Interactions between sex hormones and the gut microbiome

Important findings for the gut-brain axis have emerged, linking an altered gut microbiome to numerous central nervous system (CNS) disorders including anxiety, depression, Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and autism spectrum disorder (Holingue et al., 2020; Bostick et al., 2022). Many of these disorders include neuroinflammation as well as gastrointestinal (GI) disturbances (Bostick et al., 2022). Furthermore, these disorders often exhibit sex and age differences; for example, Alzheimer’s disease affects more females than males and occurs in older age whereas autism spectrum disorder affects more males than females and behavioral characteristics emerge in early childhood (Holingue et al., 2020). In a recent paper in Brain Behavior and Immunity, Sullivan et al. (2024) investigate the microbiome-endocrine-brain axis, in male and female mice during an early-life gut inflammatory insult. While great progress in our understanding of the gut-brain axis is occurring, studies like these that focus on sex differences, hormonal influence, and neurodevelopment are important to our full understanding of the gut-brain axis across the lifespan, in healthy and disease states.

Sullivan et al. determined a number of differences along the microbiome-endocrine-brain axis for a pediatric mouse model of inflammatory bowel disease (IBD) induced by multiple treatment periods with dextran-sodium-sulfate (DSS). Specifically for male mice, the pediatric IBD model led to increased intestinal inflammation, gut microbiome dysbiosis, decreased serum short chain fatty acid (SCFA) levels, impaired mate-seeking behaviors, smaller seminal vesicles, lower circulating androgens, decreased intestinal hormone-activating enzyme, and altered microglial morphology. Female mice with the pediatric IBD model revealed intestinal inflammation, gut microbiome dysbiosis, decreased serum SCFA levels, and altered microglial morphology, but no changes to reproductive organs or sex hormones (Sullivan et al., 2024).

IBD has been linked to altered puberty, sexual dysfunction, and infertility. During adolescence, males and females with IBD reveal delayed onset and prolonged progression of puberty (Hildebrand et al., 1994; Sullivan et al., 2024). During adulthood, males and females with IBD reveal increased rates of sexual dysfunction and infertility. This points to an important characteristic of the gut microbiome: an interaction with sex hormones. Previous research has shown that germ-free mice have altered sex hormone levels (Markle et al., 2013; Sullivan et al., 2024). Germ-free mice administered human fecal preparations engraft microbiota based on the sex of the mouse. Males and females have a different composition of the gut microbiome and these changes are dependent on age, further supporting the relationship between sex hormones and gut microbiome composition (Markle et al., 2013; Valeri and Endres, 2021; Saxena et al., 2022). Adolescence is a critical period; experiments conducted in mice to determine sex differences in the gut microbiome note the onset of puberty as the time period when these differences appear (Markle et al., 2013; Valeri and Endres, 2021). Another shift in gut microbiome composition occurs for women during menopause. A previous study in humans determined higher alpha diversity for young women (age 20–45) compared to men, but this sex difference is lost in older age due to lower alpha diversity in older women (age 60+). It is hypothesized that the decreased estrogen levels during menopause affect gut microbiome composition (Valeri and Endres, 2021). Specifically, relationships between the gut microbiome, and estrogen and testosterone have been explored.

A key factor regulating host sex hormone metabolism is a microbiome that contains the β-glucuronidase (GUS) gene. The GUS gene encodes the enzymes, β-glucuronidases, β-mannosidases, and β-glucosidases. The β-glucuronidases and β-glucosidases deconjugate, for example, estrogen in the intestines, which can then allow the estrogen to be reabsorbed into the bloodstream. Therefore, microbial β-glucuronidase and β-glucosidase levels impact host circulating estrogen levels. It is estimated that at least 60 genera of bacteria in the human microbiome have GUS genes and belong to the following phyla: Bacteroidetes (52%), Firmicutes (43%), Verrucomicrobia (1.5%), and Proteobacteria (0.5%). Dysbiosis, as seen in IBD and other disorders, can disrupt microbes that contain GUS genes, leading to altered sex hormone levels. For example, breast cancer, specifically hormone receptor-positive breast cancers have been linked with gut dysbiosis, hyperactive β-glucuronidase activity, and high systemic estrogen levels. While the role of GUS genes on estrogen levels have been highlighted, GUS genes can modulate levels of other sex hormones. Sullivan et al. determined that levels of specific GUS-producing taxa correlated with serum testosterone and/or androstenedione concentrations in male mice, including positive correlations for Eubacterium coprostanoligenes, Lactobacillus, and a negative correlation for Bacteroides thetaiotaomicron. Furthermore, they reported a significant decrease in GUS activity for DSS-treated male mice and lowered GUS activity for DSS-treated female mice. Therefore, DSS-induced gut inflammation can decrease GUS-producing taxa, leading to decreased GUS activity (Sullivan et al., 2024). Another factor regulating host testosterone metabolism is a microbiome that contains genes encoding hydroxysteroid dehydrogenases (HSDs). HSDs convert steroid hydroxyl groups to keto groups; they are expressed by the host as well as the microbiota (Collden et al., 2019). Furthermore, specific bacteria have been shown to metabolize host sex hormones; Prevotella intermedius absorb estradiol and progesterone for growth. And, Clostridium scindens produce androgens from glucocorticoids (Hu et al., 2023). As mentioned by Collden et al., the gut microbiome is considered an endocrine organ. The capacity of the gut microbiome to produce and metabolize sex hormones requires further investigation, particularly the varying composition of the microbiome and subsequent impacts on sex hormone levels.

The bi-directional relationship between sex hormones and the gut microbiota was highlighted by Sullivan et al., particularly how it develops during puberty. As shown in their pediatric IBD model, gut inflammation and gut dysbiosis can impact the sex hormones, specifically for male mice in their study. IBD has also been linked to anxiety and depression (Bisgaard et al., 2022), a further demonstration of the gut-brain connection. Sullivan et al. also discuss that hormone supplementation has been suggested for IBD symptoms, however, given the side effects, interventions at the level of the gut microbiome are likely more desirable. Given the health conditions that include gut dysbiosis, GI dysfunctions, hormonal effects, and/or neurological effects (i.e. inflammatory bowel disease, polycystic ovarian syndrome, autism spectrum disorder), more research in the area of the microbiome-endocrine-brain axis is needed. The gut microbiome is an important point for intervention among many disorders.