Hormones can have a significant impact on the body, and many of them are produced and released from the pituitary gland. In a condition called hypopituitarism, there is a problem with the production and release of hormones from the pituitary gland, which can lead to many other issues like infertility, growth problems, or a dysfunctional stress response, for example. Hypopituitarism can be caused by mutations in a gene called Sox3.
Scientists have now found that the makeup of the community of microbes in the gut, or the gut microbiome, can affect hypopituitarism symptoms in a mouse model. This research also showed that aspirin can help relieve some of the symptoms caused by hormone deficiency in mice as well. The findings have been reported in PLOS Genetics.
In this study, the investigators engineered a mouse model in which Sox3 was removed, and these mice developed symptoms of hypopituitarism at a very young age. The lack of Sox3 expression, and removal of functional Sox3 protein reduced the level of a certain cell type called NG2 glia. The researchers suggested that these cells may be crucial to the maturation of pituitary gland cells, and when they do not mature, it may lead to a reduction in hormone levels.
The removal of Sox3 was found to be interfering with the function of the hypothalamus, a region of the brain that plays a fundamental role in certain processes such as hunger; it can also signal to the pituitary gland to generate more hormones.
When the mouse model was give a low aspirin dose for 21 days, NG2 glia cell levels in the hypothalamus began to increase, and symptoms of hypopituitarism were relieved in the mice.
More research will be needed to determine why aspirin has this effect, and whether it would be a good treatment for people who carry Sox3 mutations that affect hormone production.
Mouse embryos with Sox3 mutations had also been relocated from one research facility to another during the course of the study. Curiously, when mice were born and raised in the new facility, they did not exhibit the expected symptoms. The researchers began to track down the possible causes, and suspected that the gut microbiome could be a potential reason for the discrepancy.
Indeed, when the researchers took fecal samples from the mice that did display the expected symptoms, and transferred that fecal matter to Sox3-deficient mice that did not have the symptoms, they found that the hypopituitarism symptoms once again began to appear.
Thus, the composition of the gut microbiome also appears to have a significant impact on the effect of a genetic mutation.
"It was a huge surprise to find that changes in the gut microbiome reversed hypopituitarism in the mice without Sox3. It's reinforced to me how important it is to be aware of all variable factors, including the microbiome, when working with animals in research and how nurture can influence nature," said first study author Christophe Galichet, former Senior Laboratory Research Scientist at the Crick and now Research Operations Manager at the Sainsbury Wellcome Center.
Now the researchers are interested in determining whether this effect is also seen in people.
Sources: Crick Institute, PLOS Genetics