Editors' ChoiceAutoimmunity

Gut Reaction: Microbiome Provides a Clue to Gender Bias in Autoimmunity

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Science Translational Medicine  13 Mar 2013:
Vol. 5, Issue 176, pp. 176ec43
DOI: 10.1126/scitranslmed.3006077

Men are from Mars, women are from Venus—or so the old adage goes. But who knew that our bacteria were taking sides ? What exactly differentiates men and women when it comes to disease susceptibility remains murky. One thing we all have in common is that we’re communal organisms: An ecosystem of microorganisms—some beneficial and some detrimental—inhabits our bodies. The complexity of each microbial ecosystem, or microbiota, is reflected in its collective genetic content, or microbiome. Studies of the microbiome have underscored how fundamentally intestinal microorganisms influence and are influenced by their host. Now, Markle et al. uncover an unexpected connection between microbiota, gender, and autoimmune disease.

The gender bias for many autoimmune diseases, which are generally more common in females, is well established but poorly understood. The authors make use of nonobese diabetic (NOD) mice, a model for type 1 diabetes, to investigate this link. In the NOD strain, female mice are about twice as likely to develop diabetes. This gender disparity disappears when the mice are raised under germ-free conditions that don’t allow for the development of microbiota—a tantalizing lead for the authors. Moreover, distinct features of male and female microbiomes emerge during puberty and are evident in adult mice. To test these connections between the microbiome, gender, and diabetes, Markle et al. transplanted microbiota from male mice into the intestines of young, diabetes-susceptible female mice. When female mice were transplanted this way, they acquired a “male-typic” microbiome and their incidence of diabetes dropped to resemble that of male mice. The “masculine” microbiota appeared to increase levels of testosterone, altering the host immune system and lowering the incidence of diabetes.

Overall, this work suggests a bidirectional feedback loop between the host and the microbiota in developing and reinforcing gender differences that alter susceptibility to autoimmunity. Human type 1 diabetes, which often develops before puberty, is not gender-biased, but many human autoimmune diseases are. Could microbiome-directed therapy alter the course of disease in people with a genetic susceptibility for autoimmunity? Further studies of the human microbiome will be an important next step in testing this relationship.

J. G. M. Markle et al., Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013). [Abstract]

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