Researchers at the Francis Crick Institute have found that the small intestine grows in response to pregnancy in mice. This partially irreversible change may help mice support a pregnancy and prepare for a second.
The organs of many female animals are remodelled by reproduction, but the underlying mechanisms behind the response of the gut to pregnancy have only recently begun to be investigated. For example, scientists previously identified that the fruit fly gut expands during reproduction.
In research published today in Cell , the same team found that pregnant mice had a longer small intestine from just seven days into the pregnancy. By the end of the pregnancy, around day 18, the small intestine was 18% longer.
Interestingly, the small intestine remained longer after birth, even up to 35 days after the mice had finished lactating, suggesting that this change isn't reversible. They also observed that the small intestine was even longer after a second pregnancy than the first.
Inside the small intestine, the villi (protrusions that absorb nutrients) and crypts (where the cells supplying the villi are produced) became longer and deeper at the same time as the gut lengthened, but both returned to pre-pregnancy values just seven days after weaning. The villi also didn't grow more during a second pregnancy.
The team think that a longer small intestine and villi may support increased nutrient uptake needed to support the mother and offspring during pregnancy.
Reproduction-specific effects on metabolism
The scientists altered the diet of the mice, including probiotic intake, to show that these physiological changes in pregnancy occurred regardless of nutritional change. They then took a deeper dive into what was happening in the villi.
They found that precursors of intestinal epithelial cells were rapidly growing in number and newly generated cells migrated faster up the villi in early pregnancy. These effects continued after birth into lactation but returned to pre-pregnancy rates just seven days after weaning.
By looking at which genes were switched on during pregnancy, the researchers saw the biggest number of genetic changes in enterocytes, nutrient-absorbing cells in the villi that are produced by precursor cells in the crypt. These changes were largely related to increasing metabolic activity.
One of the metabolic effects observed at a very early stage was an increase in a membrane protein called SGLT3a. Unlike like other SGLT proteins, SGLT3a does not sense glucose levels outside of the cell but responds to sodium and protons instead. An increase in SGLT3a was responsible for about 45% of the villi growth triggered by reproduction, including cell expansion, but wasn't necessary for entire small intestine lengthening.
Strikingly, supplementing the diet of female mice with sodium induced villi growth even in virgin mice.
The team believe that hormones triggered by reproduction may play a role in switching on the gene for SGLT3a, as pseudo-pregnant mice – females whose pregnancy hormone levels have increased after mating with sterile males –still showed some villi growth and intestinal lengthening.
An energy trade-off in response to a challenge
Irene Miguel-Aliaga, Group Leader of the Organ Development and Physiology Laboratory at the Crick, said: "We don't often think about organs changing size or appearance in response to triggers in adulthood rather than earlier childhood and adolescent development, but the gut is a striking example of how the body responds to a new challenge at different stages of life, in this case pregnancy.
"The presence of reversible and non-reversible changes may reflect a trade-off in energy. Maintaining a longer gut after a first pregnancy might 'prime' the body for a second, while reducing villi length back to normal might stop excessive absorption from food while it's unnecessary."
Tomotsune Ameku, former postdoctoral researcher at the Crick, now Assistant Professor at Science Tokyo and first author of the study, said: "Understanding how pregnancy impacts the body in other mammals is a critical first step to understanding this in people. We don't fully understand why the gut expands in response to pregnancy, but we think it must give an evolutionary advantage and help mice reproduce regularly.
"We're really interested in whether this is also the case in humans. But we're generally eating more and reproducing less than we used to, so intestine growth might not be as useful anymore."
The researchers are now investigating whether other cell types in the mouse intestine also experience remodelling during pregnancy, and whether this happens in humans, by looking at gut length in people who have and haven't had children.
