Early life exposure to normal bacteria of the GI tract (gut microbes) protects against autoimmune disease in mice, according to research published on-line in the January 17 edition of Science. The study may also have uncovered reasons why females are at greater risk of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and lupus compared to males.
Researchers from The Hospital for Sick Children (SickKids) found that when female mice at high risk of autoimmune (type 1) diabetes were exposed to normal gut bacteria from adult male mice, they were strongly protected against the disease. In this type of mouse strain, more than 85% of females develop autoimmune diabetes due to strong genetic risk factors. In contrast, only 25% of the females developed the disease after they were given normal male gut microbes early in life.
“Our findings suggest potential strategies for using normal gut bacteria to block progression of insulin-dependent diabetes in kids who have high genetic risk,” says principal investigator Dr. Jayne Danska. She is Senior Scientist in Genetics & Genome Biology at SickKids and Professor in the Departments of Immunology and Medical Biophysics at the University of Toronto.
A second unexpected finding was the effects of the gut microbe treatments on sex hormones. “We were surprised to see that when young female mice received normal gut microbes from adult males, their testosterone levels rose. We then showed that this hormone was essential for the gut microbe treatment to protect against the disease. It was completely unexpected to find that the sex of an animal determines aspects of their gut microbe composition, that these microbes affect sex hormone levels, and that the hormones in turn regulate an immune-mediated disease,” says Dr. Danska.
She adds, “We don’t know yet how transfer of male gut microbes into females increases their testosterone, or how this process protects against autoimmunity. This study opens up a new research arena to explore the clinical potential of altering the gut microbe community to prevent or treat immune-mediated diseases.”
Researchers from The Hospital for Sick Children (SickKids) found that when female mice at high risk of autoimmune (type 1) diabetes were exposed to normal gut bacteria from adult male mice, they were strongly protected against the disease. In this type of mouse strain, more than 85% of females develop autoimmune diabetes due to strong genetic risk factors. In contrast, only 25% of the females developed the disease after they were given normal male gut microbes early in life.
“Our findings suggest potential strategies for using normal gut bacteria to block progression of insulin-dependent diabetes in kids who have high genetic risk,” says principal investigator Dr. Jayne Danska. She is Senior Scientist in Genetics & Genome Biology at SickKids and Professor in the Departments of Immunology and Medical Biophysics at the University of Toronto.
A second unexpected finding was the effects of the gut microbe treatments on sex hormones. “We were surprised to see that when young female mice received normal gut microbes from adult males, their testosterone levels rose. We then showed that this hormone was essential for the gut microbe treatment to protect against the disease. It was completely unexpected to find that the sex of an animal determines aspects of their gut microbe composition, that these microbes affect sex hormone levels, and that the hormones in turn regulate an immune-mediated disease,” says Dr. Danska.
She adds, “We don’t know yet how transfer of male gut microbes into females increases their testosterone, or how this process protects against autoimmunity. This study opens up a new research arena to explore the clinical potential of altering the gut microbe community to prevent or treat immune-mediated diseases.”
The hygiene hypothesis
The findings support the ‘hygiene hypothesis,’ which suggests that the dramatic increase in autoimmune and inflammatory diseases over the past 50 years results from changes in our exposure to microbes. Gut microbes are essential for normal development and training of the immune system, for extracting nutrients from our food, and for protecting us from some infectious diseases. “Our gut microbial community is an essential part of ourselves – bacterial cells outnumber human cells in our bodies by more than ten to one – and we live with them as partners,” explains Dr. Danska.
Previous research has shown that children living on farms, exposed to a denser and more complex microbial environment, have fewer immune-mediated diseases compared to their village or urban-dwelling peers.
Today’s publication is the first to identify a difference between normal gut microbes in males and females reared in identical conditions, and to show that transfer of male-sourced gut bacteria protects against autoimmune disease in females with high genetic risk.
“Our findings point to a direct relationship between normal gut microbe composition and prevention of autoimmune disease. From these discoveries we can move on to characterize the relationships between gut microbes, sex hormones, and ways to control unwanted immune responses,” says Dr. Danska.
Implications for diabetes and other autoimmune diseases
The researchers’ success in preventing type 1 diabetes from developing in high-risk mice suggests that similar approaches may be applicable in preventing and treating other immune diseases, particularly those showing a female sex bias, Dr. Danska says. .
Previous research has shown that children living on farms, exposed to a denser and more complex microbial environment, have fewer immune-mediated diseases compared to their village or urban-dwelling peers.
Today’s publication is the first to identify a difference between normal gut microbes in males and females reared in identical conditions, and to show that transfer of male-sourced gut bacteria protects against autoimmune disease in females with high genetic risk.
“Our findings point to a direct relationship between normal gut microbe composition and prevention of autoimmune disease. From these discoveries we can move on to characterize the relationships between gut microbes, sex hormones, and ways to control unwanted immune responses,” says Dr. Danska.
Implications for diabetes and other autoimmune diseases
The researchers’ success in preventing type 1 diabetes from developing in high-risk mice suggests that similar approaches may be applicable in preventing and treating other immune diseases, particularly those showing a female sex bias, Dr. Danska says. .
The paper is titled “Sex-specific differences in the gut microbiome drive testosterone-dependent protection from autoimmunity.”
The paper’s co-authors are from the University of Colorado Denver, the Helmholtz Centre in Leipzig, Germany, and the University of Bern in Switzerland. The study was funded by JDRF (Juvenile Diabetes Research Foundation), Canadian Institutes of Health Research, National institutes of Health (US), Genome Canada-Ontario Genomics Institute, and SickKids Foundation.
The paper’s co-authors are from the University of Colorado Denver, the Helmholtz Centre in Leipzig, Germany, and the University of Bern in Switzerland. The study was funded by JDRF (Juvenile Diabetes Research Foundation), Canadian Institutes of Health Research, National institutes of Health (US), Genome Canada-Ontario Genomics Institute, and SickKids Foundation.
About The Hospital for Sick ChildrenThe Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision of Healthier Children. A Better World.™ For more information, please visit www.sickkids.ca.
About SickKids Centre for Research and Learning
The SickKids Centre for Research and Learning will bring together researchers from different scientific disciplines and a variety of clinical perspectives, to accelerate discoveries, new knowledge and their application to child health — a different concept from traditional research building designs. The facility will physically connect SickKids science, discovery and learning activities to its clinical operations. Designed by award-winning architects Diamond + Schmitt Inc. and HDR Inc. with a goal to achieve LEED® Gold Certification for sustainable design, the Centre will create an architectural landmark as the eastern gateway to Toronto’s Discovery District. The SickKids Centre for Research and Learning is funded by a grant from the Canada Foundation for Innovation, the Government of Ontario, philanthropist Peter Gilgan and community support for the ongoing fundraising campaign. For more information, please visit www.sickkidsfoundation.com/bepartofit.
