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Mechanisms of Bone Anabolic and Anticatabolic Activities of Probiotics

益生菌的骨合成代谢和抗分解代谢活性机制

基本信息

批准号：
10066263
负责人：
RHEINALLT MELFYN JONES
金额：
$ 51.11万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-24 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066263
关键词：
Address Anabolic Agents Anabolism Bone Density Bone Diseases Bone Marrow Bone Resorption Butyrates CD8-Positive T-Lymphocytes Cells Child Data Data Reporting Development Disease Elements Enterocytes Epithelial Cells Estrogens Event FDA approved Formulation Fright Future Generations Germ-Free Gnotobiotic Gonadal Steroid Hormones Health Homeostasis Human Immune Individual Inflammation Intervention Intestinal permeability Intestines Knockout Mice Knowledge Lactobacillus casei rhamnosus Lead Leukocyte Trafficking Leukocytes Ligands Longevity Mediating Mission Modality Molecular Morbidity - disease rate Mus Osteoblasts Osteogenesis Osteoporosis Outcome Study Ovariectomy Pathway interactions Patients Pharmaceutical Preparations Play Population Postmenopausal Osteoporosis Prevention Probiotics Production Proteins Publishing Quality of life Regulatory T-Lymphocyte Role Signal Pathway Signal Transduction Testing United States National Institutes of Health Volatile Fatty Acids WNT Signaling Pathway Woman base bone bone health bone lead bone loss bone mass bone metabolism cost cytokine deprivation disability effective intervention efficacy testing fecal transplantation feeding fracture risk gastrointestinal epithelium germ free condition gut microbiome gut microbiota high risk improved in vivo inflammatory disease of the intestine innovation men microbiome microbiota mouse model novel osteogenic preservation prevent probiotic supplementation side effect substantia spongiosa systemic inflammatory response trafficking trend

项目摘要

Summary Osteoporosis has a devastating impact on the health and quality of life of women and men. Several FDA approved drugs are available for the treatment of osteoporosis. However, in the US a low and declining number of patients at high risk for fractures do not receive adequate treatment because of the cost and the side effects of currently available drugs. This trend has generated “a crisis” in the treatment osteoporosis. Thus, there is a critical need to identify inexpensive, safe and effective interventions for both the prevention and treatment of osteoporosis. Interestingly, there is strong evidence that the gut microbiome regulates bone homeostasis in health and disease, and that probiotics protect against bone loss. In 2016, we published in JCI that sex steroid depleted germ-free mice do not undergo trabecular bone loss, demonstrating a role of the microbiota in the bone loss induced by sex steroid deprivation. We showed that Lactobacillus rhamnosus GG (LGG) and VSL#3 probiotics completely protected ovariectomized (ovx) mice from bone loss by decreasing bone resorption. Furthermore, these probiotics increased bone mass in estrogen replete controls by stimulating bone formation. New preliminary data confirm that LGG and VSL#3 exert bone anti-catabolic effects in ovx mice, as well as bone anabolic effects in estrogen replete controls. Based on preliminary data, our central hypothesis is that probiotics stimulate bone formation by generating the short-chain fatty acid (SCAFA) butyrate in the gut. Butyrate has been shown to induce regulatory T cell (Treg) expansion in the intestine. We show preliminary data that probiotics, or direct feeding of butyrate, also induces the expansion of the Treg population in the bone marrow (BM). Mechanistically, we show that Treg expansion induces the release of the osteogenic Wnt ligand Wnt10b by BM CD8+ T cells. Wnt10b then activates Wnt signaling in osteoblastic cells, leading to increased bone formation. Our published studies show that probiotics prevent bone loss in ovx mice by reversing an increase in gut permeability induced by ovx. We now hypothesize that probiotics block bone resorption in ovx mice by decreasing gut permeability via activation of ERK dependent signaling pathways in gut epithelial cells, leading to lower intestinal inflammation. We also hypothesize that probiotics block the trafficking of activated immune cells from the gut to the BM. Finally, we show that probiotics can change gut microbiome diversity, suggesting that probiotics prevent inflammation and bone loss in ovx mice by restoring gut microbiota diversity. Our hypotheses will be tested in 3 specific aims: 1) To determine if LGG and VSL#3 probiotics stimulate bone formation in intact mice via a SCFAs/Treg/ CD8+T cells/Wnt10b dependent mechanism, 2) To identify the molecular events at the gut epithelium that mediate probiotic protection against bone loss following sex steroid depletion, and 3) To determine whether probiotics mechanistically influence bone metabolism by preserving a eubiotic microbiome diversity. The outcomes of these studies are relevant to the mission of NIH by addressing novel and inexpensive interventions for osteoporosis.

