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Science 339 (6123): 1084-1088

Copyright © 2013 by the American Association for the Advancement of Science

Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity

Janet G. M. Markle,1,2 Daniel N. Frank,3 Steven Mortin-Toth,1 Charles E. Robertson,4 Leah M. Feazel,3 Ulrike Rolle-Kampczyk,5 Martin von Bergen,5,6,7 Kathy D. McCoy,8 Andrew J. Macpherson,8 Jayne S. Danska1,2,9,*

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.

1 Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada.
2 Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3 Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO 80045, USA.
4 Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
5 Department of Metabolomics, Helmholtz Center for Environmental Research, 04318 Leipzig, Germany.
6 Department of Proteomics, Helmholtz Center for Environmental Research, 04318 Leipzig, Germany.
7 Department of Biotechnology, Chemistry and Environmental Engineering, Aalborg University, 9000 Aalborg, Denmark.
8 Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, 3008 Bern, Switzerland.
9 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

* To whom correspondence should be addressed. E-mail: jayne.danska{at}sickkids.ca


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