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

Ohlsson C, Li L, Horkeby K, Lawenius L, Colldén H, Sjögren K, Baldanzi G, Engström G, Ärnlöv J, Orho-Melander M, Fall T, Grahnemo L

EBioMedicine 121 (-) 105978 [2025-11-00; online 2025-10-21]

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. 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. 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). 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. See Acknowledgements.

Bioinformatics Support for Computational Resources [Service]

PubMed 41124778

DOI 10.1016/j.ebiom.2025.105978

Crossref 10.1016/j.ebiom.2025.105978

pmc: PMC12589954
pii: S2352-3964(25)00422-0