Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations.
Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations.
复制标题
益生菌通过组蛋白甲基化刺激肥胖小鼠骨形成。
DOI：
10.7150/thno.63749
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Tyagi N
中科院分区：
文献类型：
--
作者：
Behera J;Ison J;Voor MJ;Tyagi N
原理：操纵肠道微生物组可以预防病理性骨丢失。然而，益生菌对高脂饮食（HFD）相关肥胖症的线粒体表观遗传重塑和骨骼稳态的影响仍有待探讨。在此，我们通过HFD喂养的肥胖小鼠的组蛋白甲基化机制研究了益生菌补充对线粒体生物发生和骨稳态的影响。方法：采用16 S rRNA基因测序技术研究肥胖小鼠肠道菌群组成及微生态失调。进行高分辨率（microPET/CT）成像以显示肥胖相关的结肠炎症。使用microRNA qPCR阵列研究成骨细胞中目标miRNA的肥胖相关上调。共聚焦成像评价成骨细胞线粒体质量。使用线粒体转录因子（Tfam）的过表达来研究使用喂食HFD的Tfam转基因（Tg）小鼠的糖酵解和线粒体生物能量代谢。通过microCT分析和三点弯曲分析评价骨形成和机械强度。结果如下：高分辨率成像（µ-CT）和力学测试显示，益生菌分别诱导肥胖小鼠的骨小梁体积和骨机械强度显著增加。益生菌或吲哚-3-丙酸（IPA）治疗直接对肥胖小鼠，防止肠道炎症，并改善成骨细胞矿化。从机制上讲，益生菌治疗通过促进Kdm 6 b/Jmjd 3组蛋白去甲基化酶来增加成骨细胞中线粒体转录因子A（Tfam）的表达，这抑制了Tfam启动子处的H3 K27 me 3表观遗传甲基化。此外，Tfam转基因（Tg）小鼠，喂食HFD，没有经历肥胖相关的葡萄糖摄取减少，线粒体生物合成和成骨细胞矿化。结论：这些结果表明，益生菌介导的肠道微生物组及其衍生代谢物IPA的变化可能是通过肠-骨轴调节骨粘附的新型药物。
Rationale: Manipulation of the gut microbiome can prevent pathologic bone loss. However, the effects of probiotics on mitochondrial epigenetic remodeling and skeletal homeostasis in the high-fat diet (HFD)-linked obesity remains to be explored. Here, we examined the impact of probiotics supplementation on mitochondrial biogenesis and bone homeostasis through the histone methylation mechanism in HFD fed obese mice. Methods: 16S rRNA gene sequencing was performed to study the microbiota composition in the gut and microbial dysbiosis in obese mouse model. High resolution (microPET/CT) imaging was performed to demonstrate the obese associated colonic inflammation. Obese-associated upregulation of target miRNA in osteoblast was investigated using a microRNA qPCR array. Osteoblastic mitochondrial mass was evaluated using confocal imaging. Overexpression of mitochondrial transcription factor (Tfam) was used to investigate the glycolysis and mitochondrial bioenergetic metabolism using Tfam-transgenic (Tg) mice fed on HFD. The bone formation and mechanical strength was evaluated by microCT analysis and three-point bending analysis. Results: High-resolution imaging (µ-CT) and mechanical testing revealed that probiotics induced a significant increase of trabecular bone volume and bone mechanical strength respectively in obese mice. Probiotics or Indole-3-propionic acid (IPA) treatment directly to obese mice, prevents gut inflammation, and improved osteoblast mineralization. Mechanistically, probiotics treatment increases mitochondrial transcription factor A (Tfam) expression in osteoblasts by promoting Kdm6b/Jmjd3 histone demethylase, which inhibits H3K27me3 epigenetic methylation at the Tfam promoter. Furthermore, Tfam-transgenic (Tg) mice, fed with HFD, did not experience obesity-linked reduction of glucose uptake, mitochondrial biogenesis and mineralization in osteoblasts. Conclusions: These results suggest that the probiotics mediated changes in the gut microbiome and its derived metabolite, IPA are potentially be a novel agent for regulating bone anabolism via the gut-bone axis.