Altered Gut Microbiota and Serum Metabolite Profiles Characterize Postmenopausal Bone Loss: Insights into the Gut–Bone Axis

Zhiming Guan¹Yanpin Liu²Junying Zhao²Longlong Jia²Yanyan Zhao¹Hang Pan¹Lijun Chen^2*

• ¹Shandong Second Medical University, Weifang, China
• ²National Engineering Research Center of Dairy Health for Maternal and Child, Beijing Sanyuan Foods Co., Ltd., Beijing, China

Introduction: Postmenopausal bone loss is a multifactorial condition influenced by hormonal changes, metabolic dysregulation, and gut microbiota alterations. Emerging evidence indicates the potential significance of the gut microbiota–bone link in maintaining bone homeostasis. The present study investigated the composition of the gut microbiota and serum metabolite signatures of postmenopausal women afflicted with bone loss, as well as the interrelationships between these factors, to explore the potential associations of the gut microbiota–bone link. Method: In total, 105 postmenopausal women from Beijing were classified by DXA into a bone loss group (L1–L4 T-score < −1.0; n = 58) and a normal bone mass group (L1–L4 T-score ≥ −1.0; n = 47). Gut microbiota composition was assessed by 16S rRNA sequencing and serum metabolites by UHPLC–MS/MS. Differential abundance and Spearman correlation analyses were performed in relation to BMD/T-scores and serum biochemical indicators.Results: Compared with controls, the bone-loss cohort showed lower BMD and T-scores at L1–L4 and at the femoral neck, and a longer period since menopause. Additionally, the bone-loss cohort exhibited modestly higher, yet still subnormal, circulating 25(OH)D and 25(OH)D3 concentrations, which were inversely associated with L1–L4 T-scores. The bone loss group was characterized by a diminished abundance of protective genera Prevotella and Dorea and increased levels of Limosilactobacillus and Olsenella. Prevotella and Dorea showed positive trends with L1–L4 T-scores but did not reach statistical significance. Metabolomic analysis identified 33 differential metabolites, with higher levels of flavonoids (taxifolin), L-arginine, and spermidine in the normal bone group and reduced lysophosphatidylcholine levels. N-acetylanthranilic acid (NAA) was positively correlated with L1– L4 T-scores and the relative abundances of Prevotella and Dorea. Discussion: Postmenopausal bone loss is associated with gut microbiota alterations and altered serum metabolic profiles. Although circulating 25(OH)D levels were relatively higher (yet still subnormal) in the bone-loss group, this cross-sectional observation should be interpreted as an association rather than evidence of a compensatory mechanism. Our findings indicate that NAA and its associated taxa are correlationally associated with bone-related phenotypes, supporting a testable microbiota–metabolite hypothesis that warrants validation in longitudinal or interventional studies.