A theory of everything: commensal gut bacteria link environmental exposures to sex hormones in modulating autoimmunity
Autoimmunity depends on how environmental and genetic factors interact to shape immune function. Genome-wide association studies<\/b> have found many risk alleles<\/b> linked to different autoimmune diseases. Animal models have helped researchers learn how some of these gene variants affect specific parts of the immune system. But these approaches tend to miss two puzzling patterns in autoimmunity:<\/p>
- Many autoimmune diseases strongly favor women.<\/li>
- Autoimmunity is far more common in industrialized areas than in poorer, rural areas.<\/li>
<\/ul>Meanwhile, the rising rate of autoimmunity in industrialized countries has led to the “hygiene hypothesis”<\/b>: the idea that early exposure to specific microbes is necessary for a fully working immune system. Modern, clean cities lack these beneficial exposures, which may contribute to immune dysfunction and self-reactivity. Evidence for the hygiene hypothesis is now strong enough that clinical trials are testing whether deliberate infection with parasitic worms — thought to be the main microbial exposure missing from a modern upbringing — can help control inflammatory bowel disease and multiple sclerosis2<\/sup>.<\/p>
A Mouse Model Links Gut Bacteria, Sex Hormones, and Autoimmunity<\/h2>
In a recent paper in Science<\/em>, Dr. Jayne Danska’s group at the University of Toronto proposed an idea that unifies early-life microbial exposure and sex hormone levels as drivers of autoimmune responses3<\/sup>. The group, led by first author Dr. Janet Markle, used a well-established mouse model of type-1 diabetes (T1D)<\/b>: the non-obese diabetic (NOD) mouse<\/span>. These mice are genetically prone to spontaneous, immune-mediated destruction of beta-islets around 15 weeks of age, which causes diabetes.<\/p>
Like several human autoimmune diseases, NOD mice have a 2:1 female-to-male sex bias<\/em><\/b> in developing diabetes. Markle et al. found that male mice raised under standard lab conditions were protected from diabetes compared to female mice. But when NOD mice were born and raised in germ-free conditions — meaning their intestines were never colonized by commensal bacteria — males developed the disease at the same rate as females.<\/p>
The mice’s environment also affected their sex hormone levels:<\/p>
- Male mice raised germ-free had lower serum testosterone<\/em> than those raised in standard conditions.<\/li>
- Germ-free female mice had higher testosterone than those in standard cages.<\/li>
<\/ul>Together, this data suggested that colonization with commensal bacteria protected male NOD mice against T1D<\/span>, and that this bacterial colonization somehow regulated testosterone production or use.<\/p>
Gut Bacteria Shape the Body’s Metabolic and Hormonal Profile<\/h2>
To measure how much gut microbiota influenced the general physiology of adult male and female NOD mice, the researchers used mass spectrometry to profile almost 200 unique small-molecule metabolites in serum<\/em>. Male and female NOD mice raised in standard conditions had distinct metabolite profiles. But there were few detectable differences between males and females raised germ-free.<\/p>
This data pointed to two possibilities:<\/p>
- Male and female mice responded differently to the same commensal bacteria, or<\/li>
- Male and female mice hosted different commensal communities that influenced their hormone and metabolite levels.<\/li>
<\/ul>The researchers then sequenced bacterial 16S ribosomal RNA from the intestines of NOD mice at different life stages — just after weaning, at puberty, and as adults. Male and female NOD mice had indistinguishable gut microbiota after weaning. But sex-based differences in commensal bacteria appeared at puberty and grew stronger in adulthood.<\/p>
Transplanting Male Gut Bacteria Protects Females from Diabetes<\/h2>
Having established that adult male and female NOD mice carry distinct intestinal bacterial populations, Markle et al. transplanted “male” gut microbiota into pre-pubescent female NOD mice. This changed the makeup of the recipients’ commensal populations for several weeks and raised their serum testosterone levels. Importantly, transplanting male commensal bacteria protected the female recipients from T1D<\/b>. Markers of T1D disease activity, such as beta-islet inflammation and auto-antibody production, were lower in recipients of male gut bacteria than in unmanipulated females. Treating the mice with the anti-androgen Flutamide removed this protective effect. This showed that testosterone levels were a critical regulator of autoimmune disease development<\/em>.<\/p>
What This Means for Autoimmune Disease Research<\/h2>
Markle et al. have proposed an interesting model: sexual maturation triggers sex-specific programming of intestinal commensal bacteria<\/span><\/em><\/b>. These distinct bacterial populations affect host physiology and hormonal balance differently, which in turn shapes immune function. Because gut microbiota play such a central role in immunity, changing the makeup of the intestine’s commensal communities could offer a way to treat a dysfunctional immune system.<\/p>
Researchers are already testing this approach for intestinal disorders using “fecal transplants,”<\/b> and the concept may extend to more systemic autoimmune disorders4<\/sup><\/a>. This approach would benefit from knowing the specific effects of different bacterial species on host physiology, so researchers can identify the key parts of effective therapeutic microbial regimens. It will also help to learn which changes in metabolite and hormone levels — changes that go along with shifts in commensal populations — have the biggest impact on immune function. The metabolite profiling approach used in this study could help identify natural compounds that act as immune modulators.<\/p>
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- Germ-free female mice had higher testosterone than those in standard cages.<\/li>
- Male mice raised germ-free had lower serum testosterone<\/em> than those raised in standard conditions.<\/li>
