madman
Super Moderator
Abstract
The gut microbiota is a complex system, consisting of a dynamic population of microorganisms, involved in the regulation of the host’s homeostasis. A vast number of factors are driving the gut microbiota composition including diet, antibiotics, environment, and lifestyle. However, in the past decade, a growing number of studies also focused on the role of sex in a relationship to changes in the gut microbiota composition in animal experiments as well as in human beings. Despite the progress in investigation techniques, still little is known about the mechanism behind the observed sex-related differences. In this review, we summarized current knowledge on the sex-dependent differences of the intestinal commensals and discuss the probable direct impact of sex hormones and more indirect effects such as dietary habits or antibiotics. While we have to conclude limited data on specific developmental stages, a clear role for sex hormones and most probably for testosterone emerges.
The “gut microbiota” is a term referring to the assembly of bacteria, archaea, viruses, and fungi that reside in the gastrointestinal (GI) tract of the host and to which a mutual, mostly beneficial relationship is formed (Bäckhed et al., 2005; Neish, 2009; Qin et al., 2010; Thursby and Juge, 2017). It is involved in several physiological functions, including preservation of the homeostasis of the host, regulation of immunity and metabolism, and protection against pathogens (Baümler and Sperandio, 2016; Gensollen et al., 2016). However, dysbiosis, a detrimental alteration of the microbial composition, is associated with several diseases affecting the GI tract but also with disorders of other organ systems such as metabolic diseases or allergies (Fukui et al., 2018; Kim et al., 2020; Shanahan, 2013). Along with lifespan, the GI tract is subjected to different stimuli e.g. mother’s health, mode of delivery, diet, antibiotics, and even psychological influences - all affecting the gut microbiota composition (Osadchiy et al., 2019). Besides these factors, studies carried out on human beings and animals discussed the importance of sex as a major contributor to gut microbiota variability (Sinha et al., 2019; Yurkovetskiy et al., 2013). Recently, sex has been considered to be more than a simple statistical variable and several studies were initiated considering sex as an independent research question in regard to the microbiota. Despite this effort, still, little is known about the impact of sex on the gut microbiota of human beings or of experimental animals and even less about the underlying mechanisms. We assumed that specific periods, when sex hormones undergo dynamic changes, might be the driving force for the observed differences between males and females and that the steady-state hormonal levels may play an underlying role in such differences. To prove this, we summarized in this review current knowledge on human and rodent sex-dependent differences of the gut microbiota throughout the life span. We discuss the impact of developmental stages and external factors such as diet, age, and geographic location in relation to sex and especially try to evaluate the role of sex hormones.
2. The gut microbiota composition is affected by the sex of the host during the entire lifespan
2.1 Sex-related differences in gut microbiome observed in human postnatal studies (from birth to 12 months)
2.2 Gut microbiota composition differences in relationship to sex during childhood (from 1 to 12 years)
2.3 Gut microbiota composition differences in relation to sex during adolescence (from 12 to 17 years)
2.4 Gut microbiota composition differences in relationship to sex during adulthood
3. Probable role of sex hormones on gut microbiota composition
3.1 Impact of sex hormones on gut microbiota: animal studies
3.2 Sex hormones are associated to gut microbiota sex-dependent differences in humans
3.3 Interactions of sex with environmental factors affecting the microbiome
5. Conclusions
In the current review, we provide a summary of current knowledge on the impact of sex in relation to the gut microbiota composition in both, human and animal studies. From the very first day of life, the gut microbiota starts to shape in relation to sex, showing differences in composition and alpha-diversity. Boys and girls showed for example significant differences in Actinobacteria, Firmicutes, and Bacteroidetes phyla amount with higher Bacteroidetes/Firmicutes ratio in boys compared to girls. We hypothesized that dynamic changes in sex hormones such as the testosterone peak at an early postnatal stage in boys or within puberty might be the leading cause of observed differences. However, studies carried out in the adult population showed that men and women maintain a different amount of gut microbiota phyla (Firmicutes, Verrucomicrobia, Bacteroidetes, Prevotella, Fusobacteria and Actinobacteria). In line with this, steady-state levels of sex hormones may have an important role in shaping the gut microbiome. It may be too simplistic to conclude that sex hormones are the only players in generating gut microbiota differences between men and women. However, experiments conducted on castrated male mice showed