Rethinking the Gut-Bone Axis: Diet, the Gut Ecosystem, and Skeletal Health

The gut-bone field has expanded beyond its initial focus on the gut microbiota to include microbial metabolism, epithelial barrier integrity, immune and endocrine signaling, and host-microbial interactions. This review uses a functional gut ecosystem framework to integrate these mechanisms and examine how diet and other exposures influence skeletal health.

No consistent microbial signature of osteoporosis has emerged across populations or experimental models. Instead, recent studies indicate that skeletal responses are associated with functional outputs of the gut ecosystem, including nutrient bioavailability, microbial co-metabolic products, barrier integrity, and host sensing. Gut-derived signals may act directly on bone or be further processed by the host. Diverse interventions, including whole foods, probiotics, postbiotics, and targeted therapies, can converge on these functions. Bone responds to the integrated biological signals generated by the gut ecosystem rather than microbial composition alone. Defining these functions and individual responder phenotypes may provide new approaches for preserving skeletal health.