Biosocial influences of gender identity and geography on 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 are unclear.

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

Here we show that the rectal microbiota differ significantly by both gender category and geography. TGW exhibit enrichment of estrogen-metabolizing taxa across sites, while MSM show Prevotellaceae enrichment in Atlanta only. Alpha diversity varies by location but not gender category. Neovaginal microbiota differ markedly from rectal composition, showing enrichment of skin- and gut-associated taxa and anaerobic taxa associated with HIV seroconversion. No significant rectal microbiota shifts are observed 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.