The gut microbiota is a major regulator of androgen metabolism in intestinal contents.

Hannah Colldén,Klara Sjögren,Henrik Ryberg,Matti Poutanen,Claes Ohlsson,Lars Fändriks,Liesbeth Vandenput,Andreas Landin,Erik Elebring,Maria E Nilsson,Ville Wallenius

doi:10.1152/ajpendo.00338.2019

Abstract

Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.

Highlights

Testis-derived testosterone (T) is the most abundant androgen in the systemic circulation in males, whereas the ovaries are the most important source of androgens in females of reproductive age
DHEA is not produced in mice, the mouse adrenal gland may still contribute to androgen synthesis via production of the androgen precursor androstenedione (Adione) [12, 28, 34], which can be converted to T by 17␤hydroxysteroid dehydrogenases (Fig. 1) [8]
The findings described above in mice with a normal gut microbiota (GM) composition suggested that the microbiota present in the distal intestine is responsible for the near-complete deconjugation of DHT and T, causing a substantial difference in glucuronidated and free androgen levels between the small intestine and the cecum

Summary

INTRODUCTION

The adrenal-derived androgen precursor dehydroepiandrosterone (DHEA) contributes to androgen synthesis [9]. In certain male reproductive tissues, such as prostate and seminal vesicles, T is converted into the more potent androgen dihydrotestosterone (DHT) by 5␣-reductase type 2 enzyme (SRD5a2), whereas in the liver mainly 5␣-reductase type 1 enzyme (SRD5a1) converts T into DHT [29] Another homologous enzyme, SRD5a3, has been identified [47], but whether it has the capacity to convert T to DHT is still unclear [13, 14]. The physiological relevance of the GM in androgen metabolism and in levels of glucuronidated and free androgens in different regions in the intestine is mostly unknown. We observed major GM-dependent differences in levels of glucuronidated and free androgens in the intestinal contents from the small intestine and the more distal regions of the intestine. These findings identify the GM as a major regulator of local androgen action in the intestine as well as in other peripheral tissues

MATERIALS AND METHODS

RESULTS

DISCUSSION

DISCLOSURES