Gut microbiota-derived bile acids as metabolic signaling mediators in bone remodeling: Insights into the gut–immune–bone axis

In recent years, the role of the gut microbiota in bone metabolism has received increasing attention, particularly because microbial metabolites can affect host immune and endocrine functions. Bile acids are host-derived metabolites extensively modified by intestinal microorganisms. Beyond their established role in lipid digestion, they also act as signaling molecules through the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1, commonly known as TGR5), thereby participating in immune homeostasis and inflammatory regulation. Gut microbes reshape the bile acid pool through deconjugation, 7α-dehydroxylation, oxidation, and epimerization, altering receptor activation and downstream effects. Bile acids may influence bone remodeling through the gut–immune–bone axis. By supporting intestinal barrier integrity, limiting excessive activation of inflammatory pathways such as NF-κB, and regulating the Treg/Th17 balance and immune microenvironment, they may affect osteoclast formation. Bile acid signaling has also been linked to osteoblast and osteoclast activity through FXR/TGR5-related pathways, including Wnt/β-catenin, RANKL–RANK, and cAMP signaling. In this process, immune regulation may connect intestinal bile acid signaling with changes in the bone marrow microenvironment and skeletal remodeling. However, skeletal effects vary with microbiota composition, bile acid profiles, tissue-specific receptor activity, dose, and experimental model. This review summarizes microbial bile acid transformation, immune regulation, and bone-cell responses, while considering how food and dietary factors modify the microbiota–bile acid network. Evidence from cell, animal, and human studies is compared to identify major knowledge gaps and translational challenges in osteoporosis and inflammatory bone diseases.