Gut Microsex/Genderome, Immunity and Stress in the Sexes: Comparison
Please note this is a comparison between Version 1 by George P. Chrousos and Version 2 by Sirius Huang.

Sex has been universally acknowledged as a confounding factor in every type of biological study, while there are strong sex differences in morbidity along the lifespan. Humans have almost identical genomes (99.2%), yet minor variance in their DNA produces remarkable phenotypic diversity across the human population. On the other hand, metagenomic analysis of the human microbiome is more variable, depending on the sex, lifestyle, geography, and age of individuals under study. Immune responses in humans also exhibit variations, with an especially striking sexual dimorphism, which is at play in several other physiologic processes. Sex steroids have noticeable effects on the composition of the human microbiome along the lifespan, accompanied by parallel changes in immunity and the stress response. Gut microsex/genderome, a recently coined term, defines the sexually dimorphic gut microbiome. Apart from the sex steroids, the stress hormones are also at play in the proliferation of microbes.

  • physiology
  • sexual dimorphism
  • liver
  • muscles
  • microbiome
  • body composition
  • autoimmune disorders
  • obesity

1. Introduction

The sex of a human being has always been a major element of her/his physical and psychosocial identity. Numerous physiologic processes are differentially expressed in the sexes, including sexual maturation, somatic growth, body composition, immune function, and stress response [1]. Lately, another key player in sexual differentiation has become the center of attention: the human microbiome. The latter term refers to the entire habitat of the commensal microorganisms (bacteriome, virome, mycobiome), their genomes, and the conditions of the environment they reside in [2][3][2,3]. “Microsex/genderome” describes the phenomenon of sexual dimorphism of the microbiome. It entails multidirectional interactions between the sex hormones, the various parameters of the microbiome, and the immune system [4][5][6][7][4,5,6,7].

