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

<p dir="ltr">Hyperglycemia 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 hyperglycemia-induced osteoporosis remains poorly understood. Here, we demonstrate that hyperglycemic (HG) mice develop low-turnover osteoporosis accompanied by reduced gut microbiota diversity. Fecal microbiota transplantation from HG mice (GM^HG-FMT) induced osteoporosis in recipient mice, independent of blood glucose levels. A depletion of <i>Bifidobacterium pseudolongum </i>(<i>B. pseudolongum</i>) was associated with bone loss, whereas supplementation with either microbiota of normoglycemic mice or <i>B. pseudolongum </i>alleviated osteoporosis in HG mice. Both HG and GM^HG-FMT recipient mice exhibited elevated serum 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 naïve CD4+ T cells into Th17 cells, leading to increased IL-17A production. These findings reveal a microbiome dysbiosis-driven decanoic acid/IL-17A axis in hyperglycemia-induced osteoporosis and highlight <b>the therapeutic potential of</b> microbiome associated targets.</p>