Microbiome, sex hormones and gender bias in autoimmune disease susceptibility

Many autoimmune diseases are more prevalent in women than in men, however the reasons for this gender bias are not well understood. In the past decade or so, genome wide association studies have come up with common polymorphisms associated with disease risk, however, with a few exceptions, they often appear to increase the risk only slightly. Discordance in monozygotic twins and the recent rise in autoimmune disease incidence in developed countries point to a role for environmental factors in autoimmunity. Accordingly, researchers have started to identify such factors, e.g. smoking in rheumatoid arthritis or vitamin D in multiple sclerosis. More recently, increasing interest in host-microbiota relationship and its effects on the immune system has led to studies investigating the role of the microbiome in susceptibility to autoimmune diseases.

In a study published in Science on March 1, 2013, Markle et al. show that sex differences in the composition of the microbiota contribute to gender bias in susceptibility to type 1 diabetes in a mouse model.

Non-obese diabetic (NOD) mice spontaneously develop type 1 diabetes (T1D), however there is a strong >2:1 female to male bias in incidence. Previous studies have shown a role for testosterone in disease pathogenesis, with male castration increasing, and female androgen treatment decreasing, T1D incidence. It has also been noted that T1D incidence in NOD colonies positively correlates with better hygiene conditions.

Markle et al. first look at T1D incidence in male and female NOD mice either maintained in traditional specific pathogen-free (SPF) conditions or rederived and kept in germ-free (GF) conditions. Strikingly, while disease incidence is greater and onset earlier in SPF females compared to SPF males, these differences are abolished in GF mice, indicating that sex differences in T1D susceptibility are dependent on the presence of commensal bacteria.

The authors then assess how the presence/absence of microbiota affects the levels of sex hormones. No difference in 17β-estradiol is detected between SPF and GF mice, however testosterone levels are higher in GF females compared to SPF females, and lower in GF males compared to SPF males (testosterone levels are nevertheless still lower in GF females compared to GF males). Analysis of serum metabolites reveals that absence of microbial colonization also induces changes in sex-specific features of the host metabolic profile.

While these data indicate that the microbiome regulates sex-specific hormonal and metabolic features in the host, they also raise the question of whether sex differences stem from the presence of a different microbiota in males and females or whether the same microbiome is present in both sexes but responds differently depending on the sex of the host. The authors therefore analyze the composition of the gut microbiome in males and females by sequencing 16S rRNA libraries prepared from cecal contents. No difference is detected at 3 weeks of age (weaning), however sex-specific differences in microbiome composition are visible at 6 weeks of age (puberty) and become even more apparent in adults (14 weeks of age, before onset of T1D). These results show that sexual maturation influences the composition of the gut microbial community.

To assess the influence of male versus female microbiota on T1D susceptibility in NOD mice, Markle et al. then transfer gut microbiota from adult male or female to female weanlings (indicated as M->F or F->F, respectively). They subsequently verify that at 11 weeks of age the M->F transfer has indeed induced changes in the composition of the recipient females’ gut microbiota compared to unmanipulated females. Of note, while some of the bacterial species that are differentially represented between M->F recipients and unmanipulated females also distinguish between unmanipulated males and females, some do not, meaning that the transfer leads to a gut microbial composition that is neither fully “female” nor “male”.

The authors then assess the effect of the transfers on the recipients’ hormonal and metabolic profiles. They find that testosterone levels at 7 and 14 weeks of age are higher in M->F recipients than in F->F recipients or unmanipulated females (they are still lower than in unmanipulated males though). The M->F transfer also leads to a metabolic profile distinct from those observed in either unmanipulated females or males.

Finally, the authors observe that the M->F transfer recapitulates in female recipients the relative protection from T1D usually observed in unmanipulated males: T1D incidence is significantly lower in M->F female recipients compared to unmanipulated females or F->F female recipients. Both insulitis (leukocyte infiltration in pancreatic islets) scores and anti-insulin autoantibody levels are lower in M->F mice compared to F->F or unmanipulated mice before onset of disease (pre-diabetic mice, 14 weeks of age). Interestingly, this protection is lost when the recipients are treated with an androgen-receptor antagonist.

Altogether, these data show that transfer of male microbiota to female NOD mice before puberty attenuates the autoimmune phenotype and that this effect is dependent on testosterone activity. Although this study suggests that the feedback exerted by male microbiota on testosterone levels confers a relative protection from autoimmunity in the NOD mouse, it will be interesting to investigate whether the female microbiota itself has pro-autoimmune effects and if it regulates other hormone-regulated pathways.

I found this study particularly interesting because it shows that changes in the gut microbiota early in life can modulate disease susceptibility in mice that have a strong genetic predisposition to develop the disease. Perhaps even more interesting, it identifies a direct interaction between commensal bacteria, sex hormones and disease susceptibility, showing that an extrinsic (albeit commensal) factor contributes to gender bias in autoimmune disease.

Reference
Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity. Janet G. M. Markle et al. Science 339, 1084 (2013); DOI: 10.1126/science.1233521
PMID: 23328391

ResearchBlogging.org
Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, & Danska JS (2013). Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science , 339 (6123), 1084-8 PMID: 23328391

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