Sex differences matter in the gut: effect on mucosal immune activation and inflammation (original) (raw)
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Mucosal Immunology, 2014
The incidence and severity of Crohn's disease (CD) are increased in female patients. Using SAMP1/YitFc (SAMP) mice, a spontaneous model of chronic intestinal inflammation that displays histologic and pathogenic similarities to human CD, we investigated the potential mechanism(s) contributing to sex differences observed in CD. Similar to gender differences observed in CD patients, SAMP female (SAMP-F) mice displayed an earlier onset and more severe ileitis compared with SAMP male (SAMP-M) mice. Furthermore, T-regulatory cells (Tregs) from gut-associated lymphoid tissue (GALT) of SAMP-F mice were reduced in frequency and impaired in their in vitro and in vivo suppressive functions compared with that of SAMP-M mice. Given the interaction between sex hormones and Treg function, we investigated the possible role of estrogen (E2) in SAMP ileitis. SAMP-M mice responded to exogenous E2 administration by expanding Treg frequency and reducing ileal inflammation, whereas SAMP-F mice were resistant. Conventional T cells and Tregs responded differentially to estrogen signaling, leading to distinct immunoprotective effects mediated by distinct estrogen receptor (ER) isoforms. These mechanisms were impaired in T cells from SAMP-F mice. Thus, hormone signaling influences the expansion and function of GALT Tregs in an ER-dependent manner and contributes to gender-based differences in experimental CD.
The Impact of Gut Microbiota on Gender-Specific Differences in Immunity
Frontiers in immunology, 2017
Males and females are known to have gender-specific differences in their immune system and gut microbiota composition. Whether these differences in gut microbiota composition are a cause or consequence of differences in the immune system is not known. To investigate this issue, gut microbiota from conventional males or females was transferred to germ-free (GF) animals of the same or opposing gender. We demonstrate that microbiota-independent gender differences in immunity are already present in GF mice. In particular, type I interferon signaling was enhanced in the intestine of GF females. Presumably, due to these immune differences bacterial groups, such as Alistipes, Rikenella, and Porphyromonadaceae, known to expand in the absence of innate immune defense mechanism were overrepresented in the male microbiota. The presence of these bacterial groups was associated with induction of weight loss, inflammation, and DNA damage upon transfer of the male microbiota to female GF recipient...
Immune response and autoimmune diseases: a matter of sex
2019
Immune response differs between women and men at many levels. In general, females mount stronger innate and adaptive immune responses in comparison to males. In particular, women show more effective phagocytosis and antigen presentation, stronger production of inflammatory cytokines, higher absolute number of CD4+ T cells, higher levels of circulating antibodies, in comparison to men. Genetic, epigenetic, hormonal and environmental factors contribute to sex differences in immune response. The strong immune response in women, on one hand, appears to be beneficial, leading to the reduction of pathogen load and accelerating pathogen clearance, but, on the other hand, it can be detrimental by causing autoimmune or inflammatory diseases. Accordingly, most autoimmune diseases are more prevalent in women than in men and symptoms, disease course and response to therapy may also differ between males and females. In this review, we discuss possible mechanisms for sex-specific differences in a...
The gut microbiome in autoimmunity: Sex matters
Clinical Immunology, 2015
Autoimmune diseases like rheumatoid arthritis are multifactorial in nature, requiring both genetic and environmental factors for onset. Increased predisposition of females to a wide range of autoimmune diseases points to a gender bias in the multifactorial etiology of these disorders. However, the existing evidence tol date has not provided any conclusive mechanism of genderbias beyond the role of hormones and sex chromosomes. The gut microbiome, which impacts the innate and adaptive branches of immunity, not only influences the development of autoimmune disorders but may interact with sex-hormones to modulate disease progression and sex-bias. Here, we review the current information on gender bias in autoimmunity and discuss the potential of microbiome-derived biomarkers to help unravel the complex interplay between genes, environment and hormones in rheumatoid arthritis. Recent advances in "omic"-based approaches (metagenomics, metabolomics and proteomics) and bioinformatics have facilitated our understanding of the mechanisms of a broad range of diseases and have allowed us to identify potential biomarkers for diagnosis
Sex differences in immune responses
Nature Reviews Immunology, 2016
Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.
