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Abstract Osteoporosis is characterized by decreased bone mass, microarchitectural deterioration, and increased bone fragility. High-fat diet (HFD)-induced obesity also results in bone loss, which is associated with an imbalanced gut microbiome. However, whether HFD-induced obesity or HFD itself promotes osteoclastogenesis and consequent bone loss remains unclear. In this study, we developed HFD-induced obesity (HIO) and non-obesity (NO) mouse models to evaluate the effect of HFD on bone loss. NO mice were defined as body weight within 5% of higher or lower than that of chow diet fed mice after 10 weeks HFD feeding. NO was protected from HIO-induced bone loss by the RANKL /OPG system, with associated increases in the tibia tenacity, cortical bone mean density, bone volume of cancellous bone, and trabecular number. This led to increased bone strength and improved bone microstructure via the microbiome-short-chain fatty acids (SCFAs) regulation. Additionally, endogenous gut-SCFAs produced by the NO mice activated free fatty acid receptor 2 and inhibited histone deacetylases, resulting in the promotion of Treg cell proliferation in the HFD-fed NO mice; thereby, inhibiting osteoclastogenesis, which can be transplanted by fecal microbiome. Furthermore, T cells from NO mice retain differentiation of osteoclast precursors of RAW 264.7 macrophages ex vivo. Our data reveal that HFD is not a deleterious diet; however, the induction of obesity serves as a key trigger of bone loss that can be blocked by a NO mouse-specific gut microbiome.

A long-term high-fat diet (HFD) can cause OA through biomechanical and metabolic factors, which may be related to changes in the gut microbiota. The purpose of the present study was to evaluate the roles of L. paracasei subsp. paracasei M5 (M5) and CS in the prevention of OA caused by HFD and the relationship between the gut microbiota and OA. The results showed that mice receiving an HFD had significantly increased body weight and exhibited characteristics associated with OA. Both M5 and CS effectively prevented the destruction of articular cartilage and the degradation of type II collagen caused by HFD. The level of serum and infrapatellar fat pad (IPFP) leptin was also significantly decreased. A strong predictive relationship was observed between the abundance of Ruminococcaceae_UCG-014, Streptococcus, Bacteroides and OA. In summary, we demonstrated that M5 protected against HFD-induced OA, which was probably associated with modification of the gut microbiota.