Background: Limited data exists on gender-specific microbial alterations during gender-affirming hormonal therapy (GAHT) in transgender individuals. This study aimed to fill this gap by investigating the nuanced impact of sex steroids on gut microbiota taxonomy and function. We prospectively analyzed gut metagenome changes associated with twelve weeks of GAHT in trans women and trans men.

Methods: Thirty-six transgender individuals (17 trans women, 19 trans men) provided pre- and post-GAHT stool samples. Shotgun metagenomic sequencing assessed changes in gut microbiota structure and function post-GAHT.

Results: Alpha and beta diversity remained stable during transition. However, specific species such as Parabacteroides goldsteinii and Escherichia coli showed significant abundance shifts aligned with affirmed gender. Functional metagenome analysis revealed a significant gender and transition effect (R2=4.1%, P=0.0115), particularly in fatty acid-related metabolism.

Conclusions: This study underscores distinct taxonomic and functional profiles in gut microbiota between trans men and women. GAHT induces androgenization in trans men and feminization in trans women, potentially impacting health outcomes.

Trial registration: ClinicalTrials.gov NCT02185274