Genetic causal relationship between gut microbiota and osteoporosis: analysis of 211 gut microbiota from the UK database

doi:10.12307/2025.679

Abstract

Abstract: BACKGROUND: Osteoporosis is defined as a chronic metabolic bone disease, and a large amount of evidence has shown that gut microbiota is involved in osteoporosis. However, the causal relationship between gut microbiota and osteoporosis is yet unclear.
OBJECTIVE: To evaluate the potential causal relationship between gut microbiota and osteoporosis using the two-sample Mendelian randomization.

METHODS: Pooled statistics from the MiBioGen Consortium’s Genome-Wide Association Analysis (GWAS) of gut microbiota and GWAS data from the UK Biometric Sample database for osteoporosis were used. Inverse variance weighting (IVW), MR-Egger regression, weighted median, weighted model and simple model were used to study the causal relationship between gut microbiota and osteoporosis. Sensitivity analysis was used to test whether the results of Mendelian randomization are reliable.
RESULTS AND CONCLUSION: The inverse variance weighted method showed that there was a causal relationship between gut microbiota and osteoporosis. Among them, the R7 genus of Christensenaceae (MR Egger: β=-0.007; IVW: β=-0.004, P=0.028), Coprococus 3 (MR Egger: β=-0.008; IVW: β=-0.003, P=0.046) and Trichospirillum (MR Egger: β=-0.009; IVW: β=-0.004, P=0.003) may be protective factors for osteoporosis, while Hotella (MR Egger: β=0.006; IVW: β=0.002, P=0.033) and Eubacterium oxyoxide (MR Egger: β=0.001; IVW: β=0.003, P=0.046) may be potential risk factors for osteoporosis. Eubacterium oxyoxide and Hotella can increase the risk of osteoporosis, while R7 of Christensenaceae, Coprococcus 3 and Spirillum can reduce the risk of osteoporosis. Whether this conclusion also applies to non-European populations will need to be verified in the future by large clinical trials in different groups.

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, osteoporosis, gut microbiota, single nucleotide polymorphism, causal relationship, genome-wide association analysis, inverse variance weighting method, sensitivity analysis

CLC Number:

Fang Zhijie, Ma Qiangping, Dong Wantao, Wu Junyuan, Lu Yunlin. Genetic causal relationship between gut microbiota and osteoporosis: analysis of 211 gut microbiota from the UK database[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(18): 3941-3947.

Figures/Tables 5

基于IVW的OR，霍氏菌属(OR=1.002，95%CI：1.000-1.003，P=0.033)和氧化真杆菌属(OR=1.003，95%CI：1.000-1.005，P=0.046)2个菌类所得到的OR值均> 1，表明暴露是结局的危险因素。克里斯滕森菌科R7属(OR=0.996，95%CI：0.993-0.996，P=0.028)、粪球菌3属(OR=0.997，95%CI：0.994-0.999，P=0.046)和毛螺菌属(OR=0.996，95%CI：0.994-0.999，P=0.003)3个菌类所得到的OR值均< 1，表明暴露是结局的保护因素。以上5种菌类通过IVW得到的P值均< 0.05，表明暴露与结局存在因果关联。此外，留一法敏感性分析结果稳定，MR-Egger截距测试和MR-PRESSO全局检验无水平多效性，Cochran Q检验不存在异质性。 2.2 敏感性分析结果在敏感性分析中，通过Cochran’s Q检验和MR Egger回归分析发现，文章中涉及的菌类P值均超过0.05的阈值，这说明所选工具变量SNPs之间未发现显著的异质性；使用MR-Egger截距测试和MR-PRESSO全局检验两种方法对工具变量进行水平多效性检验，结果显示：所纳入菌类P值均> 0.05，提示暴露因素的工具变量不存在水平多效性，见表2。留一法结果显示在逐一剔除SNP后，结果并没有发生改变，未见明显离群值，表明所得结果并非由单个SNP所导致，这些分析在一定程度上证明了文章结果的稳健性和可靠性，见图3。 2.3 反向孟德尔随机化结果通过对骨质疏松症及196个肠道菌群进行反向孟德尔随机化分析，共得到了5个肠道菌群与骨质疏松症之间存在反向因果关系，敏感性分析显示，反向孟德尔随机化分析不存在异质性和水平多效性，见表3。反向孟德尔随机化分析结果显示，骨质疏松症与瘤胃球菌属1及啮齿真杆菌属呈负相关，与拟杆菌科S24-7、瘤胃球菌属及消化球菌属呈正相关，见图4。"

