A newly discovered signalling pathway regulates adaptation of the mother’s intestine to the increased requirements of pregnancy and breastfeeding

06.2025
Author Dr. Martin Claßen, Bremen

Pregnancy and breastfeeding pose specific challenges for any organism, and the mother’s intestine is one of the organs that adapts to the increased nutritional demand. A study conducted in Vienna shows a previously unknown signalling pathway in the intestine which controls expansion of the intestinal epithelial cells, leading in turn to growth of the villi and an increase in surface area. This is the RANK signalling pathway Receptor Activator of Nuclear Factor κΒ and its ligand RANKL. This signalling pathway plays a role in bone formation, organogenesis of lymph nodes and thermoregulation, among other things. 
The studies were conducted on mice, and an indication of the significance of RANK was that blocking it had a negative influence on intestinal development and absorption and that its absence led to underweight baby mice. The significance for humans was demonstrated on human organoids.

Comment: New findings in physiology and pathophysiology are becoming increasingly rare. So this multicentre, multinational study, which also included very comprehensive, complex and differentiated individual experiments, is especially significant. It shows the various ways in which the mother’s organism adapts to enable optimum growth of the foetus and later the newborn baby, and how the intestine’s capacity for absorption increases accordingly. 
This study won’t yet have any direct impact on healthcare for pregnant women. Diseases with genetic mutations for the RANK signalling pathway have not yet been described in humans. However, active use of this signalling pathway in situations other than pregnancy may be feasible, for example, in children with short bowel syndrome or general malabsorption syndromes.

Reference: 
Onji, M, Sigl, V, Lendl, T, Novatchkova, M, Ullate-Agote, A, Andersson-Rolf, A, Kozieradzki, I, Koglgruber, R, Pai, TP, Lichtscheidl, D, Nayak, K, Zilbauer, M, Carranza García, NA, Sievers, LK, Falk-Paulsen, M, Cronin, SJF, Hagelkruys, A, Sawa, S, Osborne, LC, Rosenstiel, P, Pasparakis, M, Ruland, J, Takayanagi, H, Clevers, H, Koo, BK, Penninger, JM. RANK drives structured intestinal epithelial expansion during pregnancy. Nature. 2025 Jan;637(8044):156-166. DOI: 10.1038/s41586-024-08284-1