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

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 <i>in vivo</i> using eight-week-old female C57BL/6 mice subjected to bilateral ovariectomy (OVX), with treatments initiated one week postsurgery, and performed complementary <i>in vitro</i> 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 <i>Clostridium sporogenes</i> 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 <i>C. sporogenes</i>-IPA strategy with therapeutic potential in PMOP.