Gender Affirming Hormonal Therapy Induces a Gender-Concordant Gut Metagenome Transition in Transgender Individuals

Abstract Background Limited data exists regarding gender-specific microbial alterations during gender-affirming hormonal therapy (GAHT) in transgender individuals. This study aimed to investigate the nuanced impact of sex steroids on gut microbiota taxonomy and function, addressing this gap. We prospectively analyzed gut metagenome changes associated with twelve weeks of GAHT in trans women and trans men, examining both taxonomic and functional shifts. Methods Thirty-six transgender individuals (17 trans women, 19 trans men) provided pre- and post-GAHT stool samples. Shotgun metagenomic sequencing was used to assess the gut microbiota response. Results While alpha and beta diversity remained unchanged during transition, specific species, including Parabacteroides goldsteinii and Escherichia coli, exhibited significant abundance shifts aligned with affirmed gender. Overall functional metagenome analysis showed a statistically significant effect of gender and transition (R2 = 4.1%, P = 0.0115), emphasizing transitions aligned with affirmed gender, particularly in fatty acid-related metabolism. Conclusions This study provides compelling evidence of distinct taxonomic and functional profiles in the gut microbiome between trans men and women. GAHT induces androgenization in trans men and feminization in trans women, potentially impacting physiological and health-related outcomes. Trial registration clinicaltrials.gov NCT02185274