Punicalagin prevents the bone loss of diabetic mice induced by high‐fat diet via the metabolism of gut microbiota

Abstract Diabetes often induces bone loss and the dysregulation of gut microbiota (GM) is an important cause. Punicalagin (PU) was reported to regulate GM. Therefore, we hypothesized that PU could alleviate diabetes‐induced bone loss through GM and their metabolites. In this study, high‐fat diet‐induced diabetic mice showed bone erosion and poor biomechanical properties, while PU intake significantly improved the bone condition of diabetic mice. Further investigation revealed that the abundance of some beneficial bacteria, such as Akkermansia and Ruminiclostridium_9 , was higher after PU intake and highly positively correlated with the concentrations of short‐chain fatty acids (SCFAs) and serum vitamin K 2 , respectively. In addition, these bacteria were associated with the levels of bone metabolism‐related markers such as procollagen type I N‐terminal propeptide (P1NP) and runt‐related transcription factor‐2 (Runx2). Mechanistically, PU, on the one hand, promotes the metabolism of SCFAs, thereby increasing the levels of bone synthesis markers and inhibiting the secretion of bone absorption markers. On the other hand, the higher level of vitamin K 2 greatly accelerated bone mineralization and enhanced bone strength. This work provides a new perspective to explore the mechanism by which PU intervention alleviates diabetes‐induced bone loss by regulating the GM and their metabolic products.