Journal of Clinical Sexology - Vol. 2, No. 2: April-June 2019 73 Original article SEX STEROID HORMONES AND GUT MICROBIOME *Assoc. Prof. Dr. Manole Cojocaru Titu Maiorescu University of Bucharest, Faculty of Medicine Abstract: Commensal bacteria and their genes associated with host are known as microbiome. Bac- terial influence on endocrine system is difficult to understand and investigate, however new metabolomics and bioinformatics research provide information about bidirectional cross talk between host hormones and microbiome. The gut microbiota in particular plays impor- tant roles in host metabolism, immunity and even behavior. Bacteria are capable of metabo- lizing sex steroid hormones through the activity of distinct enzymes such as hydroxysteroid dehydrogenase that regulate the balance between active and inactive steroids. However, only recently has a critical mechanism of bacterial interaction been revealed: modulation of hor- monal secretion. Surprisingly, commensal bacteria can produce and secrete hormones. The gut microbiome has been shown to be influenced by estrogen, however, the gut microbiome also significantly impacts estrogen levels. This review summarizes current knowledge of the complex interplay between sex steroid hormone, and the gut microbiome. Keywords: gut microbiota, sex differences, sex steroid hormone, testosterone, estradiol *Correspondence: Assoc. Prof. Dr. Manole Cojocaru, Bucharest, Romania; e-mail : [email protected] 74 Journal of Clinical Sexology - Vol. 2, No. 2: April-June 2019 The human gut microbiome is a complex how the gut microbiota can influence hormo- microbial ecosystem that plays an important ne levels. Sex differences in the gut microbi- role in our health. The age and sex of an in- ota have been reported in humans as well (5). dividual strongly influences the bacterial Microbial composition or activity of the diversity of the gut microbiome. Based on gut can be modified by a variety of factors, available evidence, it is, however, pertinent including internal factors such as hormonal to ask if sex steroids participate in the re- changes, or external factors such as diet, an- gulation of the composition or function of tibiotics and stress (6,7). gut microbiota, or if gut microbes regulate sex steroid balance. While gonadal stero- Steroid hormones can affect the gut mi- ids can alter the gut microbiota, it appears crobiota. Sex differences have been noted in that, in turn, the gut microbiome can influ- the composition of the gut microbiota. For ence hormone levels. Gut microbiota plays example, men have higher levels of Bacte- roles in host physiology including endocrine roidetes and Prevotella than women (8-10). function. Greater microbial diversity in the The gut microbiome can influence hormo- female gut may be associated with sex hor- ne levels. Other studies suggest that steroids mones. That is why in recent years the con- influence the gut microbial communities. For ception of humanmicrobiome superorganism example, the gut microbiota undergoes pro- was proposed (1). Although the field of mi- found changes during pregnancy in women. crobiome research is new and developing, Koren et al found a large shift in the gut mi- a significant number of studies already link crobiota from the first to third trimester, with hormones and the gut microbiota. Pathoge- an increase in overall diversity and a prolife- nic bacteria also have an influence over host ration of Proteobacteria and Actinobacteria, sex hormone metabolism. Dysbiosis of the resulting in changes in metabolism (11,12). gut microbiota may also play a role in the In postmenopausal women, gut microbi- development of diseases manifested by hor- ota diversity was positively associated with monal imbalance, such as polycystic ovary the ratio of oestrogen metabolites in urine syndrome, through their modulation of hor- (13,14). mone levels (2,3). These studies highlight the reciprocal According to this theory, poor diet leads connections between sex hormones and gut to changes in gut bacterial communities, microbiota. Taken together, these studies pro- creating an increase in gut mucosal perme- vide strong evidence that the gut microbiota ability, resulting in activation of the immune is influenced by gonadal steroid hormones system. This, in turn, raises serum insulin and steroid levels can be altered by the gut levels, increases androgen production in the microbiome (15) ovaries and interferes with normal follicle development (4). Diet has profound effects on the structure The gut microbiome has a profound im- and activity of gut microorganisms (16,17). pact on human health and disease. Steroids For example, a diet rich in fats promotes can influence the gut microbiota and, in turn, the growth of the proinflammatory