offer great potential for developing therapies with far-reaching effects.

Bosch Health Campus | February 2024
[DE Copy] Gastroenterology, Elsevier Inc.

For the study, human colon organoids (blue) were cultivated with three different Treg cell cultures. Under control conditions with normal Tregs (left), tight junctions (green) can be seen between the epithelial cells, which ensure a tight connection between the cells. With inflammatory Tregs, there are hardly any tight junctions, which indicates a high permeability of the epithelium (center). If the Treg cells are treated with Vorinostat beforehand, the permeability can be eliminated (right).

Inflammation plays a central role in tumor development, tumor growth and therapy responsiveness. In Germany, around 650,000 people are affected by chronic inflammatory bowel disease, which is associated with an increased risk of colorectal cancer. Researchers are therefore working to better understand and influence the inflammatory processes.

In Crohn's disease, a chronic inflammatory bowel disease, the concentration of immune cells in the inflamed areas is increased. So-called regulatory T cells also accumulate there, however, they do not perform their normal job of fighting the inflammation. Researchers at the Bosch Health Campus and the Mayo Clinic in Rochester (USA) have now found an explanation for this: In the subgroup of regulatory T cells, the cell identity is altered in such a way that they promote inflammation instead of inhibiting it.

Every single cell determined and examined

For the study, which was published in the renowned journal "Gastroenterology", the research group led by Dr. Robyn Laura Kosinsky from the Robert Bosch Center for Tumor Diseases (RBCT) at the Bosch Health Campus refined the method of single-cell sequencing. This method involves breaking down tissue samples into single cells so that they can be individually identified. When examining the samples, the researchers found the novel subgroup of regulatory T cells. "We were able to observe that various inflammation-associated signaling pathways are upregulated in them, resulting in their pro-inflammatory profile," explains molecular biologist and cancer researcher Dr. Robyn Laura Kosinsky.

In order to curb these signals, Kosinsky and her colleagues treated the cells in cultures with the US-approved drug Vorinostat, which influences epigenetics and suppresses the pro-inflammatory function – with success: the function of the cells returned to normal.

In addition, the researchers cultivated the inflammatory cells with so-called human colon organoids, artificially created organ-like microstructures. Without treatment, the tissue was more permeable than usual – a phenomenon that researchers are familiar with in Crohn's disease patients. The gaps are caused by a loss of the so-called tight junctions, i.e. the tight cell connections. This makes it easier for bacteria to penetrate and promote inflammatory processes. The drug was also effective here: after treatment with Vorinostat, the gaps disappeared.

"Our discovery of the inflammation-promoting cell population and the possibility of reprogramming it pharmacologically could open up new opportunities to treat patients with chronic inflammatory bowel diseases in a more targeted manner and reduce their disease burden," says Kosinsky. From her point of view, it is worth checking whether the discovered T cell population is also present in other bowel diseases and whether it plays a role in the development of colorectal cancer.

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