Genetic risk factor for Crohn’s disease influences natural microbiome changes during pregnancy, mouse study finds microbiologystudy

Pregnancy is accompanied by profound changes in the body. Among other things, these affect the energy metabolism and the immune system. But the gut microbiome, i.e., the composition of the microbial community in the gut, also changes considerably, especially towards the end of pregnancy.

Researchers are investigating the function of the intestinal microbiome during pregnancy and breastfeeding and its potential significance for patients with chronic inflammatory bowel disease.

“We are interested in how these microbiome changes influence the course of disease in patients with chronic inflammatory bowel disease (IBD),” explained Professor Philip Rosenstiel, member of the board of directors of the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI) and Director of the Institute of Clinical Molecular Biology (IKMB) at the Faculty of Medicine at Kiel University (CAU) and the University Medical Center Schleswig-Holstein (UKSH).

Although it is known that the intestinal flora is linked to the development of IBD, it is unclear whether individual changes during pregnancy are related to the course of the disease before and after delivery. The research team investigated this question in an animal model for the chronic inflammatory bowel disease Crohn’s disease. The results were recently published in the journal Gut Microbes.

More inflammation in the gut, smaller offspring

“We looked at what effect a single genetic risk factor for Crohn’s disease had on the microbiome of pregnant animals,” explains study leader Rosenstiel. By switching off the Crohn’s risk gene Atg16l1 in cells of the intestinal mucosa, the condition of Crohn’s disease was simulated in the mice. The composition and metabolic activity of the intestinal microbiome was examined at various times during pregnancy and lactation and the results were compared with those of mice without gene modification.

“At the beginning of pregnancy, the microbiome of animals with and without genetic defects was very similar. Over time, however, the composition of the microbiome drifted apart between the groups. This shows us that a genetic risk factor in a very specific cell type is sufficient to influence these changes, which develop over time. Interestingly, the animals that had the Crohn’s risk factor showed more signs of inflammation and the offspring had a lower weight.”

Chemical analyses of the metabolic products showed that the altered composition of the microbial community also results in different metabolic activity. “The observed changes are linked to pro-inflammatory processes. This means that the altered microbiome could play a part in the observed tendency towards inflammation,” says Rosenstiel.

These results are not directly transferable to the situation in humans. “But it is important to understand how genetic IBD risk factors can affect pregnancy. Then you know what to look out for in the microbiome, for example.” The long-term goal is to use the microbiome changes for diagnostic purposes, for example to predict or possibly even treat a flare-up of the disease after pregnancy.

Analysis of the course of the disease and pregnancy in women with and without IBD

How pregnant women with and without chronic inflammatory bowel disease are doing, what symptoms they have and how they cope with everyday life is also the subject of the observational study “MamaIBD” at the Center of Excellence for Inflammation Medicine at the UKSH, Kiel Campus. For this purpose, clinical data as well as blood and stool samples are collected in each trimester of pregnancy, and symptoms and everyday activities are recorded using questionnaires. In women with IBD, disease activity is also recorded.

“We want to find out how chronic inflammatory bowel disease affects the everyday activity and symptoms of pregnant women,” explains assistant doctor Martina Guggeis, who is supervising the project as a clinician scientist.

The biosamples collected will be used for further scientific analysis, for example to determine how genetic risk factors and environmental influences in women with and without IBD lead to the inflammatory activity of the intestinal microbiome occurring or not.

Rosenstiel says, “We analyze the gut microbiome and look at what the gut microbiome of a woman who has an IBD flare-up after pregnancy looks like compared to a woman without a flare-up. It may be possible to use these differences as microbial biomarkers to predict a flare-up and adapt the therapy to the individual.”

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University of Kiel