遗传预测的肠道菌群、肠道菌群衍生代谢物水平与衰弱因果关联性研究

doi:10.12183/j.scjpm.2025.0701

摘要/Abstract

摘要： 目的运用孟德尔随机化（Mendelian randomization,MR）方法,深入探究肠道菌群及其衍生代谢物与衰弱之间的因果关联。方法采用逆方差加权法（inverse variance weighted,IVW）和4种基于不同假设的MR方法,利用全基因组关联研究（Gene-Wide Association Study,GWAS）汇总数据,评估207种肠道菌群及126种衍生代谢物与衰弱之间的因果关系。采用Cochran's Q检验、MR-Egger回归法、MR-PRESSO法、MR-Steiger法以及留一法敏感性分析验证结果的可靠性。结果肠道菌群的IVW结果显示,包括疣微菌门（OR=0.980）、伯克氏菌目（OR=0.970）、阿克曼菌属（OR=0.980）、嗜黏蛋白阿克曼菌种（OR=0.979）、德氏乳杆菌种（OR=0.988）、文氏真杆菌种（OR=0.978）和双形真杆菌种（OR=0.980）、解黄酮菌属（OR=1.022）、萨特氏菌属（OR=1.044）、华德萨特菌种（OR=1.044）和拟杆菌属Bacteroides massiliensis菌种（OR=1.031）等11个肠道菌群与衰弱之间存在潜在因果关联;肠道菌群衍生代谢物的MR结果显示,包括缬氨酸（OR=2.042）、犬尿氨酸（OR=1.149）、硬脂酰肉碱（OR=1.194）、油酰肉碱（OR=1.161）、可可碱（OR=0.892）和苏氨酸盐（OR=0.922）等6个肠道菌群衍生代谢物与衰弱之间存在潜在因果关系（均P_FDR>0.05）。结论肠道菌群及其衍生代谢物与衰弱风险之间存在潜在因果关系,表明其在衰弱发病机制中存在一定的作用。

关键词: 肠道菌群, 肠道菌群衍生代谢物, 衰弱, 孟德尔随机化, 潜在因果关联

Abstract: Objective To explore in depth the causal associations between gut flora, derived metabolites and frailty using Mendelian randomization studies. Methods Inverse variance weighted (IVW) and four MR methods based on different assumptions were used to assess the causal relationship between 207 gut flora and 126 derived metabolites and frailty using pooled data from the Gene-Wide Association Study (GWAS). Cochran's Q test, MR-Egger regression, MR-PRESSO, MR-Steiger and leave-one-out sensitivity analyses were used to verify the reliability of the results. Results IVW results of gut flora showed potential causal associations between 11 species of gut flora, including Verrucomicrobia (OR=0.980), Burkholderiales (OR=0.970), Akkermansia (OR=0.980), Akkermansia muciniphila(OR=0.979), Lactobacillus delbrueckii (OR=0.988), Eubacterium ventriosum (OR=0.978), Eubacterium biforme (OR=0.980), Flavonifractor (OR=1.022), Sutterella (OR=1.044), Sutterella wadsworthensis (OR=1.044), Bacteroides massiliensis (OR=1.031) with frailty. And MR results of gut flora-derived metabolites showed potential causal associations between six gut flora-derived metabolites, including valine (OR=2.042), kynurenine (OR=1.149), stearoylcarnitine (OR=1.194), oleoylcarnitine (OR=1.161), theobromine (OR=0.892), threonate (OR=0.922) with frailty. Conclusions A potential causal association between gut microbes and their derived metabolites and risk of frailty suggests a role in the pathogenesis of frailty.

Key words: Gut microbiota, Gut microbiota-derived metabolites, Frailty, Mendelian randomization, Potential causal relationship

中图分类号:

R394.2

开地日艳•库日班江, 陈亚琳, 晏师康, 石芳, 王杰, 阿卜杜乃比·吾普尔, 彭星, 李逸晗, 杨蕾. 遗传预测的肠道菌群、肠道菌群衍生代谢物水平与衰弱因果关联性研究[J]. 华南预防医学, 2025, 51(7): 701-708.

KURIBANJIANG Kaidiriyan, CHEN Yalin, YAN Shikang, SHI Fang, WANG Jie, WUPUER Abudunaibi, PENG Xing, LI Yihan, YANG Lei. Investigating causal associations between genetically predicted gut microbiota, gut microbiota-derived metabolites and frailty: A mendelian randomization study[J]. South China Journal of Preventive Medicine, 2025, 51(7): 701-708.

