But by no means all immune phenomena can be explained genetically. For example, an identical twin can develop an autoimmune disease while the other – with a practically identical genome – remains healthy. The environment has a decisive say in this.
University of Toronto immunologist Jayne Danska has spent much of her scientific career exploring the relationship between gender and the genetics of autoimmune diseases. She wanted to know to what extent risk genes affect men and women differently. In 2012, however, she made an accidental discovery that would take her work in a new direction. “It’s one of the wisdoms of science that the best discoveries are those that you haven’t even looked for,” she comments.
Danska and her team searched for risk genes for the autoimmune disease type 1 diabetes mellitus, in which the immune system attacks the insulin-producing beta cells in the pancreas. The researchers experimented with a line of mice bred in the laboratory called NOD mice (non-obese diabetic mice). These animals are suitable as models for the disease – with one important exception: Type 1 diabetes is one of the few autoimmune diseases that does not frequently affect women – female NOD mice, on the other hand, carry a twice as high risk of developing the disease as their male counterparts.
Danska knew that environmental factors and genes sometimes influence each other, and she had already looked at gut bacteria as a risk factor. Consequently, she wondered whether differences in the microbiome could be related to the increased risk of diabetes in the female animals. The team therefore raised a group of NOD mice in an environment completely free of bacteria and viruses, including the common germs that normally colonize the gut.
In doing so, Danska made the first surprising observation: the germ-free animals of both sexes developed diabetes equally often. “The sex difference completely disappeared,” she recalls. “We didn’t expect this result at all. I could hardly believe it.”
However, repeating the experiment led to the same finding, and further investigations brought new surprises: The researchers transplanted the intestinal flora of adult male NOD mice into young female animals that had not yet developed diabetes – and then grew into healthy mice without diabetes.
Danska’s research results, published in 2013, provided the first indication that “gut microbes can influence autoimmunity in females,” explains rheumatologist Martin Kriegel from the University of Münster. This is an important finding, the background to which is still unknown.
The intestinal flora of men increases testosterone levels
So far nobody knows why the male gut microbiome should have a protective effect. However, Danska and her team found evidence that testosterone plays an important role: the diabetic, aseptic male NOD mice had lower blood testosterone levels than males with normal gut flora. And female NOD rodents, which were protected from the disease with intestinal bacteria from male conspecifics, showed higher testosterone levels than females with normally colonized intestines.
All this suggests that the male microbiome increases testosterone levels and has a preventive effect on diabetes mellitus. When Danska and her colleagues transplanted the gut flora of male mice into females and then blocked the transmission of testosterone signals, the prevalence of diabetes increased again.
These observations coincide with research results on lupus erythematosus in men: If testosterone is blocked, the risk of developing the disease increases. Parallels can also be seen in studies on a mouse strain whose female animals are particularly susceptible to lupus. If the intestinal flora of the females is severely thinned out with antibiotics, the risk of disease decreases, scientists from the University of South Carolina reported in 2020.
It is still unclear how the intestinal microbiome could regulate testosterone levels or vice versa. Danska’s research suggests that the composition of the microbiome in male and female mice begins to differ during sexual maturity. This could even explain why there are hardly any gender-related differences in the frequency of type 1 diabetes in humans: the disease usually breaks out before puberty, i.e. before a gender-specific difference in intestinal flora could influence the risk. It is possible that the microbiome is modified by the sudden influx of sex hormones during puberty; But it is fairly certain that this happens reciprocally, says Kriegel: the intestinal flora reacts to the sex hormones and these in turn to the microbes.
Of course, mice are not people. Nonetheless, Danska is convinced that her research results have great relevance for autoimmune diseases that affect women more often. It is possible that certain intestinal bacteria have a decisive effect on autoimmunity. If so, tampering with the composition of the microbiome could prevent such diseases.
Danska and Kriegel hope to develop microbiome-based therapies for women at high risk of developing autoimmune diseases – that is, changing the microbiome to be more protective. Other researchers try to influence the signaling of sex hormones to reduce the risk. The more one learns about the reasons for women’s increased susceptibility, the more opportunities open up to prevent autoimmune diseases.
Given that X chromosomes, female sex hormones, and a sex-specific microbiome appear to be risk factors for autoimmune diseases, one might speculate that biology has conspired against the female sex. However, the burden of autoimmunity can also be viewed as an expression of the importance of women to the survival of our species. “After all, from an immunological point of view, women have to achieve something that is absolutely remarkable, which is simply not expected of men,” explains Danska. Autoimmunity may be the price women pay for peak physiological performance, but there is hope that science will eventually lift the burden.