similarity in the gut microbiota composition to that of female mice, suggesting an active role of male sex hormones in structuring the gut microbiota (Org et al., 2016). For humans, also educational aspects concerning sex or sex-dependent habitual differences might play an additional role, which is not abundant in laboratory animal models. This clearly hampers deducing the impact of sex in humans from the outcome of studies conducted exclusively in animal experiments. Moreover, longitudinal studies would be needed to unravel the impact of sex hormones in the long run: higher androgen levels in newborn boys, for example, predicted greater negative affectivity (Alexander and Saenz, 2011). Such personality traits contribute to the general development of sex-linked personality characteristics (Crockenberg et al., 2008) and by this might influence later life periods converging with other parameters such as the social organization (Archie and Tung, 2015), particularly important for shaping the individual's microbiota. Investigations in post-menopausal women are also still limited but they might help to evaluate the role of sex hormones. A metagenome-wide association study revealed a clear difference between pre-and post-menopausal women with, for example, depletion of Firmicutes and Roseburia spp. (Zhao et al., 2019). Moreover, a small study indicated that post-menopausal women tended to be more similar to age-matched men as to pre-menopausal women regarding e.g. Firmicutes to Bacteroidetes ratio (Santos-Marcos et al., 2018). In addition, a recent study by Mayneris-Perxachs and colleagues reported that an androgenization of the microbiome occurs as a result of the menopause of women and that testosterone plays a major role in shaping the microbiota (data from a one-year follow-up study on about 100 human subjects) (Mayneris-Perxachs et al., 2020). More such studies – together with data obtained from pubescents – should enlighten the distinct role of sex hormones as direct or indirect choirmasters of our gut microbiota in the future.
The gut microbiota is a complex system, consisting of a dynamic population of microorganisms, involved in the regulation of the host’s homeostasis. A vast number of factors are driving the gut microbiota composition including diet, antibiotics, environment, and lifestyle. However, in the past decade, a growing number of studies also focused on the role of sex in a relationship to changes in the gut microbiota composition in animal experiments as well as in human beings. Despite the progress in investigation techniques, still little is known about the mechanism behind the observed sex-related differences. In this review, we summarized current knowledge on the sex-dependent differences of the intestinal commensals and discuss the probable direct impact of sex hormones and more indirect effects such as dietary habits or antibiotics. While we have to conclude limited data on specific developmental stages, a clear role for sex hormones and most probably for testosterone emerges.
The “gut microbiota” is a term referring to the assembly of bacteria, archaea, viruses, and fungi that reside in the gastrointestinal (GI) tract of the host and to which a mutual, mostly beneficial relationship is formed (Bäckhed et al., 2005; Neish, 2009; Qin et al., 2010; Thursby and Juge, 2017). It is involved in several physiological functions, including preservation of the homeostasis of the host, regulation of immunity and metabolism, and protection against pathogens (Baümler and Sperandio, 2016; Gensollen et al., 2016). However, dysbiosis, a detrimental alteration of the microbial composition, is associated with several diseases affecting the GI tract but also with disorders of other organ systems such as metabolic diseases or allergies (Fukui et al., 2018; Kim et al., 2020; Shanahan, 2013). Along with lifespan, the GI tract is subjected to different stimuli e.g. mother’s health, mode of delivery, diet, antibiotics, and even psychological influences - all affecting the gut microbiota composition (Osadchiy et al., 2019). Besides these factors, studies carried out on human beings and animals discussed the importance of sex as a major contributor to gut microbiota variability (Sinha et al., 2019; Yurkovetskiy et al., 2013). Recently, sex has been considered to be more than a simple statistical variable and several studies were initiated considering sex as an independent research question in regard to the microbiota. Despite this effort, still, little is known about the impact of sex on the gut microbiota of human beings or of experimental animals and even less about the underlying mechanisms. We assumed that specific periods, when sex hormones undergo dynamic changes, might be the driving force for the observed differences between males and females and that the steady-state hormonal levels may play an underlying role in such differences. To prove this, we summarized in this review current knowledge on human and rodent sex-dependent differences of the gut microbiota throughout the life span. We discuss the impact of developmental stages and external factors such as diet, age, and geographic location in relation to sex and especially try to evaluate the role of sex hormones.
