基于孟德尔随机化研究探讨肠道菌群与肌少症表型的因果关联

doi:10.3877/cma.j.issn.2096-0263.2023.06.002

中华老年骨科与康复电子杂志 ›› 2023, Vol. 09 ›› Issue (06) : 333 -342. doi: 10.3877/cma.j.issn.2096-0263.2023.06.002

临床论著

基于孟德尔随机化研究探讨肠道菌群与肌少症表型的因果关联

王宁, 刘彦哲, 吴紫莺, 曾超, 雷光华, 沙婷婷, 王伊伦^†(

)

410008　长沙，中南大学湘雅医院骨科
410008　长沙，中南大学湘雅医院骨科；410008　长沙，中南大学湘雅医院老年骨关节疾病防治教育部重点实验室；410008　长沙，中南大学湘雅医院国家老年疾病临床医学研究中心；410008　长沙，中南大学湘雅医院骨关节退变与损伤湖南省重点实验室
410008　长沙，中南大学湘雅医院骨科；410008　长沙，中南大学湘雅医院老年骨关节疾病防治教育部重点实验室；410008　长沙，中南大学湘雅医院骨关节退变与损伤湖南省重点实验室

收稿日期:2023-08-09 出版日期:2023-12-05
通信作者: 王伊伦
基金资助:
湖南省自然科学基金项目(2022JJ40821); 中南大学湘雅医院青年科研基金项目(2021Q14)

Causal associations of gut Microbiota with phenotype indicators of sarcopenia: A mendelian randomization study

Ning Wang, Yanzhe Liu, Ziying Wu, Chao Zeng, Guanghua Lei, Tingting Sha, Yilun Wang^†()

Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha 410008, China
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha 410008, China

Received:2023-08-09 Published:2023-12-05
Corresponding author: Yilun Wang

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引用本文：

王宁, 刘彦哲, 吴紫莺, 曾超, 雷光华, 沙婷婷, 王伊伦. 基于孟德尔随机化研究探讨肠道菌群与肌少症表型的因果关联[J]. 中华老年骨科与康复电子杂志, 2023, 09(06): 333-342.

Ning Wang, Yanzhe Liu, Ziying Wu, Chao Zeng, Guanghua Lei, Tingting Sha, Yilun Wang. Causal associations of gut Microbiota with phenotype indicators of sarcopenia: A mendelian randomization study[J]. Chinese Journal of Geriatric Orthopaedics and Rehabilitation(Electronic Edition), 2023, 09(06): 333-342.

目的

本研究拟采用MR研究设计，以探讨肠道菌群与肌少症表型指标——握力和骨骼肌质量之间的因果关联。

方法

数据来源于英国生物银行数据库和公开发表且可获取数据的全基因组关联研究，选择131种肠道具体菌属的遗传变异作为工具变量。单核苷酸多态性（SNPs）筛选标准包括在全基因组水平显著关联、SNP之间相互独立以及工具变量的强度足够高。只有当F>10才被认为是一个足够强的工具变量，具有较低的工具偏倚可能性。采用逆方差加权法（IVW）作为主要分析方法，采用加权中位数法、MR Pleiotropy RESidual Sum and Outlier（MR-PRESSO）法以及"留一法"作为敏感性分析方法，评估131种肠道具体菌属与握力和骨骼肌质量之间的因果关联。使用MR-PRESSO方法检验水平多效性和解决异质性。

结果

本研究共纳入324 976名研究对象。工具变量SNPs数量为3~22，遗传预测因子效度检验的最小F值为14.6。IVW结果提示，共计9个经遗传学预测的肠道特定菌属与握力之间存在因果关联（P<0.05），其中Alloprevotella菌属（β=0.012 kg，95% CI：0.002，0.022）和Sellimonas菌属（β=0.014 kg，95% CI：0.006，0.022）相对丰度与握力水平呈现正向因果关联；Olsenella菌属（β=-0.012 kg，95% CI：-0.023，-0.001）和Paraprevotella菌属（β=-0.014 kg，95% CI：-0.023，-0.004）和握力水平呈现负向因果关联。并且，此4个肠道特定菌属与宿主握力之间的因果关联在不同MR敏感性分析方法中均存在统计学差异，提示结果稳定可靠，MR-PRESSO结果提示受水平多效性和异质性影响的可能较小。此外，本研究还发现，共计7个经遗传学预测的肠道特定菌属与骨骼肌质量之间存在因果关联（P<0.05），其中Eubacterium nodatum group菌属（β=0.069 kg，95% CI：0.012，0.125）与骨骼肌质量呈现正向因果关联；Erysipelatoclostridium菌属（β=-0.090 kg，95% CI：-0.162，-0.019）和Ruminococcaceae UCG011菌属（β=-0.104 kg，95% CI：-0.199，-0.010）与骨骼肌质量呈现负向因果关联。此3个肠道特定菌属与骨骼肌质量之间的因果关联在不同MR敏感性分析方法中均存在统计学差异，提示结果稳定可靠，MR-PRESSO结果提示受水平多效性和异质性影响的可能较小。

