Key points
- The gut and microbiome play an important role in the metabolism and regulation of sex hormones
- This function is particularly important for regulation of oestrogen and reducing oestrogen-related pathologies
- Oestrogen is likely to modify and improve the microbiome and gut-brain axis
- Endotoxic damage resulting from dysbiosis might also reduce testosterone levels in males
The gut and microbiome play a role in the metabolism and clearance of various hormones such as oestrogen, and the microbiome, gut and their relationship to overall health can also affect the production of sex hormones.1, 2 It is also known that oestrogen itself has an interrelationship with the gut-brain axis.1
One of the most prominent roles of the human microbiome is the regulation of steroid hormone metabolism (especially the metabolism of oestrogen, by the microbial ‘oestrabolome’3) which is of particular importance to health as oestrogens are one of the most important risk factors in the development of breast cancer.4
There are likely to be significant sex differences in the microbiome. For example, women have a higher incidence of gastrointestinal disorders. In a study to investigate this, a high-fat and high-sugar diet (to mimic the standard modern dietary pattern) was given to rats (10 weeks) who had their ovaries removed to eliminate oestrogen production, with half provided oestrogen treatment to simulate the presence or absence of oestrogen. This resulted in dramatic differences in the microbiomes of the animals with a general increase in the population of the Firmicutes (with high-fat high-sugar diet), predominantly driven by an increase in the abundance of one specific species, Lactobacillus johnsonii, only in the presence of oestrogen.5
The gut biome and oestrogen
The microbiome is critical to the gut metabolism and clearance of oestrogen from the body, a function that is known as the ‘oestrabolome’.3 It has been demonstrated that women with a more diverse gut microbiome exhibit an elevated urinary ratio of hydroxylated oestrogen metabolites to parent estrogen.6
The key functions of the gut and microbiota in respect to oestrogen are:
- The gut microbiome is a principal regulator of circulating oestrogens
- Disruptions to the gut microbiome lead to decreased circulating oestrogens
- Dysbiosis can lead to oestrogen related pathology and is implicated in oestrogen-driven cancers
- Interventions that improve the gut microbiome could impact oestrogen-mediated disease7
In a study on women with breast cancer, it was found that those with pre-treatment breast cancer had non-significantly elevated oestrogen levels. When adjusted for oestrogens and other variables, cases (those with cancer) had significantly reduced alpha diversity and altered composition of both their faecal microbiota.8
The microbiome is critical to the gut metabolism and clearance of oestrogen from the body
Animal research has further implicated oestrogen regulation by the microbiome in both males and females. Microbiome profiles in 17β-oestradiol-treated male and ovariectomized mice (resulting in decreased Proteobacteria and lipopolysaccharide biosynthesis) were associated with lower susceptibility to chronic fatigue and multiple sclerosis. Oestrogenic compounds (like isoflavones found in soy) exerted microbiome-modulating effects similar to those of 17β-oestradiol and reversed symptoms of multiple sclerosis male mice.9 Animal research also suggests a role for oestrogen in inhibiting menopausal symptoms and preserving microbial diversity,10 similarly research also suggests that pre- and probiotic supplementation (B glucans and Lactobacillus fermentum) improve the gut microbiota and reduce menopausal symptoms in oestrogen deficient rats.11
Women also have a higher prevalence of most autoimmune diseases. In vitro research has suggested a role for oestrogen in the regulation of intestinal permeability (leaky gut) implicated in autoimmune conditions. Tight junction protein zonula occludens 1 (a key regulator of intestinal permeability) was decreased in female gut tissue and was directly related to oestrogen.12
In a model of colitis (inflammation of the colon) and colorectal cancer, it was found that the removal of intestinal oestrogen receptors (ERβ/ESR2) resulted in increased inflammation and cancer and reduced microbiome diversity and the Bacteroidetes genus Prevotellaceae_ UCG_001 was overrepresented in the induced inflammation/cancer animals.13
The gut biome and testosterone
Overweight and obesity are associated both with poorer gut health and resultant endotoxin damage. In a study looking at the effects of these factors on testosterone, Adiposity (relative ‘fatness’) was associated with increased endotoxin load and inflammation (C-reactive protein and IL-6) and with reduced testosterone. In a follow-up intervention, low-dose endotoxins were given, and this induced a transient inflammatory response, followed by a decline in serum testosterone (without changes in luteinising or follicle-stimulating hormones). These findings suggest that endotoxin driven inflammation might damage the Leydig cells of the testes, impairing testosterone production.2 Animal research had previously demonstrated reduced testosterone production (and increased risk of obesity) resulting from the antibiotics doxycycline and ciprofloxacin,14, 15 an effect that was mitigated by probiotics.14
Overweight and obesity are associated both with poorer gut health and resultant endotoxin damage
References
1. Jiang Y, Meerveld BG-V, Johnson AC, Travagli RA. Role of estrogen and stress on the brain-gut axis. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2019;317(2):G203-G9.