References

[1] ARCEO-MENDOZA RM, CAMACHO PM. Postmenopausal osteoporosis: latest guidelines. Endocrinol Metab Clin North Am. 2021;50(2):167-178.
[2] ZHIVODERNIKOV IV, KIRICHENKO TV, MARKINA YV, et al. Molecular and cellular mechanisms of osteoporosis. Int J Mol Sci. 2023;24(21):15772.
[3] 中华医学会骨质疏松和骨矿盐疾病分会,章振林.原发性骨质疏松症诊疗指南(2022)[J]. 中国全科医学,2023,26(14): 1671-1691.
[4] DING K, HUA F, DING W. Gut microbiome and osteoporosis. Aging Dis. 2020;11(2): 438-447.
[5] LI S, MAO Y, ZHOU F, et al. Gut microbiome and osteoporosis: a review. Bone Joint Res. 2020;9(8):524-530.
[6] CASTANEDA M, STRONG JM, ALABI DA, et al. The Gut microbiome and bone strength. Curr Osteoporos Rep. 2020;18(6): 677-683.
[7] XU Z, XIE Z, SUN J, et al. Gut microbiome reveals specific dysbiosis in primary osteoporosis. Front Cell Infect Microbiol. 2020;10:160.
[8] XU J, ZHANG S, TIAN Y, et al. Genetic causal association between iron status and osteoarthritis: a two-sample mendelian randomization. Nutrients. 2022; 14(18):3683.
[9] FERENCE BA, HOLMES MV, SMITH GD. Using mendelian randomization to improve the design of randomized trials. Cold Spring Harb Perspect Med. 2021;11(7):a040980.
[10] KURILSHIKOV A, MEDINA-GOMEZ C, BACIGALUPE R, et al. Large scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet. 2021;53(2):156-165.
[11] LYON MS, ANDREWS SJ, ELSWORTH B, et al. The variant call format provides efficient and robust storage of GWAS summary statistics. Genome Biol. 2021;22(1):32.
[12] DAVIES NM, HOLMES MV, DAVEY SMITH G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.
[13] 梁家浩,杨舒龄,王海.基于孟德尔随机化探讨肠道菌群与儿童哮喘的因果关联[J].华西医学,2024,39(4):553-560.
[14] LI P, WANG H, GUO L, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med. 2022;20(1): 443.
[15] CAO Y, LU H, XU W, et al. Gut microbiota and Sjögren’s syndrome: a two-sample Mendelian randomization study. Front Immunol. 2023;14:1187906.
[16] PIERCE BL, AHSAN H, VANDERWEELE TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40(3):740-752.
[17] HARTWIG FP,DAVIES NM,HEMANI G, et al. Two-sample Mendelian randomization: avoiding the downsides of a powerful,widely applicable but potentially fallible technique. Int J Epidemiol. 2016;45(6):1717-1726.
[18] YUAN S, CHEN J, RUAN X, et al. Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis. Elife. 2023;12:e84051.
[19] BURGESS S, THOMPSON SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377-389.
[20] BOWDEN J, DAVEY SMITH G, HAYCOCK PC, et al. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4): 304-314.
[21] 马玮玮,陈虹谷,李彤彤,等.基于孟德尔随机化分析肠道菌群与骨密度的因果关系[J].中国骨质疏松杂志,2023,29(12): 1780-1785.
[22] LARSSON SC, BUTTERWORTH AS, BURGESS S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J. 2023;44(47): 4913-4924.
[23] YANG M, WAN X, ZHENG H, et al. No evidence of a genetic causal relationship between ankylosing spondylitis and gut microbiota: a two-sample mendelian randomization study. Nutrients. 2023; 15(4):1057.
[24] KANG L, LI P, WANG D, et al. Alterations in intestinal microbiota diversity, composition, and function in patients with sarcopenia.Sci Rep. 2021;11(1):4628.
[25] DAS M, CRONIN O, KEOHANE DM, et al. Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatology(Oxford). 2019;58(12):2295-2304.
[26] COSTEA PI, HILDEBRAND F, ARUMUGAM M. Enterotypes in the landscape of gut microbial community composition. Nat Microbiol. 2018;3(1):8-16.
[27] RAFII F. The role of colonic bacteria in the metabolism of the natural isoflavone daidzin to equol. Metabolites. 2015;5(1):56-73.
[28] 何姣姣,陈玉林,张敏,等.肠道菌群在骨质疏松症发病机制中的研究[J].中国骨质疏松杂志,2023,29(8):1197-1202.
[29] SEELY KD, KOTELKO CA, DOUGLAS H, et al. The human Gut microbiota: a key mediator of osteoporosis and osteogenesis. Int J Mol Sci. 2021;22(17):9452.
[30] XU Q, LI D, CHEN J, et al. Crosstalk between the gut microbiota and postmenopausal osteoporosis: mechanisms and applications. Int Immunopharmacol. 2022;110:108998.
[31] HE J, XU S, ZHANG B, et al. Gut microbiota and metabolite alterations associated with reduced bone mineral density or bone metabolic indexes in postmenopausal osteoporosis. Aging. 2020;12(9):8583-8604.
[32] GUAN Z, LUO L, LIU S, et al. The role of depletion of gut microbiota in osteoporosis and osteoarthritis: a narrative review. Front Endocrinol (Lausanne). 2022;13:847401.
[33] WALDBAUM JDH, XHUMARI J, AKINSUYI OS, et al. Association between dysbiosis in the gut microbiota of primary osteoporosis patients and bone loss. Aging Dis. 2023; 14(6):2081-2095.
[34] WANG N, MA S, FU L. Gut microbiota dysbiosis as one cause of osteoporosis by impairing intestinal barrier function. Calcif Tissue Int. 2022;110(2):225-235.
[35] LOCANTORE P, DEL GATTO V, GELLI S, et al. The interplay between immune system and microbiota in osteoporosis. Mediators Inflamm. 2020;2020:3686749.
[36] YAN J, CHARLES JF. Gut microbiome and bone: to build, destroy, or both? Curr Osteoporos Rep. 2017;15(4):376-384.
[37] D’AMELIO P, SASSI F. Gut microbiota, immune system, and bone. Calcif Tissue Int. 2018;102(4):415-425.
[38] GUO M, LIU H, YU Y, et al. Lactobacillus rhamnosus GG ameliorates osteoporosis in ovariectomized rats by regulating the Th17/Treg balance and gut microbiota structure. Gut Microbes. 2023;15(1):2190304.
[39] ZHAO F, GUO Z, KWOK LY, et al. Bifidobacterium lactis Probio-M8 improves bone metabolism in patients with postmenopausal osteoporosis, possibly by modulating the gut microbiota. Eur J Nutr. 2023;62(2):965-976.
[40] JIANG X, QI X, XIE C. Lactobacillus plantarum LP45 inhibits the RANKL/OPG signaling pathway and prevents glucocorticoid-induced osteoporosis. Food Nutr Res. 2023. doi: 10.29219/fnr.v67.9064