结论

本研究探讨了与肌少症可能存在因果关联的肠道特定菌属，其中Alloprevotella菌属、Sellimonas菌属和Eubacterium nodatum group菌属与肌少症表型指标存在潜在正向因果关联，Olsenella菌属、Paraprevotella菌属、Erysipelatoclostridium菌属和Ruminococcaceae UCG011菌属与肌少症表型指标存在潜在负向因果关联。这些发现为阐明肌少症发病机制、开发治疗新方法提供了理论参考。

关键词: 肠道菌群, 肌少症, 孟德尔随机化

Objective

This study aims to clarify the causal relationship between gut microbiota and phenotype indicators of sarcopenia, grip strength and skeletal muscle mass, based on Mendelian randomization (MR) study design.

Methods

According to the data derived from the British Biological Bank database and the published genome-wide association study with available data, the genetic variation of 131 specific intestinal bacteria was selected as the tool variable. The Single Nucleotide Polymorphism (SNP) selection criteria include being significantly associated with gut microbiota at the whole-genome level, mutually independent among SNPs, and having a sufficiently high instrumental variable strength. An instrumental variable is considered sufficiently strong when F>10. The inverse variance method (IVW) was used as the main analysis method, as well as the weighted median method and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) method were used as the sensitivity analysis methods, to evaluate the causal relationship among 131 gut microbiota species and grip strength and skeletal muscle mass. The MR-PRESSO method is used to test for horizontal pleiotropy and address heterogeneity.

Results

A total of 324, 976 subjects were included in this study. The number of SNPs ranges from 3 to 22, with a minimum F value of 14.6. The IVW results suggested a causal relationship between the 9 genetically predicted bacterial genera and host grip strength (P<0.05). Among them, Alloprevotella (β=0.012 kg, 95% CI: 0.002, 0.022) and Sellimonas (β=0.014 kg, 95% CI: 0.006, 0.022) showed a positive causal effect, while Olsenella (β=-0.012 kg, 95% CI: -0.023, 0.001) and Paraprevotella (β=-0.014 kg, 95% CI: -0.023, 0.004) showed negative causality. The causal associations between these four gut specific bacteria and host grip strength were statistically different in different MR sensitivity analyses, suggesting that the results were stable and reliable. In addition, a total of 7 genetically predicted gut specific bacterial genera had causal associations with host skeletal muscle mass (P<0.05), among which Eubacterium nodatum group (β=0.069 kg, 95% CI: 0.012, 0.125) showed a positive causal association with host skeletal muscle mass, while Erysipelatoclostridium (β=-0.090 kg, 95% CI: -0.162, 0.019) and Ruminococcaceae UCG011 (β=-0.104 kg, 95% CI: -0.199, 0.010) showed a negative causal association with host skeletal muscle mass. The causal associations between these three specific gut bacteria and host skeletal muscle mass were statistically different in different MR sensitivity analyses, suggesting that the results were stable and reliable. The results of MR-PRESSO suggest that the potential influence of horizontal pleiotropy and heterogeneity may be relatively small.

Conclusion

This study investigated specific gut microbiota have a causal relationship with host grip strength and skeletal muscle mass, such as Alloprevotella, Selemonas, and Eubacterium nodatum group, which have a positive causal relationship with phenotype indicators of sarcopenia, while Olsenella, Paraprevotella, Erysipelatoclostridium and Ruminococcaceae UCG011 have a negative causal relationship with phenotype indicators of sarcopenia, so as to provide theoretical references for elucidating the pathogenesis of sarcopenia and developing new treatment methods.

