Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity
Mighty Male Microbes
Both genetic and environmental factors contribute to an individual's susceptibility to autoimmune disease, but the specific environmental influences are not well characterized. Markle et al. (p. 1084, published online 17 January; see the Perspective by Flak et al.) explored how microbial factors, in particular the gut microbiota, influence susceptibility to type 1 diabetes in mice. In the non-obese diabetic (NOD) mouse model of type 1 diabetes, female mice are significantly more susceptible to disease than males; however, this difference was not apparent under germ-free conditions. Transfer of cecal contents from male NOD mice to female NOD mice prior to disease onset protected against pancreatic islet inflammation, autoantibody production, and the development of diabetes and was associated with increased testosterone in female mice. Blocking androgen receptor activity abrogated protection. Thus, the microbiota may be able to regulate sex hormones and influence an individual's susceptibility to autoimmunity.
Abstract
Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.
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Volume 339 | Issue 6123
1 March 2013
1 March 2013
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Copyright © 2013, American Association for the Advancement of Science.
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Received: 3 December 2012
Accepted: 9 January 2013
Published in print: 1 March 2013
Acknowledgments
We thank S. Bashir for assistance with metabolomic data analysis, C. Vogel Kotter for high-throughput sequencing, and E. Simpson and M. Palmert for helpful discussions. The 16S sequence data have been submitted to the National Center for Biotechnology Information short-read archive project, accession no. SRA064044. Flow cytometry was performed in the SickKids–University Health Network Flow Cytometry Facility with funds from the Ontario Institute for Cancer Research, McEwen Centre for Regenerative Medicine, Canada Foundation for Innovation, and SickKids Foundation. Roche 454 sequencing was performed at the Centre for Applied Genomics, Hospital for Sick Children. Illumina sequencing was performed at the University of Colorado School of Medicine. Supported by Canadian Institutes of Health Research (CIHR) grant 64216 and Juvenile Diabetes Research Foundation (JDRF) grant 17-2011-520 (J.S.D.), Genome Canada (administered by Ontario Genomics Institute) (J.S.D. and A.J.M.), JDRF grant 36-2008-926 and the Genaxen Foundation (A.J.M.), a CIHR Banting and Best fellowship (J.G.M.M.), and NIH grant R21HG005964 (D.N.F. and C.E.R.). J.G.M.M. and J.S.D. designed the study, analyzed data, and wrote the manuscript; J.G.M.M., D.N.F., S.M.-T., C.E.R., M.v.B., K.D.M., and A.J.M. performed experiments and analyzed data; L.M.F. and U.R.-K. performed experiments; and all authors contributed to manuscript editing.
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