2. Gut Microbiome in the Sexes: Gut Microsex/Genderome

During the first year of life, there are noteworthy differences in the concentrations of sex hormones. Analysis of the gut microbiome of neonates shows male infants have a lower diversity than females, while females exhibit a higher abundance of Clostridiales (phylum Firmicutes), and a lower abundance of Enterobacteriales (phylum Proteobacteria) [8][29]. Furthermore, a species, such as Bifidobacterium spp., comprising the earliest and most abundant colonizer, seems to be in different abundance between the sexes. A study conducted by Nagpal et al. demonstrated that male full-term babies had higher Bifidobacterium populations on the first day of life than their female counterparts [9][30]. The gut microbiome however is similar in girls and boys but develops and differentiates in a dynamic gradual manner during childhood and adolescence. There is no specific time, but time periods, for these changes in the gut microbiome, but they usually coincide with changes in daily life, such as the introduction of solid foods, adrenarche, puberty, or the beginning of increased social interactions, such as school attendance [8][29]. As far as species are concerned, Bifidobacterium spp. is in higher abundance during infancy, while Clostridium spp is profused during adulthood; yet, the simultaneous existence of these bacteria may either be representative of a contribution of each developmental stage to the composition of the gut microbiome community or that there is an operative requirement for microbial metabolites during growth and development [4].
In a recent study, the fecal samples of healthy prepubertal children were abundant in Bifidobacterium spp., Faecalibacterium spp., and members of the Lachnospiraceae, while adults held greater populations of Bacteroides spp. From a functional viewpoint, significant variances were detected regarding the relative abundances of genes involved in vitamin synthesis, amino acid degradation, oxidative phosphorylation, and triggering of mucosal inflammation. The prepubertal gut microbiome was enriched in symbiotic functions, supporting continuing growth, while the gut microbiome of the adults was associated with systemic inflammation, obesity, and/or increased risk of adiposity [10][20].
Changes in bacterial composition during adolescence to a firmer, adult-type composition is important for disease prevention, as microbial shifts could have a lasting effect on health through childhood and adulthood. The dominant bacterial genera found in the healthy gut microbiome of children include Bacteroides, Prevotella, and Bifidobacterium spp. Data from recent studies have demonstrated that the adolescent gut microbiome has significantly greater populations of Bifidobacterium and Clostridium in comparison with the seemingly healthy adult gut microbiome [11][31]. In people aged 70 years of age, or older, however, when there is an apparently decreased secretion of sex steroids, no changes in gut physiology have been recorded. In a study of 35,292 adults, total populations in colony-forming units did not exhibit age- or sex-related changes. However, individual bacterial species varied according to age: Escherichia coli and Enterococci spp. both increased, and Bacteroides spp. lessened with age. In fact, another study recorded that maintaining a high Bacteroides dominance into older age, or having a low alpha diversity, predicts decreased survival in a four-year follow-up [12][32]. Lactobacillus and Bifidobacterium spp seemed to be constant throughout adult life [13][15].
In adults, the factor of sex is a strong predictor of diversity and, therefore, it should not be overlooked in diversity analysis, particularly for key phyla such as Actinobacteria, Bacteroidetes, and Firmicutes. The composition of species is dependent on the sex, since, there seem to be sex-specific bacterial species for each sex [14][33]. Ovary-derived estrogens, or estrogens derived from the adrenal glands and/or adipose tissue, or food-derived estrogens can be further managed by the gut microbiome into estrogen-like metabolites influencing host physiology, hence coining the term “estrobolome” [15][13]. Additional studies support sex hormones as distinct players in the microbiome composition, as differences in microbiome profiles between male and female NOD mice disappeared after castration of the males, also, suggesting the strong involvement of testosterone [16][17][34,35].
In a study by Koliada et al. [18][36], the investigators revealed relative abundances of Firmicutes and Actinobacteria, as evaluated by qRT-PCR, to be significantly augmented, while those of Bacteroidetes were significantly reduced in the females vs. the males. The Firmicutes to Bacteroidetes (F/B) ratio was significantly augmented in the females in comparison with the males. Females had 31% higher odds of having an F/B ratio of more than 1 than males. This trend was apparent in all age groups, from adolescence to middle age. The difference between sexes was even more distinct in the elders (50 years of age or more). More specifically, in this age group, females presented with 56 % higher odds of having an F/B ratio > 1 than males. In other studies of human populations, sex differences in fecal microbiomes were proved principally at lower taxonomic levels [19][37]. Others found that males had three times higher odds than females of fecal matter of smaller populations of Bacteroides and higher of Prevotella [20][38]. The reduced representation of the Bacteroidetes phylum and correspondingly higher populations of members of the Firmicutes phylum, recognized to supply energy from food, are characteristic features of the “obese gut microbiota” [21][39]. Sex-specific gut microbiome differences were discovered to be BMI-related, with a higher F/B ratio in obese females than that in obese males. More specifically, no differences in F/B ratio were observed between the sexes, when considered independently of BMI. However, when all study participants were stratified according to BMI, a higher F/B ratio was observed in males who had BMI < 33 than in females of the same BMI group, whereas, males had a significantly lower F/B ratio than females in the BMI > 33 group [17][35].

3. Immunity and the Sexes

Estrogen, progesterone, and androgens produce direct effects on the function and inflammatory ability of immune cells. Males are more vulnerable to most viral infections, but females possess immunological qualities that render them more prone to distinct immune-related disease outcomes. Sex chromosome complements and related genes, together with sex steroids, play chief parts in mediating the expression of sex differences in immunity to viral illnesses. The epigenetic changes are, also, reflected by changes in the function of the immune cells [22][23][25,40]. This is in accordance with the latest findings about COVID-19 infection and its post-viral period [24][41].
Sex-specific transcriptome and methylome have been identified within several studies, independently of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism, also, occurs at the epigenetic level. Furthermore, distinct adjustments to the transcriptomic and epigenetic landscape transpire in alliance with changes in hormonal concentrations, occurring in puberty, pregnancy, menopause, and exogenous hormone therapy. Autoinflammation refers to the primary dysregulation of innate immunity with cells involved encompassing phagocytic cells (neutrophils, eosinophils, basophils, monocytes/macrophages, and dendritic cells), mast cells, epithelial and endothelial cells, natural killer cells, innate lymphoid cells, and platelets, together resulting in the production of inflammatory cytokines, such as IL-1β, and IL-18. These autoinflammatory diseases typically lack autoantibodies or MHC associations, and they seem to have a slight predominance in females [22][25].
Estrogen, progesterone, and testosterone intermingle with nuclear hormone receptors in many cell types, including the cells of the immune system. Thus, it seems that several genes are controlled by sex hormones. In addition, sex hormones can also have effects on gene expression through other mechanisms, comprising G-protein coupled receptor signaling, and rapid membrane signaling [25][42]. Autoimmunity refers to a loss of self-tolerance and a state of immune responsiveness to self-antigens. Autoimmunity causes damage in various tissues and results in diseases termed “autoimmune diseases” [26][43].
General and tissue-specific body changes have been associated with irritable bowel syndrome (IBS) via mechanisms of dysfunction of barrier permeability of the intestinal epithelium and changes in the immune system. Other studies advocate a female predominance of IBS, implying sex hormones of the females as drives in its pathogenesis. Transit duration of the GI tract also has been described to vary according to the phase of the menstrual cycle, pregnancy, and postpartum. Estrogen and testosterone seem to directly alter both the gut microbiome and immune cells. Increased concentrations of β-estradiol cause the production of IL-12 and IFN-γ, via the stimulation of the dendritic cells. Thus, activation of inflammatory pathways is activated increasing proinflammatory cytokine concentrations. Estradiol prolongs the survival of polyclonal B cells generating a proinflammatory environment and resulting in altered intestinal gut permeability, causing the migration of gut microbiota into the lamina propria, which, in turn, promotes local inflammatory processes [13][15]. In summary, testosterone and progesterone seem to be anti-inflammatory, suppressing several aspects of the immune response necessary for inflammation, whereas estradiol has bi-potential effects: proinflammatory at low concentrations and anti-inflammatory at high concentrations [27][28][44,45].

