Researchers at the Francis Crick Institute have shown that the balance of bacteria in the intestine can influence the symptoms of hypopituitarism in mice.
They also showed that aspirin could improve symptoms of hormone deficiency in mice with this condition.
People with mutations in a gene called stockings3 develop hypopituitarism, where the pituitary gland does not produce enough hormones. It can cause growth problems, infertility, and poor body responses to stress.
In research published today in PLOS GeneticsCrick scientists eliminated stockings3 of mice, causing them to develop hypopituitarism at the time of weaning (I start eating solid foods).
They discovered that mutations in stockings3 They largely affect the hypothalamus in the brain, which instructs the pituitary gland to release hormones. However, the gene is normally active in several types of brain cells, so the first task was to ask which specific cells were most affected by its absence.
The scientists observed a reduced number of cells called NG2 glia, suggesting that they play a critical role in inducing pituitary gland cell maturation around weaning, something that was not previously known. This could explain the associated impact on hormone production.
The team then treated the mice with a low dose of aspirin for 21 days. This caused the number of NG2 glia in the hypothalamus to increase and reversed the symptoms of hypopituitarism in the mice.
Although it is not yet clear how aspirin had this effect, the findings suggest that it could be explored as a potential treatment for people with stockings3 mutations or other situations in which NG2 glia are compromised.
Incidental discovery revealed role of gut bacteria in hormone production
When the National Institute of Medical Research (NIMR) merged with the Crick in 2015, mouse embryos were transferred from the first building to the second, and this included mice with stockings3 mutations.
When these mice reached the weaning stage at Crick, the researchers were surprised to discover that they no longer had the expected hormonal deficiencies.
After exploring a number of possible causes, lead author Christophe Galichet compared the microbiome (bacteria, fungi and viruses that live in the gut) in Crick mice and NIMR mice, noting several differences in their composition and diversity. This could have been due to the change in diet, aquatic environment, or other factors that accompanied the relocation.
He also examined the amount of NG2 glia in the Crick mice and found that they were also at normal levels, suggesting that the Crick-fed microbiome was somehow protective against hypopituitarism.
To confirm this theory, Christophe transplanted retained fecal matter from NIMR mice into Crick mice and observed that the Crick mice once again showed symptoms of hypopituitarism and had lower numbers of NG2 glia.
Although the exact mechanism is unknown, scientists conclude that the composition of the gut microbiome is an example of an important environmental factor that has a significant influence on the consequences of a genetic mutation, in this case influencing the function of the hypothalamus and pituitary. gland.
Christophe Galichet, former senior laboratory research scientist at the Crick and now research operations manager at the Sainsbury Wellcome Centre, said: “It was a big surprise to find that changes in the gut microbiome reversed hypopituitarism in mice without stockings3. “This reinforces to me how important it is to be aware of all the variable factors, including the microbiome, when working with animals in research and how husbandry can influence nature.”
Robin Lovell-Badge, group leader at the Crick’s Laboratory of Stem Cell Biology and Developmental Genetics, said: “Hypopituitarism can be the result of trauma, as well as rare mutations, and can have some profound effects on health. overall. In addition to suggesting possible treatment options, our work reinforces the importance of the gut-brain link. The next step of this research will be to determine exactly how aspirin and the microbiome influence NG2 glia and then study this effect in people to. to see if these relatively accessible interventions could help treat hypopituitarism.”