Li Ning, Wang Haiyang, Pei Huan, Wu Yueying, Li Lei, Ren Yu, Wang Si, Ma Yuan, Luo Miao, Yuan Jiali, Li Lvyu, Qin Dongdong
First Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, China.
Key Laboratory of Integrated Chinese and Western Medicine for Chronic Disease Prevention and Control, Yunnan University of Chinese Medicine, Yunnan Province, Kunming, China.
Front Microbiol. 2024 May 21;15:1373013. doi: 10.3389/fmicb.2024.1373013. eCollection 2024.
This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments.
We conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1β, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed.
A positive correlation was observed between and the risk of osteoporosis, while showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the was significantly reduced, while the abundance of was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors.
and may regulate the development of osteoporosis through the microbiota-gut-bone axis.
本研究旨在通过孟德尔随机化（MR）分析与动物实验相结合，阐明肠道微生物群与骨质疏松症之间的关系。
我们使用从公共数据库获得的关于肠道微生物群和骨质疏松症的开放获取全基因组关联研究（GWAS）数据，对差异细菌与骨质疏松症之间的关系进行了分析。使用两样本MR分析进行该分析，并通过逆方差加权（IVW）、MR Egger、加权中位数和加权模式方法检查因果关系。采用双侧卵巢切除术复制小鼠骨质疏松模型，通过微型计算机断层扫描（CT）、病理检查和骨转换指标进行评估。此外，对粪便样本进行16S rDNA测序，同时检测结肠样本中的分泌型免疫球蛋白A（SIgA）以及白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）炎症因子指标。通过免疫荧光和组织病理学评估紧密连接蛋白（如闭合蛋白-1、紧密连接蛋白-1和闭锁蛋白）的表达水平，并对差异细菌与相关环境因素进行相关性分析。
观察到[具体细菌名称1]与骨质疏松症风险呈正相关，而[具体细菌名称2]与骨质疏松症风险呈负相关。此外，没有异质性或多效性的证据。评估了小鼠骨质疏松模型的成功复制情况，发现去卵巢（OVX）小鼠中[具体细菌名称1]的丰度显著降低，而[具体细菌名称2]的丰度显著增加。OVX小鼠的肠道SIgA水平降低，炎症因子表达水平升高，屏障受损，结肠和血清中脂多糖（LPS）含量显著增加。[具体细菌名称1]的丰度水平与骨形成因子、肠道屏障指标、骨密度、骨体积分数和小梁骨数量呈强正相关，而与骨吸收因子和肠道炎症因子呈强负相关；[具体细菌名称2]的丰度水平与骨形成因子、肠道屏障指标和骨体积分数呈强负相关，与骨吸收因子和肠道炎症因子呈强正相关。
[具体细菌名称1]和[具体细菌名称2]可能通过微生物-肠道-骨轴调节骨质疏松症的发展。