Seminars in Immunopathology, 2018
Sex differences in immunity are well described in the literature and thought to be mainly driven by sex hormones and sex-linked immune response genes. The gastrointestinal tract (GIT) is one of the largest immune organs in the body and contains multiple immune cells in the GIT-associated lymphoid tissue, Peyer's patches and elsewhere, which together have profound effects on local and systemic inflammation. The GIT is colonised with microbial communities composed of bacteria, fungi and viruses, collectively known as the GIT microbiota. The GIT microbiota drives multiple interactions locally with immune cells that regulate the homeostatic environment and systemically in diverse tissues. It is becoming evident that the microbiota differs between the sexes, both in animal models and in humans, and these sex differences often lead to sex-dependent changes in local GIT inflammation, systemic immunity and susceptibility to a range of inflammatory diseases. The sexually dimorphic microbiome has been termed the 'microgenderome'. Herein, we review the evidence for the microgenderome and contemplate the role it plays in driving sex differences in immunity and disease susceptibility. We further consider the impact that biological sex might play in the response to treatments aimed at manipulating the GIT microbiota, such as prebiotics, live biotherapeutics, (probiotics, synbiotics and bacteriotherapies) and faecal microbial transplant. These alternative therapies hold potential in the treatment of both psychological (e.g.,
Impact of Female Gender in Inflammatory Bowel Diseases: A Narrative Review
Journal of Personalized Medicine
Inflammatory bowel diseases show a gender bias, as reported for several other immune-mediated diseases. Female-specific differences influence disease presentation and activity, leading to a different progression between males and females. Women show a genetic predisposition to develop inflammatory bowel disease related to the X chromosome. Female hormone fluctuation influences gastrointestinal symptoms, pain perception, and the state of active disease at the time of conception could negatively affect the pregnancy. Women with inflammatory bowel disease report a worse quality of life, higher psychological distress, and reduced sexual activity than male patients. This narrative review aims to resume the current knowledge of female-related features in clinical manifestations, development, and therapy, as well as sexual and psychological implications related to inflammatory bowel disease. The final attempt is to provide gastroenterologists with a roadmap of female-specific differences, ...
Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity
Science, 2013
Genome wide studies have identified common polymorphisms associated with autoimmune disease risk, among which, numerous causal variants are implicated in immune regulation. These analyses have not addressed the impact of two other critical modifiers of autoimmunity, sexual dimorphism and environmental factors. The incidences of many autoimmune syndromes display a strong female bias (1-3), yet the mechanisms of sex-mediated immune regulation are poorly understood. Evidence for a disease causal role of environmental factors include incomplete concordance in monozygotic twins, and the recent rise in autoimmune disease incidence in developed countries (4). We have identified a direct interaction between sex hormones and microbial exposures and show that microbiome manipulations can provoke testosterone-dependent protection from autoimmunity in a genetically highrisk rodent model.
Sex and strain dependent differences in mucosal immunology and microbiota composition in mice
Biology of sex differences, 2018
A dysbiosis in the intestinal microbiome plays a role in the pathogenesis of several immunological diseases. These diseases often show a sex bias, suggesting sex differences in immune responses and in the intestinal microbiome. We hypothesized that sex differences in immune responses are associated with sex differences in microbiota composition. Fecal microbiota composition (MITchip), mRNA expression in intestinal tissue (microarray), and immune cell populations in mesenteric lymph nodes (MLNs) were studied in male and female mice of two mouse strains (C57B1/6OlaHsd and Balb/cOlaHsd). Transcriptomics and microbiota data were combined to identify bacterial species which may potentially be related to sex-specific differences in intestinal immune related genes. We found clear sex differences in intestinal microbiota species, diversity, and richness in healthy mice. However, the nature of the sex effects appeared to be determined by the mouse strain as different bacterial species were e...