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. Here, we demonstrate a direct interaction between sex hormones and early life microbial exposures on the control of autoimmunity in the non-obese 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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    • "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.
    Immunity 08/2015; 43(2). DOI:10.1016/j.immuni.2015.07.013 · 21.56 Impact Factor
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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.
    08/2015; 3(8). DOI:10.14814/phy2.12488
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    • "Accordingly, cytokine transcripts in jejuna showed differential TH17 regulatory network gene transcripts in * 0401 and * 0402 mice. Similarly, Markle et al. [36] show that the commensal microbiota could reinforce the gender bias in the sensitivity of female mice versus resistance of male mice to type 1 diabetes mellitus and alter serum testosterone levels. These observations indicate that intestinal flora linked to gender, age, and genetic background may modulate the gut immune system and enhance proinflammatory conditions in susceptible individuals. "
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    ABSTRACT: Autoimmune diseases (ADs) are considered to be caused by the host immune system which attacks and destroys its own tissue by mistake. A widely accepted hypothesis to explain the pathogenic mechanism of ADs is “molecular mimicry,” which states that antibodies against an infectious agent cross-react with a self-antigen sharing an identical or similar antigenic epitope. However, this hypothesis was most likely established based on misleading antibody assay data largely influenced by intense false positive reactions involved in immunoassay systems. Thus reinvestigation of this hypothesis using an appropriate blocking agent capable of eliminating all types of nonspecific reactions and proper assay design is strongly encouraged. In this review, we discuss the possibility that low immune function may be the fundamental, common defect in ADs, which increases the susceptibility to potential disease causative pathogens located in the gastrointestinal tract (GI), such as bacteria and their components or dietary components. In addition to these exogenous agents, aberrations in the host’s physical condition may disrupt the host defense system, which is tightly orchestrated by “immune function,” “mucosal barrier function,” and “intestinal bacterial balance.” These disturbances may initiate a downward spiral, which can lead to chronic health problems that will evolve to an autoimmune disorder.
    04/2015; 2015:1-12. DOI:10.1155/2015/636207
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