The Biosocial Microbiome: Gender Identity, Geography, and Mucosal Microbial Phenotypes

Transgender women (TGW) experience unique hormonal contexts and high HIV incidence, yet the mucosal microbiome among TGW remains understudied. Sex hormones and geography may shape microbial composition, but the relative contributions of gender identity, feminizing hormone therapy (FHT), and location to mucosal microbial phenotypes among key populations such as TGW are unknown.

We conducted a multi-site study of cisgender men who have sex with men (MSM) and TGW using FHT, both without HIV, in Atlanta, Georgia, USA (n = 58; 25 TGW, 33 MSM) and Bangkok, Thailand (n = 147; 97 TGW, 50 MSM), using cross-sectional sampling (n = 205). We also conducted longitudinal sampling in TGW (n = 21) pre/post FHT initiation. Rectal mucosal swabs were collected from all participants with optional neovaginal sampling in TGW. Microbiota composition was analyzed using 16S rRNA sequencing, and associations with gender identity, geography, and serum estradiol and testosterone concentrations were assessed using linear decomposition modeling (LDM)(1) and BOUTH analysis(2).

Rectal microbiota differed significantly by both gender identity and geography via LDM and BOUTH analyses. TGW exhibited enrichment of estrogen-metabolizing taxa across sites, while MSM showed Prevotellaceae enrichment in Atlanta but not Bangkok. Alpha diversity varied by location but not gender identity. Neovaginal microbiota differed markedly from rectal composition, showing enrichment of skin- and gut-associated taxa (e.g., Prevotella, Peptostreptococcus, Porphyromonas) and anaerobic taxa associated with HIV seroconversion. Longitudinal analysis revealed no significant rectal microbiota shifts after short-term FHT initiation, possibly reflecting subtherapeutic hormone exposure.

These findings underscore the need to consider gender identity as a complex biosocial phenotype in HIV prevention and highlight the potential role of mucosal microbiota in shaping HIV vulnerability in TGW.