Glucocorticoids (GCs) are potent immune-modulating drugs with significant side effects, including glucocorticoid-induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined. To test this, male C57/Bl6J mice were treated for 8 weeks with GC (prednisolone, GC-Tx) in the presence or absence of broad-spectrum antibiotic treatment (ABX) to deplete the microbiota. Long-term ABX prevented GC-Tx-induced trabecular bone loss, showing the requirement of gut microbiota for GIO. Treatment of GC-Tx mice with a probiotic (Lactobacillus reuteri [LR]) prevented trabecular bone loss. Microbiota analyses indicated that GC-Tx changed the abundance of Verrucomicobiales and Bacteriodales phyla and random forest analyses indicated significant differences in abundance of Porphyromonadaceae and Clostridiales operational taxonomic units (OTUs) between groups. Furthermore, transplantation of GC-Tx mouse fecal material into recipient naïve, untreated WT mice caused bone loss, supporting a functional role for microbiota in GIO. We also report that GC caused intestinal barrier breaks, as evidenced by increased serum endotoxin level (2.4-fold), that were prevented by LR and ABX treatments. Enhancement of barrier function with a mucus supplement prevented both GC-Tx-induced barrier leakage and trabecular GIO. In bone, treatment with ABX, LR or a mucus supplement reduced GC-Tx-induced osteoblast and osteocyte apoptosis. GC-Tx suppression of Wnt10b in bone was restored by the LR and high-molecular-weight polymer (MDY) treatments as well as microbiota depletion. Finally, we identified that bone-specific Wnt10b overexpression prevented GIO. Taken together, our data highlight the previously unappreciated involvement of the gut microbiota and intestinal barrier function in trabecular GIO pathogenesis (including Wnt10b suppression and osteoblast and osteocyte apoptosis) and identify the gut as a novel therapeutic target for preventing GIO. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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肠道菌群和糖皮质激素诱导的骨质疏松症的屏障功能的参与。

糖皮质激素（GCs）是有效的免疫调节药物，具有明显的副作用，包括糖皮质激素诱导的骨质疏松症（GIO）。气相色谱直接诱导成骨细胞和骨细胞凋亡，但也会改变肠道菌群组成。尽管已知肠道菌群有助于调节骨密度，但从未研究过其在GIO中的作用。为了对此进行测试，在存在或不存在广谱抗生素治疗（ABX）的情况下，使用GC（泼尼松龙，GC-Tx）对雄性C57 / B16J小鼠进行了8周的治疗，以消耗微生物。长期使用ABX可以预防GC-Tx引起的小梁骨丢失，这表明GIO需要肠道菌群。用益生菌（路氏乳杆菌[LR]）治疗GC-Tx小鼠可预防小梁骨丢失。微生物群分析表明，GC-Tx改变了疣状疣和门生细菌的丰度，而随机森林分析表明，两组之间的卟啉单胞菌科和梭菌操作分类单位（OTU）的丰度存在显着差异。此外，将GC-Tx小鼠粪便材料移植到未经处理的未经处理的野生型WT小鼠体内导致骨质流失，支持了微生物群在GIO中的功能性作用。我们还报告说，GC引起肠屏障破坏，如血清内毒素水平升高（2.4倍）所证明，而LR和ABX治疗可防止这种破坏。用粘液补充剂增强屏障功能可防止GC-Tx诱导的屏障渗漏和小梁GIO。在骨骼中，用ABX，LR或粘液补充剂治疗可减少GC-Tx诱导的成骨细胞和骨细胞凋亡。LR和高分子量聚合物（MDY）处理以及微生物群耗竭恢复了骨骼中Wnt10b的GC-Tx抑制作用。最后，我们确定了骨骼特异性Wnt​​10b的过度表达阻止了GIO。综上所述，我们的数据强调了肠道菌群和肠屏障功能在小梁GIO发病机理（包括Wnt10b抑制以及成骨细胞和骨细胞凋亡）中的未曾发现的参与，并确定了肠道是预防GIO的新型治疗靶标。©2019美国骨骼和矿物质研究学会。我们的数据强调了肠道菌群和肠屏障功能在小梁GIO发病机理（包括Wnt10b抑制以及成骨细胞和骨细胞凋亡）中的未曾发现的参与，并确定了肠道是预防GIO的新型治疗靶标。©2019美国骨骼和矿物质研究学会。我们的数据强调了肠道菌群和肠屏障功能在小梁GIO发病机理（包括Wnt10b抑制以及成骨细胞和骨细胞凋亡）中的未曾发现的参与，并确定了肠道是预防GIO的新型治疗靶标。©2019美国骨骼和矿物质研究学会。