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ORIGINAL RESEARCH article

Front. Endocrinol.

Sec. Bone Research

Volume 16 - 2025 | doi: 10.3389/fendo.2025.1623933

This article is part of the Research TopicMetabolic and Biomechanical Factors in Bone Fragility: New Frontiers in Understanding and Managing OsteoporosisView all 3 articles

The novel organoselenium compound 4aa ameliorates osteoporosis by modulating gut microbiota composition and fecal metabolite profiles

Provisionally accepted
Chaoming HuChaoming Hu1Yao WuYao Wu2Junhao TuJunhao Tu1Mengjia YiMengjia Yi1Yixin MaoYixin Mao1,3Yang ChenYang Chen1,3Xiaoyu SunXiaoyu Sun2,4*Zengqiang SongZengqiang Song2Shengbin HuangShengbin Huang3*Shufan ZhaoShufan Zhao1,5*Bin LiBin Li1
  • 1Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, wenzhou, China
  • 2school of Pharmaceutical Sciences, Wenzhou Medical University, wenzhou, China
  • 3Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
  • 4Department of Periodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
  • 5Department of Oral Maxillofacial Surgery, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China

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The gut microbiota plays a key role in regulating bone homeostasis. Our previous work demonstrated that the novel organic selenium compound β-trifluoroethoxy dimethyl selenide (4aa alleviates osteoporosis; however, its mechanism remains unclear.The cytotoxicity of 4aa in osteoblast (MC3T3-E1) and osteoclast precursor (RAW264.7) cells was evaluated using CCK-8 assays. Ovariectomized (OVX) and sham-operated mice were treated with various concentrations of 4aa for 8 weeks, including a subgroup pretreated with antibiotics (ABX) to deplete the gut microbiota. Femoral bone structure was assessed by micro-computed tomography (micro-CT), osteoclast numbers were quantified, gut microbial composition was analyzed via 16S rRNA sequencing, and fecal metabolites were profiled using LC-MS/MS.Results: 4aa concentrations below 20 μM were non-cytotoxic to MC3T3-E1 and RAW264.7 cells. In vivo, 4aa significantly improved femoral bone mass and trabecular microarchitecture in OVX mice. Gut microbiota analysis revealed increased relative abundances of Dubosiella, Akkermansia, and Bacillus spp following 4aa administration. Metabolomic profiling identified marked alterations in citronellal, tyrosol, kaempferol, leukotriene D4, clomipramine, and phenol sulfate level. Moreover, 4aa elevated butyric acid levels and reduced the accumulation of α-ketoisovaleric acid (α-KIV), contributing to the inhibition of osteoclast differentiation.4aa prevents estrogen deficiency-induced bone loss by modulating gut microbial composition and function. These findings support the therapeutic of 4aa as a microbiota-targeted therapeutic strategy for osteoporosis management.

Keywords: Osteoporosis, β-trifluoroethoxy dimethyl selenide, Gut Microbiota, gut metabolites, α-KIV

Received: 06 May 2025; Accepted: 17 Jul 2025.

Copyright: © 2025 Hu, Wu, Tu, Yi, Mao, Chen, Sun, Song, Huang, Zhao and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Xiaoyu Sun, school of Pharmaceutical Sciences, Wenzhou Medical University, wenzhou, China
Shengbin Huang, Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Shufan Zhao, Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, wenzhou, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material