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

Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada.
Science (Impact Factor: 33.61). 01/2013; 339(6123). DOI: 10.1126/science.1233521
Source: PubMed


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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Available from: Ulrike Elisabeth Rolle-Kampczyk, Oct 22, 2014
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    • "DISCUSSION A number of studies have documented the ability of gut commensals to affect the expression of autoimmunity at proximal as well as distal sites. The effects can be inhibitory, such as diabetes in NOD mice (Markle et al., 2013; Wen et al., 2008), but more often are enhancing, such as several models of arthritis, EAE, and colitis (Berer et al., 2011; Chappert et al., 2013; Garrett et al., 2010; Lee et al., 2011; Morton et al., 2014; Wu et al., 2010; Yoshitomi et al., 2005). The mechanisms are complex and might involve several unrelated microorganisms in concert (Garrett et al., 2010). "
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    ABSTRACT: Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune-privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. Our findings not only have implications for the etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes might be a more common trigger of autoimmune diseases than is currently appreciated. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Immunity
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    • "The gut microbiota of T1D animal models and T1D patients is altered with a lower proportion of butyrate-producing bacteria species (i.e., Firmicutes Clostridium) than controls (de Goffau et al., 2013; Giongo et al., 2011; Roesch et al., 2009). Furthermore, the partial protection against autoimmune diabetes observed in the male NOD mice compared to the female counterpart has been associated with difference in the composition of their gut microbiota (Markle et al., 2013; Yurkovetskiy et al., 2013). In these studies, the transfer of gut microbiota from male to female NOD mice confers protection against diabetes that is attributed to hormonal-dependent mechanism. "
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    ABSTRACT: Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Immunity
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    • "Strong correlations have been made between the composition of gut microbes and development of metabolic disease, in both human and animal models (Joyner et al. 2000; Larsen et al. 2010; Howitt and Garrett 2012; Zhang et al. 2013). Moreover, sex hormones (e.g., estrogen and testosterone) have been shown to influence microbial communities (Kornman and Loesche 1982; Markle et al. 2013), and gut microbes reciprocally affect the metabolism and systemic levels of these hormones (Adlercreutz et al. 1984; Plottel and Blaser 2011; Flores et al. 2012). For estrogen, these effects appear to be mainly regulated by estrogen receptor beta (ERb), which is the primary estrogen receptor in the gut. "
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    ABSTRACT: The increased risk for cardiometabolic disease with the onset of menopause is widely studied and likely precipitated by the decline in endogenous estradiol (E2), yet the precise mechanisms are unknown. The gut microbiome is involved in estrogen metabolism and has been linked to metabolic disease, suggesting its potential involvement in the postmenopausal phenotype. Furthermore, menopause-associated risk factors, as well as gut ecology, are altered with exercise. Therefore, we studied microbial changes in an ovariectomized (OVX vs. Sham) rat model of high (HCR) and low (LCR) intrinsic aerobic capacity (n = 8-10/group) in relation to changes in body weight/composition, glucose tolerance, and liver triglycerides (TG). Nine weeks after OVX, HCR rats were moderately protected against regional adipose tissue gain and liver TG accumulation (P < 0.05 for both). Microbial diversity and number of the Bacteroidetes phylum were significantly increased in LCR with OVX, but unchanged in HCR OVX relative to Sham. Plasma short-chain fatty acids (SCFA), produced by bacteria in the gut and recognized as metabolic signaling molecules, were significantly greater in HCR Sham relative to LCR Sham rats (P = 0.05) and were decreased with OVX in both groups. These results suggest that increased aerobic capacity may be protective against menopause-associated cardiometabolic risk and that gut ecology, and production of signaling molecules such as SCFA, may contribute to the mediation. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    Full-text · Article · Aug 2015
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