Xianling Gubao capsule alleviates osteoporosis: Modulation of gut-bone axis and Wnt signaling

Abstract

BACKGROUND

Osteoporosis is a prevalent metabolic bone disorder that poses significant health burdens. The Xianling Gubao capsule (XLGB), a traditional Chinese medicine, has demonstrated clinical effectiveness in combating osteoporosis; however, its underlying mechanism, particularly concerning the gut-bone axis, remains inadequately understood. We hypothesized that XLGB exerts its anti-osteoporotic effects by modulating the gut-bone axis and associated signaling pathways.

AIM

To investigate the anti-osteoporotic mechanism of XLGB via the gut-bone axis and Wnt/β-catenin signaling.

METHODS

An ovariectomized rat model of postmenopausal osteoporosis was established. The rats received low, medium, or high doses of XLGB for eight weeks. Bone microstructure was assessed using micro-computed tomography, serum bone metabolism markers were quantified by enzyme-linked immunosorbent assay, gut microbiota composition was characterized through 16S rRNA gene sequencing, fecal metabolites profiles were analyzed via non-targeted metabolomics (liquid chromatography-mass spectrometry), and expression levels of key genes and proteins involved in relevant pathways were evaluated by quantitative polymerase chain reaction and western blotting.

RESULTS

The medium dose of XLGB produced the most significant therapeutic effects. The medium dose of XLGB significantly increased bone mineral density, improved trabecular microstructure, and elevated serum osteogenic markers (e.g., osteocalcin, procollagen type I N-terminal propeptide). Additionally, it ameliorated gut microbiota dysbiosis (e.g., normalized the Firmicutes/Bacteroidota ratio), reversed metabolic disturbances, and activated the Wnt/β-catenin pathway (upregulating wingless-type MMTV integration site family, member 3A, β-catenin, and Runt-related transcription factor 2) while suppressing peroxisome proliferator-activated receptor gamma protein expression.

CONCLUSION

XLGB alleviates osteoporosis by modulating the gut-bone axis, correcting metabolic disturbances, and rectifying the osteogenic-adipogenic imbalance through the Wnt/β-catenin and peroxisome proliferator-activated receptor gamma pathways.

Keywords: Osteoporosis; Xianling Gubao capsule; Gut microbiota; Ovariectomized rats; Wnt/β-catenin

Core Tip: This study demonstrates that the Xianling Gubao capsule (XLGB) alleviates osteoporosis by modulating the gut-bone axis. Utilizing a multi-omics approach, we reveal that XLGB not only improves bone microstructure and serum bone markers but also rectifies ovariectomy-induced gut microbiota dysbiosis and metabolic disturbances. More importantly, we identify that its core mechanism involves the activation of the osteogenic Wnt/β-catenin pathway while simultaneously suppressing the adipogenic peroxisome proliferator-activated receptor gamma pathway, thereby rebalancing osteogenic-adipogenic differentiation in the bone marrow. This provides a novel mechanistic basis for XLGB’s anti-osteoporotic effects and underscores the gut-bone axis as a promising therapeutic target.