Relationship between intervertebral disc degeneration and 473 gut microbiotas: what can be learned from big data information in the FinnGen database

doi:10.12307/2025.689

Abstract

Abstract: BACKGROUND: Some research has suggested that regulation of gut microbiota may influence the course of intervertebral disc degeneration. However, the causal relationship of gut microbiota on intervertebral disc degeneration is unknown.
OBJECTIVE: To assess the potential causal relationship between gut microbiota and intervertebral disc degeneration using a Mendelian randomization method.
METHODS: Genome-wide association analysis summary statistics for 473 gut microbiota and genome-wide association analysis summary data for intervertebral disc degeneration from the R11 of the FinnGen database (46 205 cases of intervertebral disc degeneration and 322 314 controls) from the most recent publicly available publication were applied. Inverse variance weighting, MR-Egger regression, weighted median, weighted modeling, and simple modeling were used to investigate the causal relationship between gut microbiota and intervertebral disc degeneration. Sensitivity analyses were used to test whether the results of Mendelian randomization analyses were reliable. Reverse Mendelian randomization was performed with all gut microbiota as the outcomes for effect analysis and sensitivity analysis.
RESULTS AND CONCLUSION: (1) The results of the inverse variance weighting method of the forward Mendelian randomization method showed that the order Trichosporonaceae, the family UBA-6960, the family Anaerobes thermophilus, the family Salmonellaceae, the genus Pseudomonas tufts, the species Gordonella and the species Euclidia showed a positive correlation with intervertebral disc degeneration. The order Spirochaetes, the order Pseudomonas, the family Spirochaetaceae, the genus CAG-776, the genus Helicobacter, the species CAG-448 sp003150135, the species CAG-776 sp000438195, the species Brautella -A sp000285855 and the species Hanson’s Brautella showed a negative correlation with intervertebral disc degeneration. (2) The results of reverse Mendelian randomization showed that intervertebral disc degeneration was positively correlated with the genus Bartonella rosea, the genus Geobacillus C, the species Escherichia fumigatus, the species Propionibacterium fumigatus, the species UBA-1777 sp900319835, the species Pseudomonas aeruginosa and the species Bacillus subtilis, while negatively correlated with the species Streptomyces mingoldii, the species Prevotella sp000434975, the species Brault’s A sp000285855, the species CAG-194 sp002441865 and the species CAG-590 sp000431135. (3) No heterogeneity or horizontal pleiotropy was found in the two-way sensitivity analysis. (4) The results described above indicate that the causal relationship between gut microbiota and intervertebral disc degeneration based on the Finnish database contributes to the exploration on new biomarkers for the early prediction and treatment of intervertebral disc degeneration in clinical practice. In addition, the establishment of a large database and the integration of medical data from multiple centers can be drawn upon in biomedical research in China to provide a solid foundation for studying the relationship between gut microbiota and intervertebral disc degeneration. We will strengthen communication and cooperation with research teams in other countries to jointly promote the research on the relationship between gut microbiota and diseases and contribute to the development of global medicine.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Mendelian randomization, intervertebral disc degeneration, gut microbiota, genome-wide association analysis, single nucleotide polymorphisms, inverse variance weighting method, horizontal pleiotropy, sensitivity analysis

CLC Number:

Wang Zikun, Li Shudong, Gao Shuang, Fan Shuhao, Li Cheng, Meng Chunyang. Relationship between intervertebral disc degeneration and 473 gut microbiotas: what can be learned from big data information in the FinnGen database[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(20): 4369-4378.

