Published online 19 September 2008 | Nature | doi:10.1038/news.2008.1121

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Gut microbes fend off diabetes in mice

Naturally occurring bacteria help keep the immune system in check

Microbes that call the intestines home help ward off type 1 diabetes in mice, researchers have found.

Diabetes patientCould avoiding diabetes be a matter of guts?Punchstock

The findings, published online today by Nature1, are the latest in a series of revelations about the impact that resident bacteria may have on health. Humans, mice and other animals are home to a complex community of trillions of microbes, mostly living harmlessly in their guts, their skin and elsewhere. In humans the effects of this 'microbiome' on metabolism and the immune system have been linked to obesity2 and inflammatory bowel disease3. Now type 1 diabetes, an autoimmune disease that affects the pancreas, can be added to the list.

“We knew that MyD88 was a key player, so we decided we'd get rid of it.”

Alexander Chervonsky
University of Chicago

A link to the microbiome could provide an explanation for the rising rates of this disease, particularly in developed countries. For years, researchers have put forward possible explanations in terms of infection, lifestyle and environment: a particular virus infection, perhaps, or chemicals found in certain processed foods. "The problem is, we've never found out what that trigger is," says Denis Daneman, chairman of paediatrics at the Hospital for Sick Children in Toronto, who is currently investigating ways that diet may increase the risks.

Circulating signals

Over a decade ago, some researchers noted that a diabetes-prone strain of mouse is even more likely to develop the disease when it is grown in a sterile, microbe-free environment. The observation suggested that exposure to bacteria could somehow help stave off the disease.

Immunologist Alexander Chervonsky of the University of Chicago and his colleagues decided to take a closer look at how the immune system's interactions with intestinal microbes might influence diabetes. MyD88, a protein known to be a key regulator of immune responses to resident microbes, stood out as a candidate for further study. "We knew that MyD88 was a key player," says Chervonksy. "So we decided we'd get rid of it."

“It's going to become clear that the effects of the microbiota extend well past the intestine.”

Sarkis Mazmanian
Caltech

Although most mice belonging to this diabetes-prone strain develop the disease, none of those that lacked the MyD88 gene became diabetic. If the 'knockout' mice were kept in a sterile environment, though, they still developed diabetes. Additional investigation showed that those raised in a sterile environment but inoculated with a cocktail of gut bacteria developed the condition a lot less frequently than their totally bacteria-free peer group, with only 34% of them getting ill, rather than 80% 1.

Chervonsky and his colleagues also found that loss of MyD88 altered the composition of microbial species in the gut. They hypothesize that the protein's controlling effect on the bacteria may diminish the degree to which the bacteria protect against diabetes. That would explain why, in the presence of bacteria, Myd88 worsens the risks, but in the absence of bacteria it has no bearing on the disease at all.

The results fit the 'hygiene hypothesis', which suggests that if organisms encounter fewer microbes than evolution has led them to expect, they will be at higher risk of autoimmune diseases. "The hypothesis is that if you are exposed to a whole lot of pathogens, you jazz up your immune system and protect against the insult that leads you down the path of type 1 diabetes," says Chervonsky. "If you don't, your immune system remains relatively naive."

“This is still very much a study done in a very controlled environment.”

Bhagirath Singh
Canadian Institutes of Health Research

The results confirm that bacteria in the gut have power over more than just digestion, says microbiologist Sarkis Mazmanian of the California Institute of Technology in Pasadena. Immune cells circulate throughout the body, and could pick up signals from bacteria in the gut and transmit those messages to other parts of the body — such as, in the case of diabetes, the pancreas.

"It's going to become clear that the effects of the microbiota extend well past the intestine," Mazmanian predicts. More widespread effects may make the various projects aimed at characterizing the human microbiome interesting to researchers in a broader range of disciplines (see Microbiology: The inside story).

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Chervonsky and his colleagues want to discover the bacterial products that are important in staving off diabetes, in the hope that they could be purified and used to prevent the disease in humans. However, because the studies were done in mice, it remains unclear whether the same relationship will hold in humans. Several previous findings from the same mouse strain have failed to translate into the clinic.

"This is still very much a study done in a very controlled environment," cautions Bhagirath Singh, scientific director of the Institute of Infection and Immunity at the Canadian Institutes of Health Research in London, Ontario. "But I can see that the implications could extend far beyond just the lab." 

  • References

    1. Wen, L. et al. Nature doi:10.1038/nature07336 (2008).
    2. Turnbaugh, P.J., et al. Nature 444, 1027–1031 (2006).
    3. Mazmanian, S.K., Round, J.L. & Kasper, D.L. Nature 453, 620-625 (2008). | Article | ChemPort |
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