Balancing the gut

Researchers from the Cluster of Excellence “Precision Medicine in Chronic Inflammation” in Kiel and Charité – Universitätsmedizin Berlin have uncovered a critical mechanism that controls immune reactions against microorganisms in the intestine. The results of the international study may contribute to the development of new therapies for chronic inflammatory bowel disease. They have been published in the journal Nature Immunology*.

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 led by Prof. Dr. Alexander Scheffold of Kiel University (CAU) and the Cluster of Excellence “Precision Medicine in Chronic Inflammation” has uncovered a critical mechanism that establishes the balance between immune system and microbiota.

The researchers Dr. Christian Neumann (Charité), Dr. Sascha Rutz (Genentech, San Francisco), Prof. Dr. Axel Kallies (University of Melbourne and Walter and Eliza Hall Institute of Medical Research, Melbourne), Prof. Scheffold and colleagues 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 Scheffold. C-Maf prevents the immune system from attacking the microbiota. “If this molecule is missing, the gut’s immune system overreacts and the microbiota composition changes considerably,” added first author Dr. Neumann of Charité’s Institute of Microbiology, Infectious Diseases and Immunology. 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,” emphasises Prof. Scheffold. “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.

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*Neumann C et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis. Nat Immunol. 2019 Feb 18. doi: 10.1038/s41590-019-0316-2.

The Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI) has won funding from 2019 to 2025 through the German Excellence Strategy (ExStra). Around 300 members from eight institutes at five locations are involved: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH), Muthesius University, Kiel Institute for the World Economy (IfW), Leibniz Institute for Science and Mathematics Education (IPN)), Lübeck (University of Lübeck, UKSH), Plön (Max Planck Institute for Evolutionary Biology), Borstel (Research Center Borstel – Leibniz Lung Center) and Großhansdorf (Lungenclinic Grosshansdorf). The aim is to draw on the multifaceted research approach to chronic inflammatory diseases of barrier organs, and transfer this interdisciplinarity to healthcare more intensively.

Joint Press Release of the Charité – Universitätsmedizin Berlin and the Cluster of Excellence PMI at Kiel University