2. The gut microbiota composition is affected by the sex of the host during the entire lifespan
2.1 Sex-related differences in gut microbiome observed in human postnatal studies (from birth to 12 months)
2.2 Gut microbiota composition differences in relationship to sex during childhood (from 1 to 12 years)
2.3 Gut microbiota composition differences in relation to sex during adolescence (from 12 to 17 years)
2.4 Gut microbiota composition differences in relationship to sex during adulthood
3. Probable role of sex hormones on gut microbiota composition
3.1 Impact of sex hormones on gut microbiota: animal studies
3.2 Sex hormones are associated to gut microbiota sex-dependent differences in humans
3.3 Interactions of sex with environmental factors affecting the microbiome
5. Conclusions
In the current review, we provide a summary of current knowledge on the impact of sex in relation to the gut microbiota composition in both, human and animal studies. From the very first day of life, the gut microbiota starts to shape in relation to sex, showing differences in composition and alpha-diversity. Boys and girls showed for example significant differences in Actinobacteria, Firmicutes, and Bacteroidetes phyla amount with higher Bacteroidetes/Firmicutes ratio in boys compared to girls. We hypothesized that dynamic changes in sex hormones such as the testosterone peak at an early postnatal stage in boys or within puberty might be the leading cause of observed differences. However, studies carried out in the adult population showed that men and women maintain a different amount of gut microbiota phyla (Firmicutes, Verrucomicrobia, Bacteroidetes, Prevotella, Fusobacteria and Actinobacteria). In line with this, steady-state levels of sex hormones may have an important role in shaping the gut microbiome. It may be too simplistic to conclude that sex hormones are the only players in generating gut microbiota differences between men and women. However, experiments conducted on castrated male mice showed similarity in the gut microbiota composition to that of female mice, suggesting an active role of male sex hormones in structuring the gut microbiota (Org et al., 2016). For humans, also educational aspects concerning sex or sex-dependent habitual differences might play an additional role, which is not abundant in laboratory animal models. This clearly hampers deducing the impact of sex in humans from the outcome of studies conducted exclusively in animal experiments. Moreover, longitudinal studies would be needed to unravel the impact of sex hormones in the long run: higher androgen levels in newborn boys, for example, predicted greater negative affectivity (Alexander and Saenz, 2011). Such personality traits contribute to the general development of sex-linked personality characteristics (Crockenberg et al., 2008) and by this might influence later life periods converging with other parameters such as the social organization (Archie and Tung, 2015), particularly important for shaping the individual's microbiota. Investigations in post-menopausal women are also still limited but they might help to evaluate the role of sex hormones. A metagenome-wide association study revealed a clear difference between pre-and post-menopausal women with, for example, depletion of Firmicutes and Roseburia spp. (Zhao et al., 2019). Moreover, a small study indicated that post-menopausal women tended to be more similar to age-matched men as to pre-menopausal women regarding e.g. Firmicutes to Bacteroidetes ratio (Santos-Marcos et al., 2018). In addition, a recent study by Mayneris-Perxachs and colleagues reported that an androgenization of the microbiome occurs as a result of the menopause of women and that testosterone plays a major role in shaping the microbiota (data from a one-year follow-up study on about 100 human subjects) (Mayneris-Perxachs et al., 2020). More such studies – together with data obtained from pubescents – should enlighten the distinct role of sex hormones as direct or indirect choirmasters of our gut microbiota in the future.
