The circulating dihydrotestosterone/testosterone ratio is increased by gut microbial 5α-reductase activity in females.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-10-21 DOI:10.1016/j.ebiom.2025.105978

Claes Ohlsson, Lei Li, Karin Horkeby, Lina Lawenius, Hannah Colldén, Klara Sjögren, Gabriel Baldanzi, Gunnar Engström, Johan Ärnlöv, Marju Orho-Melander, Tove Fall, Louise Grahnemo

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引用次数: 0

Abstract

Background: Dihydrotestosterone (DHT), the most potent ligand to the androgen receptor, is synthesised from testosterone (T) by 5α-reductase type 1 and 2. While type 1 is expressed in several non-reproductive tissues in both sexes, men also express high levels of the high-affinity type 2 isoform in reproductive tissues; yet women have a higher circulating DHT to T (DHT/T) ratio than men. We hypothesised that the high DHT/T ratio in women is caused by high gut microbiota (GM) 5α-reductase activity or altered β-glucuronidase-induced androgen reabsorption from the gut.

Methods: We used a large cross-sectional subsample of the Swedish CArdioPulmonary bioImage Study (2897 women and 4338 men, 50-65 years of age) with GM composition and functionality determined by metagenome sequencing and circulating androgens determined by liquid chromatography-tandem mass spectrometry.

Findings: We confirmed that women had higher (+194%) circulating DHT/T ratio than men. The relative abundance of microbial genes for 5α-reductase type 1 (P = 3 × 10^-4), but not β-glucuronidase, was positively associated with the DHT/T ratio in women. In women, the GM relative abundances of Odoribacter splanchnicus and Parabacteroides distasonis were positively associated with the relative abundance of microbial genes for 5α-reductase type 1 (P < 2 × 10^-149) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10^-6; P. distasonis P = 5 × 10^-5). In mechanistic studies, we observed very high DHT/T ratio in intestinal content of female conventionally-raised but not germ-free mice. In female mice, the DHT/T ratio was 86.9% higher in serum from the portal vein than in inferior vena cava (P = 0.007).

Interpretation: These findings demonstrate that the circulating DHT/T ratio is increased by GM 5α-reductase activity in females. We propose that the GM acts as an endocrine organ influencing the androgenic status in females.

Funding: See Acknowledgements.

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雌性肠道微生物5α-还原酶活性增加了循环双氢睾酮/睾酮比率。

背景：双氢睾酮（DHT）是雄激素受体最有效的配体，由睾酮(T)通过5α-还原酶1型和2型合成。虽然1型在两性的一些非生殖组织中表达，但男性在生殖组织中也表达高水平的高亲和力2型异构体；然而女性的循环DHT/T比男性高。我们假设女性的高DHT/T比率是由高肠道微生物群（GM） 5α-还原酶活性或β-葡萄糖醛酸酶改变引起的肠道雄激素重吸收引起的。方法：我们使用瑞典心肺生物图像研究的大断面亚样本（2897名女性和4338名男性，50-65岁），通过宏基因组测序确定GM成分和功能，通过液相色谱-串联质谱测定循环雄激素。结果：我们证实女性的循环DHT/T比男性高（+194%）。5α-还原酶1型微生物基因的相对丰度与女性DHT/T比值呈正相关（P = 3 × 10-4），而β-葡萄糖醛酸酶基因的相对丰度与女性DHT/T比值呈正相关。在女性中，内脏臭杆菌和异裂副杆菌的GM相对丰度与5α-还原酶1型微生物基因的相对丰度（P < 2 × 10-149）和循环DHT/T比值呈正相关（内脏臭杆菌P = 3 × 10-6，异裂副杆菌P = 5 × 10-5）。在机制研究中，我们观察到传统饲养但非无菌的雌性小鼠肠道内容物中DHT/T比率非常高。雌性小鼠门静脉血清DHT/T比下腔静脉高86.9% （P = 0.007）。解释：这些发现表明，在女性中，GM 5α-还原酶活性增加了循环DHT/T比率。我们认为转基因基因作为一种内分泌器官影响女性的雄激素状态。资助：见致谢。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.