参考文献

[1] Zeng XZ, Meng LB, Jia N, et al.Epidemiological status and associated factors of frailty and pre-frailty in older adults with asthma in China: A national cross-sectional study[J]. Front Public Health, 2023, 11: 1136135.
[2] Zeng XZ, Meng LB, Jia N, et al.Prevalence of frailty and pre-frailty and related factors in older adults with cardio-cerebral vascular disease in China: A national cross-sectional study[J]. Front Public Health, 2023, 11: 1168792.
[3] Wang X, Wu M.Research progress of gut microbiota and frailty syndrome[J]. Open Med, 2021, 16(1): 1525-1536.
[4] Hoogendijk EO, Afilalo J, Ensrud KE, et al.Frailty: Implications for clinical practice and public health[J]. Lancet, 2019, 394(10206): 1365-1375.
[5] Jin HY, Liu X, Xue QL, et al.The association between frailty and healthcare expenditure among Chinese older adults[J]. J Am Med Dir Assoc, 2020, 21(6): 780-785.
[6] Han L, Clegg A, Doran T, et al.The impact of frailty on healthcare resource use: A longitudinal analysis using the Clinical Practice Research Datalink in England[J]. Age Ageing, 2019, 48(5): 662-668.
[7] 方志杰,马抢平,董万涛,等. 肠道菌群与骨质疏松症的遗传关系:来自英国数据库211个肠道微生物群分析[J]. 中国组织工程研究,2025,29(18):3941-3947.
[8] Xu Y, Liu X, Liu X, et al.The roles of the gut microbiota and chronic low-grade inflammation in older adults with frailty[J]. Front Cell Infect Microbiol, 2021, 11: 675414.
[9] 许玉双. 衰弱相关菌群失调对肠道屏障功能的作用和机制探讨[D]. 武汉:华中科技大学,2022.
[10] Ticinesi A, Nouvenne A, Cerundolo N, et al.Gut microbiota, muscle mass and function in aging: A focus on physical frailty and sarcopenia[J]. Nutrients, 2019, 11(7): 1633.
[11] Guo Y, Zhu G, Wang F, et al.Distinct serum and fecal metabolite profiles linking with gut microbiome in older adults with frailty[J]. Front Med, 2022, 9: 827174.
[12] Davies NM, Holmes MV, Smith GD.Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362: k601.
[13] Sekula P, Del Greco FM, Pattaro C, et al.Mendelian randomization as an approach to assess causality using observational data[J]. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
[14] Lopera-Maya EA, Kurilshikov A, van der Graaf A, et al. Effect of host genetics on the gut microbiome in 7, 738 participants of the Dutch Microbiome Project[J]. Nat Genet, 2022, 54(2): 143-151.
[15] Shin SY, Fauman EB, Petersen AK, et al.An atlas of genetic influences on human blood metabolites[J]. Nat Genet, 2014, 46(6): 543-550.
[16] Atkins JL, Jylhava J, Pedersen NL, et al.A genome-wide association study of the frailty index highlights brain pathways in ageing[J]. Aging Cell, 2021, 20(9): e13459.
[17] Broadbent JR, Foley CN, Grant AJ, et al.Mendelianrandomization v0.5.0: Updates to an R package for performing Mendelian randomization analyses using summarized data[J]. Wellcome Open Res, 2020, 5: 252.
[18] Kamat MA, Blackshaw JA, Young R, et al.Phenoscanner v2: An expanded tool for searching human genotype-phenotype associations[J]. Bioinformatics, 2019, 35(22): 4851-4853.
[19] 艾楠,王馨晨,刘星宇,等. 抑郁症与非酒精性脂肪性肝病因果关系的双向孟德尔随机化研究[J]. 山西医科大学学报,2024,55(9):1163-1169.
[20] Xu H, Wu Z, Feng F, et al.Low vitamin D concentrations and BMI are causal factors for primary biliary cholangitis: A Mendelian randomization study[J]. Front Immunol, 2022, 13: 1055953.
[21] Tin A, Koettgen A.Mendelian randomization analysis as a tool to gain insights into causes of diseases: A primer[J]. J Am Soc Nephrol, 2021, 32(10): 2400-2407.
[22] Gao Y, Fan ZR, Shi FY.Hypothyroidism and rheumatoid arthritis: A two-sample Mendelian randomization study[J]. Front Endocrinol, 2023, 14: 1179656.
[23] Xu Y, Wang Y, Li H, et al.Altered fecal microbiota composition in older adults with frailty[J]. Front Cell Infect Microbiol, 2021, 11: 696186.
[24] Zhao L, Deng X, Ding N, et al.Diminished representation of vitamin-B12-producing bacteria in constipated elders with frailty[J]. iScience, 2024, 27(8): 110403.
