Division of Endocrinology, Metabolism and Lipids, Department of Medicine and.
Emory Microbiome Research Center, Emory University, Atlanta, Georgia, USA.
J Clin Invest. 2024 Mar 26;134(10):e175410. doi: 10.1172/JCI175410.
Gender-affirming hormone therapy (GAHT) is often prescribed to transgender (TG) adolescents to alleviate gender dysphoria, but the effect of GAHT on the growing skeleton is unclear. We found GAHT to improve trabecular bone structure via increased bone formation in young male mice and not to affect trabecular structure in female mice. GAHT modified gut microbiome composition in both male and female mice. However, fecal microbiota transfers (FMTs) revealed that GAHT-shaped gut microbiome was a communicable regulator of bone structure and turnover in male, but not in female mice. Mediation analysis identified 2 species of Bacteroides as significant contributors to the skeletal effects of GAHT in male mice, with Bacteroides supplementation phenocopying the effects of GAHT on bone. Bacteroides have the capacity to expand Treg populations in the gut. Accordingly, GAHT expanded intestinal Tregs and stimulated their migration to the bone marrow (BM) in male but not in female mice. Attesting to the functional relevance of Tregs, pharmacological blockade of Treg expansion prevented GAHT-induced bone anabolism. In summary, in male mice GAHT stimulated bone formation and improved trabecular structure by promoting Treg expansion via a microbiome-mediated effect, while in female mice, GAHT neither improved nor impaired trabecular structure.
性别肯定激素治疗（GAHT）通常被开给跨性别（TG）青少年，以减轻性别焦虑，但 GAHT 对不断生长的骨骼的影响尚不清楚。我们发现 GAHT 通过增加年轻雄性小鼠的骨形成来改善小梁骨结构，而对雌性小鼠的小梁结构没有影响。GAHT 改变了雌雄小鼠的肠道微生物组组成。然而，粪便微生物群转移（FMT）显示，GAHT 塑造的肠道微生物组是雄性而非雌性小鼠骨骼结构和周转率的可传播调节剂。中介分析确定了 2 种拟杆菌是雄性小鼠 GAHT 对骨骼影响的重要贡献者，拟杆菌的补充可模拟 GAHT 对骨骼的作用。拟杆菌具有在肠道中扩大 Treg 群体的能力。因此，GAHT 扩增了雄性而非雌性小鼠的肠道 Treg，并刺激它们向骨髓（BM）迁移。证明 Treg 的功能相关性，药物抑制 Treg 扩增可防止 GAHT 引起的骨合成代谢。总之，在雄性小鼠中，GAHT 通过微生物组介导的作用促进 Treg 扩增来刺激骨形成和改善小梁结构，而在雌性小鼠中，GAHT 既没有改善也没有损害小梁结构。
