Pregnancy is a significant physiological process where a woman’s body undergoes various adaptations to support both the mother and the developing child. While changes in organs like the breasts and immune system are well-known, an international research team led by Josef Penninger and Masahiro Onji from the Medical University of Vienna has discovered that the Intestine also undergoes a complete transformation during pregnancy and nursing.
This includes doubling the intestinal surface area and substantial structural reorganization. The team provides the first genetic and mechanistic evidence explaining how this expansion occurs. It has important implications for the health of both mothers and their babies and potentially influences transgenerational health.
The study observed that the intestinal villi undergo significant reorganization during pregnancy and breastfeeding, doubling their surface area. This research, conducted using genetically modified mice and intestinal organoids from both mice and humans, identified the RANK receptor/RANK ligand (RANK/RANKL) system as crucial for this enlargement.
The system is regulated by sex and lactation hormones. Mice lacking the RANK/RANKL system in the Intestine showed impaired villous expansion during pregnancy and breastfeeding, highlighting its essential role in this process.
For decades, the RANK/RANKL system has been studied for its critical roles in essential processes, such as bone turnover, mammary gland biology, breast cancer, and immune tolerance during pregnancy. The Penninger group has contributed to developing drugs for bone loss, which millions use, and is also involved in clinical trials for breast cancer prevention and cancer immunotherapies.
The researchers have now found that the intestinal changes induced by the RANK/RANKL system, reversible after breastfeeding ends, are vital for ensuring proper feeding and nourishment of infants.
Lead author Masahiro Onji said, “Our study shows that the impairment of this intestinal expansion by the lack of the RANK/RANKL system during pregnancy changes the milk of the nursing mothers. This results in lower baby weights and transgenerational long-term metabolic consequences.”
Study leader Josef Penninger said, “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 Intestine adapts to enhanced nutrient demand of mothers, which is probably the case in all pregnant and nursing mammals.”
How mothers adapt to the demands of pregnancy and breastfeeding is a key question in evolutionary biology and human health. During this period, female hormones influence various organs, altering their structure and functions to support the mother’s health and the offspring’s development. While it has been known that pregnant women have increased nutrient requirements, this crucial aspect of maternal adaptation has not been extensively studied until now.
Josef Penninger, summarising the impact of the findings, said, “By identifying the RANK/RANKL system as the driving force behind intestinal adaptation during pregnancy and lactation, our study contributes to a deeper understanding of biological processes that are of fundamental importance for evolution and human health.”
Sex and pregnancy hormones control the massive expansion of the Intestinal Tract during pregnancy and breastfeeding. These hormones activate the RANK/RANKL system in gut stem cells. This signaling provides a survival signal to the intestinal cells, prompting them to grow much larger.
As a result, the intestinal surface area nearly doubles, enhancing the molecular machinery responsible for absorbing sugars, proteins, and fats. Additionally, this growth induces significant architectural changes in the intestinal villi, likely slowing down the flow of food and further optimizing nutrient uptake.
Josef Penninger said, “Our team has discovered an amazing new way for mothers’ bodies to change to keep babies healthy. Hardly anybody knew about this, apart from a few old studies that have largely been forgotten. We have also found that this system, via stem cells, can directly affect tumors in the Intestine; maybe we can learn from pregnant and nursing mothers to reversibly rewire this system to develop new treatments and a better understanding of intestinal cancer or gut regeneration.”
Journal Reference:
- Onji, M., Sigl, V., Lendl, T. et al. RANK drives structured intestinal epithelial expansion during pregnancy. Nature (2024). DOI: 10.1038/s41586-024-08284-1