2. Academic Validation
  3. Gut Microbiota-Decanoic Acid-Interleukin-17A Axis Orchestrates Hyperglycemia-Induced Osteoporosis in Male Mice

Gut Microbiota-Decanoic Acid-Interleukin-17A Axis Orchestrates Hyperglycemia-Induced Osteoporosis in Male Mice

  • Diabetes. 2025 Oct 27:db250471. doi: 10.2337/db25-0471.
Tao Jiang 1 2 3,  Changkun Li 1 2,  Zhengcan Pan 1 2,  Yizhu Wang 1 2,  Xiaojing Chen 1 2,  Jiaxi Song 1 2,  Kecheng Zhu 1 2,  Yuying Yang 1 2,  Yanfang Hou 4,  Lihao Sun 1 2,  Hongyan Zhao 1 2,  Jianmin Liu 1 2,  Yanyun Gu 1 2,  Bei Tao 1 2
Affiliations

Affiliations

  • 1 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the Peoples Republic of China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4 Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
PMID: 41144501 DOI: 10.2337/db25-0471
Abstract

Hyperglycemia (HG) is a well-established risk factor for secondary osteoporosis, primarily due to suppressed osteoblast activity. While gut microbiota (GM) dysbiosis has been implicated in various diseases, its role in HG-induced osteoporosis remains poorly understood. Here, we demonstrate that HG mice develop low-turnover osteoporosis accompanied by reduced GM diversity. Fecal microbiota transplantation (FMT) from HG mice (GMHG-FMT) induced osteoporosis in recipient mice, independent of blood glucose levels. A depletion of Bifidobacterium pseudolongum was associated with bone loss, whereas supplementation with either microbiota of normoglycemic mice or B. pseudolongum alleviated osteoporosis in HG mice. Both HG and GMHG-FMT recipient mice exhibited elevated serum interleukin-17A (IL-17A) levels, and anti-IL-17A antibody treatment mitigated osteoporosis in the GMHG-FMT model. Furthermore, decanoic acid levels were elevated in the feces of HG mice and the serum of GMHG-FMT recipients. Decanoic acid promoted the differentiation of naive CD4+ T cells into T helper17 cells, leading to increased IL-17A production. These findings reveal a microbiome dysbiosis-driven decanoic acid/IL-17A axis in HG-induced osteoporosis and highlight the therapeutic potential of microbiome-associated targets.

Article highlights: This study investigated the role of gut microbiota dysbiosis in hyperglycemia-induced osteoporosis, a condition with unclear mechanisms. We explored whether gut microbiota dysbiosis drives bone loss in hyperglycemia and identified key microbial and molecular pathways. Hyperglycemic mice showed disturbed gut microbiota symbiosis, decreased Bifidobacterium pseudolongum, and elevated decanoic acid, which promoted T helper 17 differentiation and interleukin-17A (IL-17A) production, leading to osteoporosis. Fecal microbiota transplantation from control mice, B. pseudolongum supplementation, and IL-17A blockade alleviated bone loss, highlighting both B. pseudolongum supplementation and IL-17A inhibition as potential therapeutic strategies for hyperglycemia-induced osteoporosis.

Figures
Products