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.

Biological sex influences antibody responses to routine vaccinations in the first year of life

“…The microbiota, especially the intestinal microbiota, plays a crucial role in the development and regulation of the immune system, and its composition affects how individuals respond to vaccinations . Sex hormones play a key role in bacterial‐host interactions, and sex differences in the microbiota might therefore influence immune responses . As delivery mode and feeding method strongly affect the composition of the infant microbiota, these factors might be expected to influence vaccine responses.…”

“…14 Sex hormones play a key role in bacterial-host interactions, 15 and sex differences in the microbiota might therefore influence immune responses. 16,17 As delivery mode and feeding method strongly affect the composition of the infant microbiota, 18 these factors might be expected to influence vaccine responses. However, in our study, we did not observe any significant impact of delivery mode or feeding method on vaccines responses.…”

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

“…To further understand the protective effects of ES-62 on the gut-metabolic tissue axis, it is worth considering that the actions identified by machine learning to be most robustly predictive of ES-62 improvement of healthspan in either sex are actually anti-PC IgM and IgG antibody responses. That female mice exhibit comparable levels of these antibodies may argue against a role for them in promoting extension of lifespan in male HCD-fed mice: however, the well-documented evidence that females generally make stronger immune responses and consequently are better at fighting infection per se [56][57][58], raises the possibility that ES-62 induction of such "natural" antibodies may be particularly important to its lifespan-extending effects in male mice. Pertinently, male mice make poor ABC responses and have their anti-PC IgG responses significantly reduced by HCD, perhaps making them innately more susceptible to atherosclerosis [59] and (PC-containing) bacterial infection in old age [45][46][47].…”

“…ES-62 promotes healthspan and lifespan mice [25,68]: we therefore plan to attempt to determine whether they are also ES-62 targets, although we have not been able to detect any significant effects on their very low levels (~0.1% live SVF cells) in the visceral adipose tissues examined to date. Intriguingly, there is increasing evidence that NKT cells, like other cells of the innate immune system including eosinophils and macrophages, exhibit (infection and disease-dependent) sexual dimorphisms in their responses: since these sex-biases are influenced by each of sex chromosomes, hormones and bidirectional interactions with the microbiota, they may vary over the lifecourse impacting on disease susceptibility and longevity [20,57,58,70]. In any case, since we cannot correlate the ES-62 promotion of a type-2 inflammatory adipose microenvironment with protection against adipocyte hypertrophy (that normally results in increased adipokine secretion, hypoxia and adipocyte cell death causing inflammation and fibrosis) in either the gonadal or retroperitoneal visceral fat beds in HCD-fed mice, we consider that an ILC2/eosinophil/M2-like macrophage-driven immunoregulatory mechanism is unlikely to contribute to the helminth product's extension of median lifespan of male HCD-fed mice.…”

Parasitic worm-derived ES-62 promotes health- and life-span in high calorie diet-fed mice

“…The failure of ES-62 to restore these commensals, and promote Treg responses in general 9 , may go some way to explaining why the helminth product does not extend lifespan in female HCD-fed mice but only in the male cohorts, which given their lower levels of Verrucomicrobia may be innately less susceptible to the pathological consequences of gut dysfunction. Certainly, there is sexual dimorphism in (microbiota-driven) immune responses and consequently, disease susceptibility with notably the stronger immune responses to infection evident in females predisposing them to chronic inflammatory disorders 62,63 .…”