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
{"title":"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。","authors":"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","doi":"10.1016/j.ebiom.2025.105978","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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<sup>-4</sup>), 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<sup>-149</sup>) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10<sup>-6</sup>; P. distasonis P = 5 × 10<sup>-5</sup>). 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).</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>See Acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105978"},"PeriodicalIF":10.8000,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The circulating dihydrotestosterone/testosterone ratio is increased by gut microbial 5α-reductase activity in females.\",\"authors\":\"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\",\"doi\":\"10.1016/j.ebiom.2025.105978\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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<sup>-4</sup>), 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<sup>-149</sup>) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10<sup>-6</sup>; P. distasonis P = 5 × 10<sup>-5</sup>). 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).</p><p><strong>Interpretation: </strong>These findings demonstrate that the circulating DHT/T ratio is increased by GM 5α-reductase activity in females. 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The circulating dihydrotestosterone/testosterone ratio is increased by gut microbial 5α-reductase activity in females.
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.
EBioMedicineBiochemistry, 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.
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