Gut-resident regulatory T cells (GTregs) play a pivotal role in maintaining bone health under postmenopausal osteoporotic conditions

Osteoporosis is a skeletal condition characterized by the deterioration of bone tissue. The immune system plays a crucial role in maintaining bone homeostasis and combating the development of osteoporosis. Immunoporosis is the term used to describe the recent convergence of research on the immune system's role in osteoporosis. The gut harbors the largest component of the immune system, and there is growing evidence that intestinal immunity plays a vital role in regulating bone health. Gut-resident regulatory T cells are essential in inhibiting immune responses and preventing various inflammatory manifestations. Our findings show that gut-resident regulatory T cells are pivotal in the pathophysiology of postmenopausal osteoporosis. We investigated the potential of gut-resident regulatory T cells in regulating the development of bone cells in vitro. We observed that gut-resident regulatory T cells significantly enhance osteoblastogenesis with concomitant inhibition of osteoclastogenesis in a cell ratio-dependent manner. We further report that the deficiency of short-chain fatty acids in osteoporotic conditions substantially disrupts the composition of gut-resident regulatory T cells, leading to a loss of peripherally derived regulatory T cells and an expansion of thymus-derived regulatory T cells. Moreover, the administration of probiotics Lactobacillus rhamnosus (UBLR-58) and Bifidobacterium longum (UBBL-64) modulated the gut-resident regulatory T cells compartment in a short-chain fatty acid-dependent manner to mitigate inflammatory bone loss in postmenopausal osteoporosis. Notably, short-chain fatty acid-primed gut-resident regulatory T cells were found to be significantly more effective in inhibiting osteoclastogenesis compared with unprimed gut-resident regulatory T cells. Altogether our results, for the first time, highlight the crucial role of gut-resident regulatory T cells in the pathophysiology of postmenopausal osteoporosis, with potential clinical implications.