Key words: Gut microbiota, Sarcopenia, Mendelian randomization

图1 本研究的设计流程图

表1 招募时的研究对象体征

体征类别	数据
招募时的所有研究对象（例）	324 976
年龄（岁，±s）	56.4±8.1
体质指数（kg/m²，±s）	27.4±4.8
女性[例（%）]	174 139（53.6）
肌少症[例（%）]	561（0.2）
握力（kg，±s）	22.4±5.3
骨骼肌质量（kg，±s）	32.9±11.3

表1 招募时的研究对象体征

体征类别	数据
招募时的所有研究对象（例）	324 976
年龄（岁，±s）	56.4±8.1
体质指数（kg/m²，±s）	27.4±4.8
女性[例（%）]	174 139（53.6）
肌少症[例（%）]	561（0.2）
握力（kg，±s）	22.4±5.3
骨骼肌质量（kg，±s）	32.9±11.3

图2 经遗传学预测的肠道特定菌属与宿主握力之间提示因果关联的森林图

表2 使用IVW方法总结菌属与握力之间的因果关联

组别	肠道菌群	N（SNPs）	β（95% CI）	P值
菌属^*	Eubacterium nodatum group	11	0.010（0.002，0.017）	0.013
菌属^**	Alloprevotella	6	0.012（0.002，0.022）	0.020
菌属^*	Faecalibacterium	10	-0.025（-0.043，-0.006）	0.011
菌属^**	Olsenella	11	-0.012（-0.023，-0.001）	0.036
菌属^*	Parabacteroides	6	0.030（0.008，0.051）	0.006
菌属^**	Paraprevotella	13	-0.014（-0.023，-0.004）	0.007
菌属^*	Ruminococcaceae UCG005	14	0.017（0.001，0.032）	0.032
菌属^**	Sellimonas	9	0.014（0.006，0.022）	0.001
菌属^*	Tyzzerella3	12	0.157（0.010，0.305）	0.037

表2 使用IVW方法总结菌属与握力之间的因果关联

组别	肠道菌群	N（SNPs）	β（95% CI）	P值
菌属^*	Eubacterium nodatum group	11	0.010（0.002，0.017）	0.013
菌属^**	Alloprevotella	6	0.012（0.002，0.022）	0.020
菌属^*	Faecalibacterium	10	-0.025（-0.043，-0.006）	0.011
菌属^**	Olsenella	11	-0.012（-0.023，-0.001）	0.036
菌属^*	Parabacteroides	6	0.030（0.008，0.051）	0.006
菌属^**	Paraprevotella	13	-0.014（-0.023，-0.004）	0.007
菌属^*	Ruminococcaceae UCG005	14	0.017（0.001，0.032）	0.032
菌属^**	Sellimonas	9	0.014（0.006，0.022）	0.001
菌属^*	Tyzzerella3	12	0.157（0.010，0.305）	0.037

图3~6 菌属对握力因果影响的留一法分析森林图。图3 Alloprevotella菌属；图4 Sellimonas菌属；图5 Olsenella菌属；图6 Olsenella菌属

图7 经遗传学预测的肠道特定菌属与宿主骨骼肌质量之间提示因果关联的森林图

表3 利用IVW方法总结菌属与骨骼肌质量之间的因果关联

组别	肠道菌群	N（SNPs）	β（95% CI）	P
菌属^*	Eubacterium fissicatena group	9	-0.055（-0.104，-0.007）	0.025
菌属^**	Eubacterium nodatum group	11	0.069（0.012，0.125）	0.017
菌属^*	Coprobacter	11	0.078（0.023，0.133）	0.006
菌属^**	Erysipelatoclostridium	15	-0.090（-0.162，-0.019）	0.013
菌属^*	Odoribacter	7	0.124（0.019，0.229）	0.021
菌属^**	Ruminococcaceae UCG011	8	-0.104（-0.199，-0.010）	0.030
菌属^*	unknowngenus.id.826	14	-0.073（-0.145，-0.001）	0.047

表3 利用IVW方法总结菌属与骨骼肌质量之间的因果关联

组别	肠道菌群	N（SNPs）	β（95% CI）	P
菌属^*	Eubacterium fissicatena group	9	-0.055（-0.104，-0.007）	0.025
菌属^**	Eubacterium nodatum group	11	0.069（0.012，0.125）	0.017
菌属^*	Coprobacter	11	0.078（0.023，0.133）	0.006
菌属^**	Erysipelatoclostridium	15	-0.090（-0.162，-0.019）	0.013
菌属^*	Odoribacter	7	0.124（0.019，0.229）	0.021
菌属^**	Ruminococcaceae UCG011	8	-0.104（-0.199，-0.010）	0.030
菌属^*	unknowngenus.id.826	14	-0.073（-0.145，-0.001）	0.047

图8~10 菌属对握力因果影响的留一法分析森林图。图8 Eubacterium nodatum group菌属；图9 Erysipelatoclostridium菌属；图10 Ruminococcaceae UCG011菌属

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Causal associations of gut Microbiota with phenotype indicators of sarcopenia: A mendelian randomization study

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Causal associations of gut Microbiota with phenotype indicators of sarcopenia: A mendelian randomization study