<i>Lactobacillus acidophilus</i> Ameliorates Inflammatory Bone Loss Under Postmenopausal Osteoporotic Conditions via Modulating the Gut‐Resident RORγT ⁻ pTreg Cell Population

Research in the past decade has elucidated the explicit role of the immune system in the pathophysiology of osteoporosis. Recent studies have further unraveled the complex interactions between bone and immune cells and explored safe, effective immunomodulatory approaches-such as probiotics-for preventing and managing osteoporosis. As a result, various immune factors have continuously been discovered to play specific roles in maintaining bone homeostasis. The role of Tregs in the context of postmenopausal osteoporosis (PMO) is already well established. While Foxp3⁺ Tregs are mostly matured in the thymus (tTregs), some are also produced from Foxp3^-CD4⁺ T-cell precursors in the peripheral tissues (i.e., pTregs). Notably, the specific role of pTregs and tTregs in PMO remains to be elucidated. Here, we reveal that estrogen-deficient inflammatory conditions in PMO disrupt the balance of tTregs and pTregs. Interestingly, within pTregs, the population of RORγT^- pTregs and RORγT⁺ pTregs is further altered, along with simultaneous expansion of Th17 cells-likely through the conversion of RORγT^- pTregs into Th17 cells. Notably, supplementation with Lactobacillus acidophilus (LA) restores the homeostasis of RORγT^- pTregs and Th17 cells in a butyrate-mediated manner. Moreover, it was observed that butyrate-primed RORγT^- pTregs have reduced osteoclastogenic potential. Collectively, our findings for the first time reveal the pivotal role of gut resident RORγT^- pTregs-Th17 cell axis in the pathophysiology of PMO.