2. Academic Validation
  3. Farrerol alleviates microbiota dysbiosis-associated osteoporosis in IBD by inhibiting PI3K-AKT/MAPK signaling pathways

Farrerol alleviates microbiota dysbiosis-associated osteoporosis in IBD by inhibiting PI3K-AKT/MAPK signaling pathways

  • Phytomedicine. 2025 Sep 19:148:157279. doi: 10.1016/j.phymed.2025.157279.
Ninglu Yin 1,  Yuangang Su 1,  Chaofeng Wang 1,  Jiamin Liang 1,  Tongtong Guo 1,  Jinmin Zhao 2,  Zemin Ling 3,  Ren Xu 4,  Qian Liu 5
Affiliations

Affiliations

  • 1 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed By the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi 530021, China; Life Sciences Institute, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi, 530021, China.
  • 2 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed By the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi 530021, China.
  • 3 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed By the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi 530021, China; Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, 628 Zhenyuan Road, Xinhu Subdistrict, Guangming District, Shenzhen 518107, China. Electronic address: lingzm3@mail.sysu.edu.cn.
  • 4 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed By the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi 530021, China; Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China. Electronic address: xuren526@xmu.edu.cn.
  • 5 Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed By the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi 530021, China. Electronic address: liuqian@gxmu.edu.cn.
PMID: 40992062 DOI: 10.1016/j.phymed.2025.157279
Abstract

Background: IBD, a global health concern, elevates osteoporosis risk primarily due to gut dysbiosis and chronic inflammation. While knowledge of the gut-bone axis advances, its exact mechanisms remain unclear, and effective treatments are still lacking.

Methods: In vivo, we assessed FA's effects on femoral bone mass in UC mice and analyzed gut microbiota changes via 16S rRNA Sequencing. Metabolomics measured short-chain fatty acids to evaluate their role in bone loss. We performed RNA Sequencing on femoral BMMs to identify FA-regulated genes and pathways. In vitro studies examined FA's mechanisms in inflammation and osteoclastogenesis using immunofluorescence, bone resorption assays, and molecular analyses.

Results: FA demonstrated significant protective effects against DSS-induced colitis. Specifically, it increased beneficial gut bacteria and short-chain fatty acid levels while reducing intestinal inflammation. Importantly, FA treatment reduced osteoclast-specific markers and inhibited nuclear translocation of key transcription factors. Moreover, FA suppressed bone resorption and osteoclastogenesis, thereby mitigating inflammatory bone remodeling. At the molecular level, FA exerted its protective effects by blocking PI3K-AKT and MAPK pathway activation, which subsequently inhibited osteoclast differentiation and function, ultimately preventing bone loss.

Conclusions: This study demonstrated FA's protective effect against osteoporosis in UC mice through bone microstructure analysis and functional assays. FA reduced colonic inflammation and mucosal damage by modulating gut microbiota composition and fatty acid levels. These findings suggest FA mitigates bone loss by decreasing intestinal inflammation, improving gut flora, and suppressing osteoclast formation.

Keywords

Farrerol; Gut microbiome; Inflammatory bowel disease; Osteoporosis.

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