Introduction
One of the strongest risk factors for developing autoimmunity is female sex (1). Although the mechanistic reasons underlying the strong female sex-bias in autoimmune conditions are unclear, it is likely to be strongly influenced by sex-differences in immune system function. Generally, innate and adaptive immune responses are stronger in females than males. Classic examples include heightened interferon type 1 production by activated female plasmacytoid dendritic cells (pDCs) (2) and stronger humoral immune responses in females, with higher antibody titres at baseline and in response to vaccination (3).
Sex determinants such as sex-chromosomes and sex-hormones influence differences in immune system function. Immune system-related genes are encoded on the X and Y chromosomes (4), and sex steroid hormones such as testosterone, oestrogens and progesterone directly impact immune cells by binding to intracellular and extracellular sex hormone receptors (5). However, this is not the whole picture. Sex influences a wide variety of host responses, which could have indirect effects on the immune system. This is supported by evidence demonstrating that the sex-bias in some experimental models of autoimmunity is sensitive to environmental factors. For example, differences in disease risk or severity are less pronounced in certain housing conditions or in germ-free mice (6). These data suggest that the commensal organisms that colonize barrier surfaces-more commonly known as microbiota-may directly impact sex-bias-associated autoimmune disease risk.
The term microbiota refers to the collection of micro-organisms that share our body space, the greatest number of which are located in the gastro-intestinal tract (7). Recently, it has become evident that pathological changes to the gut-microbiota, or dysbiosis, play a central role in influencing the aberrant immune responses that contribute to autoimmune development (8). Animal models have been pivotal in demonstrating this association. For example, K/BxN mice, which develop a spontaneous erosive arthritis, and SKG mice, which develop a severe spondyloarthropathy, do not develop arthritis when housed in germ-free conditions or when treated with broad spectrum antibiotics (9, 10). Treatment with oral antibiotics suppresses disease in a wide variety of inducible models of autoimmunity, ranging from arthritis models (11) to models of multiple sclerosis (MS) and uveitis (12-15). Multiple studies have also demonstrated that changes to the gut-microbiota are associated with the progression of autoimmune models including collagen-induced arthritis (16) and systemic lupus erythematosus (SLE) (17). This review will summarize recent research suggesting that sex influences the gut-microbiota and that sex-hormones directly impact the gut-microbiota, which in turn influences the production of sex-hormones. These data highlight how two risk factors influencing autoimmunity, sex and dysbiosis, communicate and how animal research can give insights into these biological processes. We also discuss evidence from specific experimental models where sexual dimorphism in the gut-microbiota impacts autoimmune disease development. The purpose of this review is to accentuate the diverse effects sex can have on host physiology, demonstrating the importance of reporting sex-dependent effects by including both sexes in animal research.
