The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility

Abstract

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., anxiety, depression) and physiological (e.g., irritable bowel disease) disorders differentially affecting males and females.

Keywords: Adaptive immunity; Bacteriotherapy; Faecal microbiota transplant; Innate immunity; Probiotics; Sex differences; Sex hormones.

Fig. 1

The microgenderome revealed. The gastrointestinal tract (GIT) is a site of intense immune homeostasis in which the microbiota plays a pivotal role. Many studies show that the GIT microbiota differs in males and females. Likely causes include differing sex hormone levels in males and females, in part driven by sex differences in systemic sex hormone concentrations, but also influenced by the microbiota themselves. Sex differences in the microbiota composition drive sex differences in both innate and adaptive immunity, and the sex-differential innate and adaptive immune systems in turn drive sex differences in the microbiota composition. A normal, healthy microbiota allows immune homeostasis to be maintained, but loss of the healthy microbiota (dysbiosis) can drive inflammation and susceptibility to inflammatory and autoimmune diseases. Moreover, the GIT microbiota communicates with the brain and vice versa in what has been termed the microbiota-gut-brain axis, likely contributing to sex differences in susceptibility to a number of neuropsychiatric conditions. The response to therapeutic alteration of the microbiota using prebiotics, live biotherapeutics (probiotics, synbiotics and bacteriotherapies) or FMT is also likely to be different in males and females, although this has not been specifically studied to date. DC = dendritic cell, MØ = macrophage, IECs = intestinal epithelial cells