Figures/Tables 8

2.1 肠道菌群对椎间盘退变的因果关系文章基于工具变量的筛选标准，全基因组统计学显著阈值P < 1×10-5 ；以逆方差加权法作为主要参考依据，以P < 0.05为标准，对473个肠道菌群进行孟德尔随机化分析。所纳入单一单核苷酸多态性的 F 统计量均大于10，说明所有单核苷酸多态性均为强工具变量。在正向孟德尔随机化分析过程中，共筛选出41种肠道菌群与椎间盘退变存在因果关系，包含776个单核苷酸多态性。其中18个单核苷酸多态性与CAG-448种sp003150135相关，19个单核苷酸多态性与汉逊布劳氏菌种相关，15个单核苷酸多态性与毛螺菌属相关，21个单核苷酸多态性与CAG-776属相关，18个单核苷酸多态性与戈登氏菌属相关，14个单核苷酸多态性与欧陆森氏菌属-C相关，18个单核苷酸多态性与盐单胞菌科相关，25个单核苷酸多态性与短螺旋菌科相关，18个单核苷酸多态性丛毛单胞菌属相关，16个单核苷酸多态性与UBA-6960科相关，25个单核苷酸多态性与短螺旋菌目相关，12个单核苷酸多态性与嗜热厌氧杆菌科相关，21个单核苷酸多态性与CAG-776种sp000438195相关，13个单核苷酸多态性与布劳特氏菌种-A sp000285855相关，18个单核苷酸多态性与螺杆菌属相关，18个单核苷酸多态性与CAG-448属相关，21个单核苷酸多态性与堆囊菌属相关，12个单核苷酸多态性与卡氏双歧杆菌种相关，11个单核苷酸多态性与嗜氢菌属相关，18个单核苷酸多态性与UBA-3792属相关，23个单核苷酸多态性与大肠杆菌属相关，19个单核苷酸多态性与真杆菌种-F sp000434115相关，18个单核苷酸多态性与多形粪球菌种相关，22个单核苷酸多态性与奇异菌科相关，19个单核苷酸多态性与CAG-433科相关，19个单核苷酸多态性与梭杆菌属-A相关，21个单核苷酸多态性与CAG-1000种sp000434555相关，16个单核苷酸多态性与经黏液真杆菌种sp001304935相关，13个单核苷酸多态性与UBA-11963属相关，14个单核苷酸多态性与发光杆菌属相关，22个单核苷酸多态性与蓝细菌门相关，21个单核苷酸多态性与金黄色葡萄球菌种相关，22个单核苷酸多态性与大肠杆菌属相关，17个单核苷酸多态性与RUG-420种sp900317985相关，28个单核苷酸多态性与鲸杆菌属-A相关，23个单核苷酸多态性与独岛杆菌属相关，26个单核苷酸多态性与劳森氏菌种sp900066645相关，30个单核苷酸多态性与CAG-632属相关，18个单核苷酸多态性与CAG-488种sp000434055相关，13个单核苷酸多态性与费氏弧菌属相关。其中通过水平多效性和异质性检验，发现独岛杆菌属与劳森氏菌种sp900066645具有显著性(P < 0.05)，说明这两种肠道菌群不仅与暴露因素有关，还与其他潜在的混杂因素有关，故排除这两种肠道菌群的影响。综上，文章中展示与椎间盘退变具有显著因果关系的16种肠道菌群的孟德尔随机化分析结果，见表1。逆方差加权法分析的结果显示，毛螺菌目(OR=1.225，95%CI：1.070-1.403，P=0.003)，UBA-6960科(OR=1.228，95%CI：1.053-1.431，P=0.009)，嗜热厌氧杆菌科(OR=1.189，95%CI：1.041-1.357，P=0.011)，盐单胞菌科(OR=1.434，95%CI：1.115-1.843，P=0.005)，丛毛单菌属(OR=1.233，95%CI：1.055-1.441，P=0.008)，戈登氏菌属(OR=1.118，95%CI：1.036-1.205，P=0.004)，欧陆森氏菌属(OR=1.154，95%CI：1.047-1.272，P=0.004)，与椎间盘退变呈现正相关。短螺旋菌目(OR= 0.902，95%CI：0.834-0.974，P=0.009)，假单胞菌目(OR=0.646，95%CI：0.486-0.857，P=0.002)，短螺旋菌科(OR=0.885，95%CI：0.813-0.964，P= 0.005)，CAG-776属(OR=0.921，95%CI：0.871-0.973，P=0.004)，螺杆菌属(OR=0.825，95%CI：0.709-0.959，P=0.012)，CAG-448种sp003150135 (OR=0.929，95%CI：0.888-0.971，P=0.001)，CAG-776种sp000438195 (OR=0.927，95%CI：0.874-0.983，P=0.011)，布劳特氏菌种-A sp000285855(OR=0.860，95%CI：0.765-0.967，P=0.012)，汉逊布劳氏菌种(OR=0.891，95%CI：0.824-0.962，P=0.003)，与椎间盘退变呈现负相关，见图2。根据异质性检验和水平多效性检验结果，通过Cochran’s Q检验结果表明，所选工具变量之间没有明显的异质性，MR-Egger截距检验结果表明，所选工具变量之间没有明显的水平多效性，P 值均大于0.05。由此证明，此孟德尔随机化分析结果不存在异质性和水平多效性，见表2。留一法检验结果显示不存在单个单核苷酸多态性对因果关系估计值产生较大影响，因此证明，此孟德尔随机化分析结果较为稳定，见图3。 2.2 椎间盘退变对肠道菌群的因果关系通过对椎间盘退变与473种肠道菌群进行反向孟德尔随机化分析，共检测到12种肠道菌群与椎间盘退变间存在反向因果关系，见表3，分析结果显示，椎间盘退变与玫瑰巴氏菌属、地电细菌属 C、弗氏埃希菌种、弗氏丙酸杆菌种、UBA-1777种sp900319835、铜绿假单胞菌种和韦氏芽孢杆菌种呈正相关，与明串珠菌属、普雷沃氏菌种sp000434975、布劳特氏菌种-A sp000285855、CAG-194种sp002441865和CAG-590种sp000431135呈负相关，见图4。反向孟德尔随机化结果敏感性分析结果显示，均未发现存在异质性或水平多效性。"

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