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Review
. 2023 Jan 4;165(2):R61-R74.
doi: 10.1530/REP-22-0303. Print 2023 Feb 1.

Sex, puberty, and the gut microbiome

Laura Sisk-Hackworth  1 , Scott T Kelley  1 , Varykina G Thackray  2
Affiliations
Review

Sex, puberty, and the gut microbiome

Laura Sisk-Hackworth et al. Reproduction. .

Abstract

In brief: Sex differences in the gut microbiome may impact multiple aspects of human health and disease. In this study, we review the evidence for microbial sex differences in puberty and adulthood and discuss potential mechanisms driving differentiation of the sex-specific gut microbiome.

Abstract: In humans, the gut microbiome is strongly implicated in numerous sex-specific physiological processes and diseases. Given this, it is important to understand how sex differentiation of the gut microbiome occurs and how these differences contribute to host health and disease. While it is commonly believed that the gut microbiome stabilizes after 3 years of age, our review of the literature found considerable evidence that the gut microbiome continues to mature during and after puberty in a sex-dependent manner. We also review the intriguing, though sparse, literature on potential mechanisms by which host sex may influence the gut microbiome, and vice versa, via sex steroids, bile acids, and the immune system. We conclude that the evidence for the existence of a sex-specific gut microbiome is strong but that there is a dearth of research on how host-microbe interactions lead to this differentiation. Finally, we discuss the types of future studies needed to understand the processes driving the maturation of sex-specific microbial communities and the interplay between gut microbiota, host sex, and human health.

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Conflict of interest statement

Disclosure Summary: The authors have nothing to disclose.

Figures

Figure 1.
Figure 1.
Sex differences in the human gut microbiome arise during puberty. Studies providing evidence of sex differences are categorized by developmental stage, type of data analysis (eg. 16S rRNA gene sequencing, metagenomics, or untargeted metabolomics) and observed effect on the gut microbiome. Created with BioRender.com.
Figure 2.
Figure 2.
Activation of the hypothalamic–pituitary–gonadal axis during puberty. 1) Gonadotropin-releasing hormone (GnRH) production is stimulated by kisspeptin secreted from neurons in the hypothalamus. 2) GnRH induces pituitary gonadotrope cells to produce and secrete the gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). 3) In males, LH signaling in testicular Leydig cells results in testosterone production, while in females LH stimulates testosterone production in ovarian theca cells, which is then converted to estrogen in granulosa cells by aromatase. 4A) Testosterone exerts negative feedback in the hypothalamus and pituitary, while 4B) estrogen exerts both negative and positive feedback. 5) Sex steroids may directly or indirectly modulate the gut microbiome to be sexually dimorphic. Created with BioRender.com.
Figure 3.
Figure 3.
Enterohepatic circulation of sex steroids and bile acids. 1) Sex steroids (S) are conjugated with glucuronide from uridine 5’-diphosphoglucuronic acid (UDP-GlcA) by liver enzymes. Bile acids (BAs) are synthesized and conjugated with glycine (Gly) or taurine (Tau) in the liver. 2) Sex steroid glucuronides (S-glucuronide) and primary bile acids are transported to the gallbladder and excreted into the small intestine via the bile duct. 3) Gut bacteria deconjugate S-glucuronide and transform BAs into secondary BAs or other BA metabolites. 4) S-glucuronides that are not deconjugated are excreted through the feces. 5) Secondary BAs, other BAs metabolites, and deconjugated sex steroids are primarily reabsorbed through the hepatic portal vein to the liver. Alternatively, they are excreted through feces or returned to circulation, to be reabsorbed by the liver or excreted through urine. Created with BioRender.com.
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