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

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 (GM HG -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 GM HG -FMT recipient mice exhibited elevated serum interleukin-17A (IL-17A) levels, and anti–IL-17A antibody treatment mitigated osteoporosis in the GM HG -FMT model. Furthermore, decanoic acid levels were elevated in the feces of HG mice and the serum of GM HG -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.