Gram-ne- Journal of Clinical Sexology - Vol. 2, No. 2: April-June 2019 75 gative microorganisms, which in turn can al- as they are both derivatives of cholesterol ter immune homeostasis (18) which contains cyclic steroid nucleus. They can both be recycled through enterohepatic Understanding the role of the gut micro- circulation-a process, in part, regulated by biome in human health presents a number of the gut microbiome. Therefore, the action of challenges. Human gut microbiota contribu- gut microbes on these steroids is critical in tes to changes in composition of circulating determining whether they are excreted or re- hormones and, on the other hand, hormones cycled. Various microbial modifications also can influence gut microbiome (19). alter the cytotoxicity and/or potency of the- The gut microbiome is critical for ma- se steroids. The term “sterolbiome” has been intaining a normal estrous cycle, testost- recently proposed to describe the genetic erone levels, and reproductive function. potential of the gut microbiome to produce Gut microbes modulate the enterohepatic endocrine molecules from endogenous and recirculation of estrogens and androgens, exogenous steroids. Furthermore, the gut mi- affecting local and systemic levels of sex ste- crobiome also modulates glucocorticoids and roid hormones. Gut bacteria can also gene- androgens through reductive and oxidative rate androgens from glucocorticoids. Similar reactions. The ability of gut microbes to to bile acids, endogenous sex steroid hormo- convert steroids anaerobically through side- nes such as androgens, estrogens, and pro- chain cleavage has been known for decades, gestogens, are derived from cholesterol. but the pathways involved have only been Gut microbial metabolism affects systemic recently identified. The gut microbiome is hi- levels, potency, and the half-life of estrogen ghly sensitive to environmental perturbation; metabolites (20). therefore, variations in diet, hormonal status, exercise (duration and intensity), and stress Humans harbor over 100 trillion micro- levels should be considered when designing bes, with the gastrointestinal tract being the microbiome studies in humans. Further, it has most densely populated body habitat. Gut mi- been shown that gut microbiota differences crobial communities include members of the are mediated by sex hormones and the influ- Bacteria, Archaea, and Eukarya (fungi, pro- ences of gonadectomy on bile acid profiles tozoa) domains, as well as viruses. Sex ste- significantly differ between sexes (24). roid hormones also modulate gastrointestinal health (21,22). In addition to bacterial pathogens, bacte- ria from human microbiota play an important In females, GI permeability fluctuates role in the metabolism of sex hormones. The throughout the estrous cycle, and ovariec- estrobolome is defined as the gene reperto- tomy-induced estrogen deficiency leads to ire of the microbiota of the gut that are ca- compromised barrier function (23). pable of metabolizing estrogens. Dysbiosis This evidence supports that, besides the and a reduction of gut microbiota diversity role in reproductive functions, sex steroid impacts the estrobolome. A reduction in gut hormones play important roles in gastro- microbiota diversity leads to a decrease in the intestinal homeostasis. Sex steroid hormo- estrogen metabolism through a lack of estro- nes and bile acids share structural similarity gen metabolizing bacteria. A lack of estrogen 76 Journal of Clinical Sexology - Vol. 2, No. 2: April-June 2019 metabolizing bacteria leads to a decrease in with direct evidence of testosterone synthesis circulating estrogens which may influence from bacteria that inhabit the gut alludes to hypoestrogen-related disease ( 25,26). Fig. 1, the existence of the “testobolome” (26) Fig 2 Gut epithelial barrier integrity can also be Testosterone has been shown to be pro- modified by estrogen (27). duced in the gut by Clostridium scindens. Remarkably, administration of antibiotics Evidence of an increase in testosterone le- leads to a 60-fold increase in the fecal excre- vels due to gut microbiome transfer coupled tion of conjugated estrogens in pregnant wo- Fig. 1 Estrogen-gut microbiome interactions exhibit physiological and clinical implications (25) Journal of Clinical Sexology - Vol. 2, No. 2: April-June 2019 77 Fig. 2 The estrobolome and enterohepatic circulation of estrogens (26). men, highlighting the central role of the gut bes remained unexplored. The current study microbiome in modulating the reabsorption investigates the relationship between gut of estrogens (28,29). microbes and serum levels of testosterone in men and estradiol in women. These results Several studies have assessed compositio- demonstrate that sex steroid hormone