Immunity, Friendly Flora, and Type I Diabetes

September 23, 2008

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 Immunity, Friendly Flora, and Type I Diabetes
Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing -cells. Its incidence has increased during the past several decades in developed countries1, 2, suggesting that changes in the environment (including the human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility3 or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products4, 5. Here we show that specific pathogen-free NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.

From press release:

In a dramatic illustration of the potential for microbes to prevent disease, researchers at Yale University and the University of Chicago showed that mice exposed to common stomach bacteria were protected against the development of Type I diabetes.

The findings, reported in the journal Nature, support the so-called "hygiene hypothesis" – the theory that a lack of exposure to parasites, bacteria and viruses in the developed world may lead to increased risk of diseases like allergies, asthma, and other disorders of the immune system.

The results also suggest that exposure to some forms of bacteria might actually help prevent onset of Type I diabetes, an autoimmune disease in which the patient's immune system launches an attack on cells in the pancreas that produce insulin.

The root causes of autoimmune disease have been the subject of intensive investigation by scientists around the world.

In the past decade, it has become evident that the environment plays a role in the development of some overly robust immune system responses. For instance, people in less-developed parts of the world have a low rate of allergy, but when they move to developed countries the rate increases dramatically. Scientists have also noted the same phenomenon in their labs.

Non-obese diabetic (NOD) mice develop the disease at different rates after natural breeding, depending upon the environment where they are kept. Previous research has shown that NOD mice exposed to killed (i.e., non-active) strains of tuberculosis or other disease-causing bacteria are protected against the development of Type I diabetes. This suggests that the rapid "innate" immune response that normally protects us from infections can influence the onset of Type 1 diabetes.

In the Nature paper, teams led by Li Wen at Yale and Alexander V. Chervonsky at the University of Chicago showed that NOD mice deficient in innate immunity were protected from diabetes in normal conditions. However, if they were raised in a germ-free environment, lacking "friendly" gut bacteria, the mice developed severe diabetes. NOD mice exposed to harmless bacteria normally found in the human intestine were significantly less likely to develop diabetes, they reported.

"Understanding how gut bacteria work on the immune system to influence whether diabetes and other autoimmune diseases occurs is very important," Li said. "This understanding may allow us to design ways to target the immune system through altering the balance of friendly gut bacteria and protect against diabetes."

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