2. Tremellen K, McPhee N, Pearce K, Benson S, Schedlowski M, Engler H. Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age. American journal of physiology Endocrinology and metabolism. 2018;314(3):E206-E13.
3. Kwa M, Plottel CS, Blaser MJ, Adams S. The Intestinal Microbiome and Estrogen Receptor–Positive Female Breast Cancer. JNCI: Journal of the National Cancer Institute. 2016;108(8).
4. Parida S, Sharma D. The Microbiome–Estrogen Connection and Breast Cancer Risk. Cells. 2019;8(12):1642.
5. Ozark PA, Blythe SN, Toporikova N, Whitworth GB. Effects of Diet-induced Obesity and Estrogen on the Female Rat Fecal Microbiome. The FASEB Journal. 2017;31(1_supplement):138.2-.2.
6. Fuhrman BJ, Feigelson HS, Flores R, Gail MH, Xu X, Ravel J, et al. Associations of the Fecal Microbiome With Urinary Estrogens and Estrogen Metabolites in Postmenopausal Women. The Journal of Clinical Endocrinology & Metabolism. 2014;99(12):4632-40.
7. Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen–gut microbiome axis: physiological and clinical implications. Maturitas. 2017;103:45-53.
8. Goedert JJ, Hua X, Bielecka A, Okayasu I, Milne GL, Jones GS, et al. Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota. British Journal of Cancer. 2018;118(4):471-9.
9. Kaliannan K, Robertson RC, Murphy K, Stanton C, Kang C, Wang B, et al. Estrogen-mediated gut microbiome alterations influence sexual dimorphism in metabolic syndrome in mice. Microbiome. 2018;6(1):205.
10. Park S, Kim DS, Kang ES, Kim DB, Kang S. Low-dose brain estrogen prevents menopausal syndrome while maintaining the diversity of the gut microbiomes in estrogen-deficient rats. American Journal of Physiology-Endocrinology and Metabolism. 2018;315(1):E99-E109.
11. Jeong S-Y, Kang S, Hua CS, Ting Z, Park S. Synbiotic effects of β-glucans from cauliflower mushroom and Lactobacillus fermentum on metabolic changes and gut microbiome in estrogen-deficient rats. Genes & nutrition. 2017;12(1):31.
12. Zhou Z, Zhang L, Ding M, Luo Z, Yuan S, Bansal MB, et al. Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues. Clinical Immunology. 2017;183:174-80.
13. Ibrahim A, Hugerth LW, Hases L, Saxena A, Seifert M, Thomas Q, et al. Colitis-induced colorectal cancer and intestinal epithelial estrogen receptor beta impact gut microbiota diversity. International Journal of Cancer. 2019;144(12):3086-98.
14. Xie C, Bian Y, Feng H, Zhao Y, Wang L, Li Y, et al. Reversal of ciprofloxacin-induced testosterone reduction by probiotic microbes in mouse testes. General and Comparative Endocrinology. 2019;284:113268.
15. Hou X, Zhu L, Zhang X, Zhang L, Bao H, Tang M, et al. Testosterone disruptor effect and gut microbiome perturbation in mice: Early life exposure to doxycycline. Chemosphere. 2019;222:722-31.
