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Gut Microbes, Sex Hormones, Autoimmune Risk Interrelated

By Anette Breindl
Science Editor

Autoimmune diseases are one area where it's a man's world. "Many autoimmune diseases are much more frequent in females," Jayne Danska told BioWorld Today. "That's been known for decades. But we don't have any insight into how to take that insight and do something useful for women with it."

In the Jan 18, 2012, issue of Science, Danska, who is at the Hospital for Sick Children Research Institute in Toronto, and her colleagues presented evidence that one way to do something useful for women might be to make their microbiomes more similar to those of men.

When they transplanted highly diabetes-prone young female mice with gut bacteria from adult males, the female animals "were dramatically protected from diabetes."

Danska and her team did their studies as part of a more general look at the reasons for the growing incidence in autoimmune disease in the developed world. That incidence has been growing at a rapid clip over the past decades – much more quickly than genetic changes can make their way into a population.

"This implicates recent changes in the environment," Danska said. And one rather massive change has been people's exposure to microbes, or lack thereof, over the past few decades.

For their studies, Danska and her team looked at the nonobese diabetic, or NOD, mouse. Those animals develop diabetes at a very high rate overall. That rate, though, is influenced by several factors. Females are more susceptible than males – 85 percent of female NOD mice will develop diabetes, which is more than twice the rate of males.

Tellingly, disease incidence also is "affected by the cleanliness of the colony in which they live." Animals that live in colonies with higher bacterial load have a lower incidence of diabetes.

Danska and her team wanted to test the idea that both sex and cleanliness might interact in the gut microbiome, which recently has been shown to affect the body far beyond its area of residence. (See BioWorld Today, March 28, 2012.)

For their experiments, Danska and her team first delivered animals into a completely germ-free environment – where the animals don't have a gut microbiome because they never encounter bacteria that can colonize their gut. Under such conditions, male NOD mice were about as likely to develop diabetes as females, pointing to the microbiome as a source of protection.

A germ-free environment also changed testosterone levels in both males and females: Males without a microbiome had lower testosterone levels than normal, while testosterone levels rose in microbe-free females. The authors saw no effect on female sex hormones.

When the authors transplanted male microbiomes into germ-free females, such transplants raised their testosterone levels and lowered their risk of developing Type I diabetes. Treating the females with an androgen blocker prevented the protection, which showed that the testosterone is somehow necessary for protection.

The work brings to light complex interactions between the biology of sex hormones, gut microbes and disease. Danska and her team are trying to understand the immunological mechanism of the protection they have observed, as well as working on model systems that can model the distal human gut well enough so that realistic microbiomes can be cultured outside of the gut.

In the more practical realm, "how this is going to be translated is something we talk about often," she said. The work does suggest that "if you could durably alter their gut microbiome composition, you could prevent or delay disease onset" in individuals with high genetic risk. "But I don't think we're going to do it with uncharacterized feces from the human gut."

Such feces are being used in other work. A study in the Jan. 16, 2013, issue of the New England Journal of Medicine showed that fecal transplants beat out antibiotics for the treatment of recurrent C. difficile infections. But the risk-benefit analysis is different for treatments that are given in hopes of preventing a disease that someone may never develop in the first place, and especially for doing so in children.

In Danska's opinion, though, microbiome work will ultimately change the therapeutic landscape in fundamental ways that go beyond specific diseases. "Biologics," she said, "now becomes a much larger umbrella."

Bacteria, Danska pointed out, are "relatively cheap to grow" – certainly, growing a vat of E. coli is cheaper than producing monoclonal antibodies. And so, such approaches present "a huge opportunity," but also will require "a huge shift."

"How that's going to infiltrate industry is really an interesting question," Danska said. "But the writing is on the wall that it will."