Researchers have uncovered a critical mechanism that controls immune reactions against microorganisms in the intestine. The results of the international study published in the journal Nature Immunology may contribute to the development of new therapies for chronic inflammatory bowel disease.

The immune system protects against the spread of pathogenic germs in the intestine. At the same time, it allows the colonisation of beneficial microorganisms. Conversely, the composition of the microorganisms in the intestine, the so-called microbiota, has an influence on the quality of the immune reaction. An international research group has uncovered a critical mechanism that establishes the balance between immune system and microbiota.

The researchers studied molecular regulators of immune-microbiome interactions in mice. The team focused on so-called regulatory T cells. These are immune cells that prevent harmless or even useful microorganisms in the intestine from being attacked by the immune system. "We have identified a molecule, c-Maf, which is critical for the development and function of specific regulatory T cells in the gut," explains the author. C-Maf prevents the immune system from attacking the microbiota. c-Maf controlled T_reg cell–derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal T_reg cells.

"If this molecule is missing, the gut's immune system overreacts and the microbiota composition changes considerably," added first author. This change in composition proved remarkably stable: When the researchers transferred the altered microbiota to mice with intact c-Maf-dependent regulatory T cells, they also developed an overreaction of the intestinal immune system.

"These results show that both the immune system and the microbiota mutually contribute to establishing and maintaining the balance in the gut," emphasizes the author. "This could explain how a microbial imbalance can contribute to chronic inflammatory bowel disease and why the treatment often fails". These findings could lead to new therapeutic approaches that, for example in the case of inflammatory bowel disease, aim to influence and harmonize both immune response and microbiota.

In the future, the team would like to study how an established pathological interaction between intestinal bacteria and the immune system can be destabilized in patients and restored to its original state.

https://www.charite.de/en/service/press_reports/artikel/detail/alles_im_gleichgewicht/

https://www.nature.com/articles/s41590-019-0316-2