Lactobacillus acidophilus ameliorates inflammatory bone loss under post-menopausal osteoporotic conditions via preventing the pathogenic conversion of gut resident pTregs into Th17 cells

Research in the past decade has elucidated the explicit role of immune system in the pathophysiology of osteoporosis. Recent studies revealed more details of bone immune interaction and explored various safe and effective immunomodulatory therapies, such as probiotics for the prevention and management of osteoporosis. As a result, various immune factors have continuously been discovered to play specific roles in maintaining bone homeostasis. The role of the Tregs is already well established in the context of post-menopausal osteoporosis (PMO). While Foxp3 ⁺ Tregs are mostly matured in the thymus (tTregs), some are also produced from Foxp3 ⁻ CD4 ⁺ T-cell precursors in the peripheral tissues (pTregs). Intriguingly, the specific role of pTregs or tTregs in PMO is still warranted. Foxp3 is required for the suppressive function of Treg cells, but its stability has been debated. Here, we reveal that RORγT ^- FoxP3 ⁺ pTregs (in the intestine and bone marrow) but not FoxP3 ⁺ tTregs show plastic behavior and loss of FoxP3 expression transdifferentiate pTregs into ex-Foxp3 Tregs (i.e., osteoclastogenic Th17 cells), under estrogen-deficient PMO conditions. Interestingly, Lactobacillus acidophilus (LA) supplementation in a butyrate-mediated manner stabilizes the expression of FoxP3 in pTregs. Furthermore, butyrate-primed pTregs are more potent in inhibiting osteoclastogenesis than the control pTregs. Altogether, our findings for the first time reveal that pTreg-Th17 cell axis do play a pivotal role in the pathophysiology of PMO, and probiotic-LA mitigates PMO-induced bone loss via augmenting the immunoporotic potential of pTregs.