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Intestinal microbes reprogram genetic activity of gut mucosa

March 05, 2020

Scientists from the German Cancer Research Center and the Hebrew University in Jerusalem demonstrated in mice that intestinal bacteria reprogram DNA activity in cells of the gut mucosa and thus have a considerable impact on the development of the healthy gut. Acute intestinal inflammation induced under experimental conditions led to a huge increase in the activity of inflammation-related and cancer-promoting genes in the mucous membrane cells of microbe-colonized animals.

A large body of research work indicates that the intestinal microbiota - in other words, all the microorganisms that colonize the human gut - and its composition are linked to a whole series of diseases. The illnesses range from inflammatory diseases of the intestine and metabolic disorders such as obesity and diabetes to cancer, autism, and depression.

These studies usually only show links and do not clarify the mechanisms by which the intestinal microbes affect the human body. Frank Lyko from the German Cancer Research Center (DKFZ) and Yehudit Bergman from the Hebrew University in Jerusalem teamed up to address this issue.

To do so, the researchers compared the DNA of the gut mucosal cells in mice with a normal microbiome with those of mice who had grown up in sterile conditions. They focused on analyzing DNA methylation, known as epigenetic marking, which prevents DNA-binding proteins from attaching to the DNA at these sites, hence restricting the activity of the genes there.

The researchers noticed considerable differences in the methylation patterns between sterile and microbe-colonized animals. In the latter, they found a group of "sentinel genes" activated by demethylation, which are responsible for the normal regeneration of the intestinal mucosa in the healthy gut.

Both the microbe-colonized mice and the sterile animals were treated using a chemical that attacks the intestinal mucosa, thus inducing acute inflammation. In the microbe-colonized animals, this treatment led to a reduction in DNA methylation in the gut mucosal cells, particularly affecting a number of regulatory elements. As a result, many genes that play a role in inflammation and in cancer were activated.

In contrast, the chemical hardly caused any changes in genetic activity in the microbe-free mice. "That shows that the differences in methylation are due to the bacteria and not to the chemical," Frank Lyko explained. However, if the microbiome of the microbe-colonized mice was transferred to the microbe-free animals, methylation of the intestinal mucosal cells was reduced in these mice too.

The team of German and Israeli researchers realized that this effect apparently depends on the demethylating enzymes TET2 and TET3: If they were turned off genetically, treatment with the chemical hardly caused any changes in the genome methylation.

"The microbiome seems to have a considerable influence on the animals' health: It ensures normal intestinal development by using epigenetic programming to activate genes that steer regeneration of the gut mucosa. In the microbe-free mice, however, this activation does not take place," Frank Lyko explained. "During acute inflammation, the gut microbes also cause a change in genetic activity, and genes are dysregulated that are also dysregulated in patients with intestinal inflammation and cancer of the colon. This once again underlines the key role that microbes play in epigenetic regulation," he added.
-end-
The work was funded by the Helmholtz-Israel Cooperation in Personalized Medicine.

Ihab Ansari, Günter Raddatz, Julian Gutekunst, Meshi Ridnik, Daphne Cohen, Monther Abu-Remaileh, Timur Tuganbaev, Hagit Shapiro, Eli Pikarsky, Eran Elinav, Frank Lyko and Yehudit Bergman: The microbiota programs DNA methylation to control intestinal homeostasis and inflammation. Nature Microbiology 2020, DOI: https://doi.org/10.1038/s41564-019-0659-3

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. At DKFZ, more than 1,300 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful.

DKFZ's Cancer Information Service (KID) provides individual answers to all questions about cancer for patients, the general public, and health care professionals. Jointly with partners from Heidelberg University Hospital, DKFZ runs the National Center for Tumor Diseases (NCT) located in Heidelberg and Dresden, and, also in Heidelberg, the Hopp Children's Cancer Center (KiTZ). In the German Cancer Consortium (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center at the NCT and DKTK sites is an important contribution to the endeavor of translating promising approaches from cancer research into the clinic in order to improve the chances of cancer patients.

DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

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