Fig. 3.

The nexus between gut microbiota (GM) and bone. The GM maintains bone homeostasis and under conditions of dysbiosis, results in abnormal bone remodeling contributing towards osteo-pathologies. A leaky gut allows the translocation of GM species from the intestinal lumen into the lamina propria which hosts a multitude of immune cells. GM species and derived short chain fatty acids (SCFAs) induce the dendritic cells (DCs) to stimulate Th17 and Th1 cells which further participate in inhibiting osteoclastogenesis via the production of cytokines such as interferon (IFN)-γ, interleukin (IL)-10, IL-4, and transforming growth factor (TGF)-β. Secretion of a variety of interleukins drive activation of Th17 cells which promote osteoclastogenesis via tumor necrosis factor (TNF)-α, IL-17, and receptor activator for nuclear factor kappa-B (RANK)- receptor activator for nuclear factor kappa-B ligand (RANKL) signaling. Also, production of IL-22 by Th17 and innate lymphoid cells (ILCs) maintains gut membrane integrity. Bregs are activated directly by the bacteria-derived lipopolysaccharide (LPS) via toll like receptor-4 (TLR4) signaling which inhibits maturation of osteoclast precursors directly and indirectly by inducing Tregs to suppress bone resorption. Secretion of TGF-β by Tregs function to convert pre-osteoblasts into osteoblasts, thus inducing bone formation.