Engineered probiotic-derived indole-3-propionic acid inhibits ubiquitination via AHR signaling to treat postmenopausal osteoporosis

作者：Xueli Qiu, Lijun Wu, Fengxian Jiang, Huajian Shan, Lei Sheng, Bo Tian, Heng Wang, Hao Cui, Lide Tao, Chenyang Wu, Yuqian Yao, Chao Wang, Xiaozhong Zhou, Y.‐W. ZHANG, Jinyu Bai · 发表于：Gut Microbes · 年份：2026 · DOI：10.1080/19490976.2025.2612620 · 被引用次数：7 · 研究领域：Gut microbiota and health、Bone Metabolism and Diseases、Probiotics and Fermented Foods

Postmenopausal osteoporosis (PMOP) has a high incidence in middle-aged and elderly women, leading to an increased risk of fractures and elevated rates of disability and mortality. In this work, we identified the reduction of indole-3-propionic acid (IPA) as a potential key factor contributing to the decline in bone mass observed in postmenopausal women. Mechanistically, IPA activates AhR, leading to the stabilization of key proteins in Wnt and NF-κB pathways that regulate bone formation and resorption. We evaluated efficacy in vivo using eight-week-old female C57BL/6 mice subjected to bilateral ovariectomy (OVX), with treatments initiated one week postsurgery, and performed complementary in vitro assays. Intraperitoneal IPA (20 mg/kg, 3× per week for 8 weeks) increased the trabecular bone mineral density (Tb.BMD) by ~68% versus OVX controls, whereas engineered Clostridium sporogenes that enhances IPA biosynthesis led to an even greater increase of ~118%. Together, these findings highlight the gut–bone axis as a central framework linking microbiota-derived IPA to skeletal remodeling and provide preclinical proof-of-concept for an engineered C. sporogenes–IPA strategy with therapeutic potential in PMOP.