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Abstract：
Postmenopausal osteoporosis is characterized by excess osteoclastogenesis which leads to net bone loss and brittle fractures. Studies have demonstrated that estrogen deficiency-associated bone loss is microbiota-dependent and could be prevented by probiotics and prebiotics. In this study, we report that orally administered lactulose (20 g/kg, 6 weeks) orally administered significantly inhibited osteoclastogenesis, bone resorption, and prevented ovariectomy (OVX)-induced bone loss in mice. Lactulose increased intestinal Claudin 2, 3 and 15, compared to the OVX group, and lowered pro-osteoclastogenic cytokines levels including tumor necrosis factor-α, interleukin(IL)-6, receptor activator of nuclear factor kappa-Β ligand (RANKL), and IL-17 as well as increased the anti-inflammatory cytokine IL-10 in the intestine, peripheral blood, and bone marrow. Lactulose significantly preserved the number of Foxp3+ Treg cells in the intestines compared with that in OVX mice. Lactulose altered the composition of intestinal microbiota measured by 16s rDNA sequencing and increased intestinal and serum short-chain fatty acids (SCFAs) levels including acetate, propionate and butyrate which were decreased in OVX mice as measured by gas chromatography. Oral administration of lactulose for 2 weeks significantly lowered the level of bone resorption marker C-telopeptide of type 1 collagen-1 in healthy male young volunteers (aging 20-25 years). In conclusion, lactulose inhibited osteoclastogenesis and bone resorption by altering the intestinal microbiota and increasing SCFAs. Lactulose could serve as an ideal therapeutic agent for postmenopausal osteoporosis.
摘要：
绝经后骨质疏松症的特征是过度的破骨细胞生成，导致净骨丢失和脆性骨折。研究表明，雌激素缺乏相关的骨丢失是微生物群依赖性的，可以通过益生菌和益生元预防。在这项研究中,我们报道口服乳果糖(20g/kg，6周)口服显著抑制破骨细胞生成,骨吸收，并防止卵巢切除术（OVX）诱导的小鼠骨丢失。与OVX组相比，乳果糖增加了肠道claudin2、3和15，并降低了包括肿瘤坏死因子-α在内的促破骨细胞细胞因子水平，白细胞介素（IL）-6，核因子κB受体活化因子配体（RANKL），和IL-17以及增加肠道中的抗炎细胞因子IL-10，外周血,还有骨髓.与OVX小鼠相比，乳果糖显着保留了肠道中Foxp3Treg细胞的数量。乳果糖改变了通过16srDNA测序测量的肠道微生物群的组成，并增加了包括乙酸盐在内的肠道和血清短链脂肪酸（SCFA）水平，通过气相色谱法测量，OVX小鼠中丙酸和丁酸盐含量降低。口服乳果糖2周可显着降低健康男性年轻志愿者（年龄20-25岁）中1型胶原蛋白1的骨吸收标志物C-端肽的水平。总之,乳果糖通过改变肠道微生物群和增加SCFA抑制破骨细胞生成和骨吸收。乳果糖可作为绝经后骨质疏松症的理想治疗药物。