概括骨质疏松症对女性和男性的健康和生活质量具有毁灭性影响。多项 FDA 批准的药物可用于治疗骨质疏松症。然而，在美国，这一比例较低且正在下降。由于费用和治疗费用的原因，许多骨折高危患者没有得到足够的治疗目前可用药物的副作用。这种趋势给骨质疏松症的治疗带来了“危机”。因此，迫切需要确定廉价、安全和有效的干预措施来预防和预防和骨质疏松症的治疗。有趣的是，有强有力的证据表明肠道微生物组调节骨骼健康和疾病的体内平衡，益生菌可以防止骨质流失。 2016年，我们发表在JCI 性类固醇耗尽的无菌小鼠不会出现骨小梁丢失，这证明了性类固醇剥夺引起的骨质流失中的微生物群。我们发现鼠李糖乳杆菌 GG (LGG) 和 VSL#3 益生菌通过减少骨质流失，完全保护卵巢切除 (ovx) 小鼠免受骨质流失骨吸收。此外，这些益生菌通过刺激雌激素充足的对照组，增加了骨量骨形成。新的初步数据证实 LGG 和 VSL#3 在 ovx 中发挥骨抗分解代谢作用小鼠，以及雌激素充足对照中的骨合成代谢效应。根据初步数据，我们中央假设益生菌通过产生短链脂肪酸（SCAFA）来刺激骨骼形成肠道中的丁酸。丁酸盐已被证明可以诱导肠道中调节性 T 细胞 (Treg) 的扩增。我们初步数据表明，益生菌或直接喂养丁酸盐也会诱导 Treg 细胞的扩张骨髓（BM）中的人口。从机制上讲，我们表明 Treg 扩张会诱导释放 BM CD8+ T 细胞的成骨 Wnt 配体 Wnt10b。然后 Wnt10b 激活成骨细胞中的 Wnt 信号传导，导致骨形成增加。我们发表的研究表明，益生菌可防止 ovx 小鼠骨质流失通过逆转 ovx 引起的肠道通透性增加。我们现在假设益生菌会阻碍骨骼通过激活 ERK 依赖性信号通路降低肠道通透性，从而减少 ovx 小鼠的吸收肠道上皮细胞，导致下肠道炎症。我们还假设益生菌可以阻止将激活的免疫细胞从肠道运输到骨髓。最后，我们证明益生菌可以改变肠道微生物组多样性，表明益生菌通过恢复 ovx 小鼠的炎症和骨质流失来预防炎症和骨质流失肠道微生物群多样性。我们的假设将在 3 个具体目标中进行测试：1) 确定 LGG 和 VSL#3 是否成立益生菌通过 SCFAs/Treg/CD8+T 细胞/Wnt10b 依赖性刺激完整小鼠的骨形成机制，2) 确定肠道上皮介导益生菌保护的分子事件性类固醇消耗后骨质流失，以及 3) 确定益生菌是否会产生机械影响通过保留益生微生物组多样性来促进骨代谢。这些研究的结果与 NIH 的使命是解决骨质疏松症的新颖且廉价的干预措施。