[25] Derrien M, Belzer C, De Vos WM.Akkermansia muciniphila and its role in regulating host functions[J]. Microb Pathog, 2017, 106: 171-181.
[26] 曾炜,管张烁,沈大鹏,等. 老年衰弱发病机制的研究进展[J]. 现代医药卫生,2024,40(16):2855-2858,2872.
[27] Picca A, Ponziani FR, Calvani R, et al.Gut microbial, inflammatory and metabolic signatures in older people with physical frailty and sarcopenia: Results from the Biosphere Study[J]. Nutrients, 2020, 12(1): 65.
[28] Kang L, Li P, Wang D, et al.Alterations in intestinal microbiota diversity, composition, and function in patients with sarcopenia[J]. Sci Rep, 2021, 11(1): 4628.
[29] Walsh ME, Bhattacharya A, Sataranatarajan K, et al.The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging[J]. Aging Cell, 2015, 14(6): 957-970.
[30] Aliwa B, Horvath A, Traub J, et al.Altered gut microbiome, bile acid composition and metabolome in sarcopenia in liver cirrhosis[J]. J Cachexia Sarcopenia Muscle, 2023, 14(6): 2676-2691.
[31] 唐鑫钰,黄贤涛,马曌,等. 老年衰弱与肌少症[J]. 海南医学,2023,34(15):2272-2276.
[32] Tian G, Wang W, Xia E, et al.Dendrobium officinale alleviates high-fat diet-induced nonalcoholic steatohepatitis by modulating gut microbiota[J]. Front Cell Infect Microbiol, 2023, 13: 1078447.
[33] Erridge C, Pridmore A, Eley A, et al.Lipopolysaccharides of Bacteroides fragilis, Chlamydia trachomatis and Pseudomonas aeruginosa signal via Toll-like receptor 2[J]. J Med Microbiol, 2004, 53(Pt 8): 735-740.
[34] Fan KC, Lin CC, Liu YC, et al.Altered gut microbiota in older adults with mild cognitive impairment: A case-control study[J]. Front Aging Neurosci, 2023, 15: 1162057.
[35] Hatayama K, Ebara A, Okuma K, et al.Characteristics of intestinal microbiota in Japanese patients with mild cognitive impairment and a risk-estimating method for the disorder[J]. Biomedicines, 2023, 11(7): 1789.
[36] 郑静,陈申,崔焱. 机构老年人衰弱与轻度认知障碍的相关性研究[J]. 实用老年医学,2019,33(2):206-208.
[37] Jang IY, Park JH, Kim JH, et al.The association of circulating kynurenine, a tryptophan metabolite, with frailty in older adults[J]. Aging (Albany NY), 2020, 12(21): 22253-22265.
[38] Kaiser H, Yu K, Pandya C, et al.Kynurenine, a tryptophan metabolite that increases with age, induces muscle atrophy and lipid peroxidation[J]. Oxid Med Cell Longev, 2019, 2019: 9894238.
[39] Sas K, Szabó E, Vécsei L.Mitochondria, oxidative stress and the kynurenine system, with a focus on ageing and neuroprotection[J]. Molecules, 2018, 23(1): 191.
[40] Lustgarten MS, Fielding RA.Metabolites associated with circulating interleukin-6 in older adults[J]. J Gerontol A Biol Sci Med Sci, 2017, 72(9): 1277-1283.
[41] Taetzsch T, Valdez G.NMJ maintenance and repair in aging[J]. Curr Opin Physiol, 2018, 4: 57-64.
[42] 杨锦竹,何凌骁,方亚. 老年衰弱生物标志物研究进展[J]. 中国公共卫生,2023,39(8):1073-1077.
[43] 白丹丹,肖卫华. 支链氨基酸及代谢中间产物对胰岛素抵抗的调控及其机制[J]. 生理学报,2023,75(2):291-302.
[44] Liu H, Zhang Q, Hao Q, et al.Associations between sarcopenia and circulating branched-chain amino acids: A cross-sectional study over 100,000 participants[J]. BMC Geriatr, 2024, 24(1): 541.
[45] Chen S, Dong Y, Aiheti N, et al. Metabolome-wide Mendelian randomization assessing the causal relationship between blood metabolites and sarcopenia-related traits[J]. J Gerontol A Biol Sci Med Sci, 2024, 79(4): glae051.
[46] Yang W, Jiang W, Guo S.Regulation of macronutrients in insulin resistance and glucose homeostasis during type 2 diabetes mellitus[J]. Nutrients, 2023, 15(21): 4671.
[47] 杨伟,王洁妤. 老年糖尿病患者合并肌肉减少症发病机制及治疗研究进展[J]. 疑难病杂志,2024,23(9):1131-1135.
[48] Erukainure OL, Oyebode OA, Chuturgoon AA, et al.Potential molecular mechanisms underlying the ameliorative effect of Cola nitida (Vent.) Schott & Endl. on insulin resistance in rat skeletal muscles[J]. J Ethnopharmacol, 2024, 319: 117249.
[49] Bhat JA, Kumar M.Neuroprotective effects of theobromine in permanent bilateral common carotid artery occlusion rat model of cerebral hypoperfusion[J]. Metab Brain Dis, 2022, 37(6): 1787-1801.