4. Stress Response in the Sexes

The hypothalamic–pituitary–adrenal (HPA) axis is a neuroendocrine complex that holds control of hormonal reactions to internal and external cues, acting like stressors, and it exhibits sex-biased activity [29][53]. Data from animal studies have demonstrated progesterone and its products, the neuroactive steroid allopregnanolone, as central parts of stress and in stress-related psychopathology. These hormones are mainly produced in the brain but, also, in the periphery during stress and they downregulate anxiety symptoms and HPA axis activity in lab animals. While 5α-dihydro-progesterone seems to have a downregulatory action on subjective anxiety via the progesterone receptors, allopregnanolone acts on GABA-A receptors, decreasing subjective anxiety, along with the ability to learn and memorize, as well as saccadic eye velocity, both via a decrease in corticotropin-releasing hormone (CRH) release and arginine vasopressin (AVP) secretion, resulting in motivation for affiliation during times of stress [30][48]. This phenomenon seems to be exacerbated when the concentrations of progesterone are high [31][54].
Estrogens upregulate HPA axis action, increasing the release of the stress-related secretagogues at multiple sites due to the broad expression of estrogen receptors (ERs). In the adrenal gland, estradiol increases the adrenal response to adrenocorticotropic hormone (ACTH) administration [32][55], while androgens are consistently reported to inhibit HPA axis activation and action [29][33][34][53,56,57]. A quite recent study revealed that stress-induced activation of the HPA axis may be triggered by estrogen-dependent upregulation of AVP in the median eminence of female rats [35][58]. Most likely, estradiol instigates dysregulation of the HPA axis feedback, as evidenced by the inability of dexamethasone to suppress diurnal and stress-induced ACTH and corticosterone secretion, as demonstrated in female rats. In addition, the ability of estradiol to hamper glucocorticoid negative feedback occurs specifically via ERα acting at the level of the paraventricular nucleus (PVN) of the hypothalamus [36][59].
Androgens have an inhibitory effect on basal and stress-induced glucocorticoid (GCs) concentrations via central and peripheral actions, while estrogens have a stimulatory effect not only by impairing glucocorticoid negative feedback but also by centrally stimulating the HPA axis. As shown by Vamvakopoulos and Chrousos, the CRH gene has estrogen-response elements in its promoter and responds to estrogen stimulation [37][38][60,61]. This effect of estrogens is affected by the presence or absence of progesterone that counteracts estrogen-stimulating action [39][40][62,63].
It seems that sex chromosomes influence sex-specific biology in utero, even if the data are scarce [41][64]. A rise in testosterone concentrations in male fetuses starts shaping the male brain during the prenatal period differently than the female brain. These “organizational effects” possibly occur before puberty. The cerebral regions involved in glucocorticoid regulation at rest and after stress are, thus, entangled in a sex-specific manner. After puberty, the increased concentrations of all gonadal hormones cooperate with glucocorticoid hormones in specific crosstalk through their nuclear receptors. In addition, stress occurring during the prenatal period, early in life (first 5 years), and adolescence prime the long-term glucocorticoid stress response through epigenetic mechanisms, in a sex-specific manner. Overall, different molecular mechanisms explain sex-specific glucocorticoid stress responses that mediate important gender effects in humans [42][65].
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