Male Bacteria Oppose Diabetes

This editorial piece has largely been provided by Olive Leavy – editor of Nature Reviews Immunology.[1]

Although numerous gene polymorphisms associated with autoimmune disease risk have been identified, additional factors — including environmental factors and sexual dimorphism (with a higher incidence of autoimmunity in females) — are also thought to have important roles in driving disease.

Reporting in Science, Markle et al.[2] now describe a causal link between differences in male and female microbiota, sex hormone levels and autoimmune disease development in genetically susceptible mice.

The scientists utilised mice in differing stages of bacterial microbiota composition. Non-obese diabetic (NOD) mice develop spontaneous type 1 diabetes (T1D), and previous studies using these mice have shown that disease incidence has a strong female bias and can be prevented in females with testosterone treatment. In this study, the authors found that, in contrast to the sex bias in disease incidence found in mice housed under specific pathogen-free (SPF) conditions, disease incidence was similar in female and male NOD mice under germ-free conditions, suggesting a role for the microbiota in disease protection in males.

Then they undertook analysis of serum metabolite levels the results of which identified a subset of glycerophospholipids and sphingolipids that distinguished SPF male and female mice, but not germ-free males and females, suggesting that commensal gut colonisation mediates sex-dependent metabolic effects. In addition, serum testosterone levels were higher in SPF versus germ-free male mice.

Sex-specific differences were apparent at puberty and were most evident in adult mice. To determine whether the transfer of microbiota could confer sex-specific protection, female NOD weanlings were gavaged with cecal contents (a faecal transplanatation) from either adult male or adult female NOD mice. The microbiome of female recipients of male microbiota was stably altered and distinct from that of both male and female NOD mice. Female recipients of male microbiota had higher levels of serum testosterone and altered glycerophospholipid and sphingolipid metabolites compared with untreated female mice or with female recipients of adult female microbiota.

These data suggest that the transfer of male gut microbiota promotes hormonal and metabolic changes in recipient female NOD mice.

Importantly, disease incidence (characterised by hyperglycaemia, autoantibody production and insulitis) was greatly reduced in female mice that received male microbiota compared with controls.

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