When women are pregnant and breast-feeding their babies, their body changes and various organs, such as the breasts or the immune system, adapt to ensure the health of both mother and child. This happens throughout evolution in all mammals. An international research team led by Josef Penninger and Masahiro Onji from the Medical University of Vienna now reports the surprising finding that the intestine also completely changes in pregnant and lactating women, causing a doubling of the intestinal surface area and a surprising structural reorganization. The researchers also provide the first genetic and mechanistic evidence for how this intestinal epithelial expansion occurs in mothers, with direct implications for the transgenerational health of babies. The study is published in “Nature“.
A multinational team led by Josef Penninger (MedUni Vienna, IMBA – Institute of Molecular Biotechnology, Vienna, University of British Columbia, Canada, Helmholtz Center for Infection Research, Germany) observed that intestinal villi reorganize during pregnancy and lactation and increase significantly in size. doubling its surface. The studies were carried out in genetically modified mice and mouse and human intestinal organoids: self-organizing three-dimensional tissues derived from stem cells in the intestine. Mechanistically, the researchers identified the RANK receptor/RANK ligand (RANK/RANKL) system as the key to small intestinal villi enlargement during reproduction, which is regulated by lactation and sex hormones. When mice were engineered to lack the RANK/RANKL system in the intestine, villus expansion during pregnancy and lactation was significantly impaired.
Fundamental importance for evolution.
For decades, researchers have studied the RANK/RANKL system as a key facilitator of essential evolutionarily conserved processes. The Penninger group has already identified key functions of the RANK/RANKL system in bone turnover, in the biology of the mammary gland, in breast cancer and in immune tolerance during pregnancy, contributing to the development of drugs against bone loss used by millions of people. people and clinical trials are being conducted for breast cancer prevention and cancer immunotherapies. Researchers have now discovered that these intestinal changes, which appear to be completely reversible when breastfeeding is stopped, are important for proper feeding and nutrition in babies. “Our study shows that the impairment of this intestinal expansion due to the lack of the RANK/RANKL system during pregnancy modifies the milk of lactating mothers. This results in lower weight of babies and long-term transgenerational metabolic consequences,” he says. leading author Masahiro Onji. “Mothers need to eat for themselves and their babies. These new studies provide for the first time a molecular and structural explanation of how and why the gut changes to adapt to mothers’ increased nutrient demand, which likely occurs in all pregnant and lactating women,” adds study leader Josef Penninger.
How mothers adapt to the demands of pregnancy and breastfeeding remains a central question of evolution and human health. During this phase, female hormones influence multiple organs to control and change their structure and functions, which is crucial for the health of the mother and the development of the offspring. It was known that pregnant women have higher nutrient demands. However, this fundamental aspect has not been well studied until now: “By identifying the RANK/RANKL system as the driving force of intestinal adaptation during pregnancy and lactation, our study contributes to a deeper understanding of the biological processes that are of fundamental importance for evolution and human health,” Josef Penninger summarizes the impact of the results.
This massive expansion is controlled by sex and pregnancy hormones, which modify the stem cells in the intestine through the RANK/RANKL system and then give the intestinal cell a survival signal to grow much larger. This growth then leads to a near doubling of the intestinal surface area, which also increases the molecular machinery for the absorption of sugar, proteins and fats, and even leads to a profound architectural change in the intestinal villi, which likely slows down the flow. of food, again maximizing nutrient absorption. Josef Penninger: “Our team has discovered a surprising new way to change the mother’s body to keep babies healthy. Almost no one knew about it, apart from some old studies that have largely been forgotten. We have also discovered that this system, through stem cells, can directly affect tumors in the intestine; perhaps we can learn from pregnant and lactating mothers to reversibly reconfigure this system to develop new treatments and a better understanding of intestinal cancer or intestinal regeneration.”
The study was a close collaboration between the Medical University of Vienna, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, the Institute of Life Sciences in Vancouver, the Helmholtz Center for Infection Research in Braunschweig, the Hubrecht Institute in Utrecht and the University of Kiel. Researchers from the University of Tokyo and the University of Cambridge also participated.