Association between gut microbiota and polycystic ovary syndrome: a Mendelian randomization study
CHEN Ying1, LIU Ke1, LIU Bin1, SUN Xiaohui1, HE Zhixing2, MAO Yingying1, YE Ding1
1. School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; 2. Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
Abstract:Objective To investigate the causal relationship between gut microbiota and polycystic ovary syndrome (PCOS) using a Mendelian randomization (MR) study, so as to provide insights into the pathogenesis of PCOS and the formulation of prevention and treatment strategies. Methods The genetic data on gut microbiota was derived from a meta-analysis of genome-wide association studies (GWAS) involving 18 340 participants. The genetic data on PCOS was sourced from two GWAS meta-analyses in European populations, serving as the discovery set and the validation set, respectively. A two-sample MR analysis was conducted using the discovery set, with the inverse variance weighted (IVW) method as the primary approach. Sensitivity analyses employed the weighted median method, MR-Egger regression, and the MR-PRESSO test. The validation set was utilized for verification, and a meta-analysis was performed to combine the results from the two datasets. Results Forward MR analysis results showed that nine types of gut microbiota were statistically associated with PCOS (all P<0.05). Specifically, the association of family Streptococcaceae (OR=1.442, 95%CI: 1.097-1.895), genus Actinomyces (OR=1.359, 95%CI: 1.036-1.784), genus Ruminococcaceae UCG 011 (OR=0.755, 95%CI: 0.619-0.921), genus Sellimonas (OR=0.766, 95%CI: 0.657-0.893) and genus Streptococcus with PCOS (OR=1.496, 95%CI: 1.136-1.972) remained consistent in the sensitivity analysis. Reverse MR analysis showed no evidence for the causal association between PCOS and the aforementioned five types of gut microbiota (all P>0.05). The MR analysis results of the validation set showed that there was no statistical association between the aforementioned five types of gut microbiota and PCOS (all P>0.05). However, the associations remained significant for genus Actinomyces (OR=1.226,95%CI:1.010-1.503) and genus Streptococcus (OR=1.266,95%CI:1.042-1.452) in the meta-analysis (both P<0.05). Conclusion This study provides the evidence that genus Actinomyces and genus Streptococcus are causally associated with PCOS.
陈颖, 刘可, 刘彬, 孙晓慧, 何志兴, 毛盈颖, 叶丁. 肠道菌群与多囊卵巢综合征的孟德尔随机化研究[J]. 预防医学, 2024, 36(9): 801-805.
CHEN Ying, LIU Ke, LIU Bin, SUN Xiaohui, HE Zhixing, MAO Yingying, YE Ding. Association between gut microbiota and polycystic ovary syndrome: a Mendelian randomization study. Preventive Medicine, 2024, 36(9): 801-805.
[1] JOHAM A E,NORMAN R J,STENER-VICTORIN E,et al.Polycystic ovary syndrome[J].Lancet Diabetes Endocrinol,2022,10(9):668-680. [2] TREMELLEN K,PEARCE K.Dysbiosis of gut microbiota(DOGMA):a novel theory for the development of polycystic ovarian syndrome[J].Med Hypotheses,2012,79(1):104-112. [3] GUO J B,SHAO J,YANG Y,et al.Gut microbiota in patients with polycystic ovary syndrome:a systematic review[J]. Reproductive Sci,2022,29(1):69-83. [4] QI X Y,YUN C C,SUN L L,et al.Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome[J].Nat Med,2019,25(8):1225-1233. [5] KURILSHIKOV A,MEDINA-GOMEZ C,BACIGALUPE R,et al.Large-scale association analyses identify host factors influencing human gut microbiome composition[J].Nat Genet,2021,53(2):156-165. [6] DAY F,KARADERI T,JONES M R,et al.Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria[J].PLoS Genet,2018,14(12):1-20. [7] TYRMI J S,ARFFMAN R K,PUJOL-GUALDO N,et al.Leveraging northern european population history:novel low-frequency variants for polycystic ovary syndrome[J].Hum Reprod,2022,37(2):352-365. [8] DAVIES N M,HOLMES M V,DAVEY SMITH G.Reading Mendelian randomisation studies:a guide,glossary,and checklist for clinicians[J/OL].BMJ,2018,362[2024-07-05].https://doi.org/doi: 10.1136/bmj.k601. [9] PALMER T M,LAWLOR D A,HARBORD R M,et al.Using multiple genetic variants as instrumental variables for modifiable risk factors[J].Stat Methods Med Res,2012,21(3):223-242. [10] BRION M J,SHAKHBAZOV K,VISSCHER P M.Calculating statistical power in Mendelian randomization studies[J].Int J Epidemiol,2013,42(5):1497-1501. [11] GONZALEZ F,CONSIDINE R V,ABDELHADI O A,et al.Saturated fat ingestion promotes lipopolysaccharide-mediated inflammation and insulin resistance in polycystic ovary syndrome[J].J Clin Endocrinol Metab,2019,104(3):934-946. [12] JOBIRA B,FRANK D N,PYLE L,et al.Obese adolescents with PCOS have altered biodiversity and relative abundance in gastrointestinal microbiota[J].J Clin Endocrinol Metab,2020,105(6):2134-2144. [13] LIU R,ZHANG C H,SHI Y,et al.Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome[J].Front Microbiol,2017,8:1-12. [14] VELEZ L M,SELDIN M,MOTTA A B.Inflammation and reproductive function in women with polycystic ovary syndromedagger[J].Biol Reprod,2021,104(6):1205-1217. [15] ABRAHAM GNANADASS S,DIVAKAR PRABHU Y,VALSALA GOPALAKRISHNAN A.Association of metabolic and inflammatory markers with polycystic ovarian syndrome(PCOS):an update[J].Arch Gynecol Obstet,2021,303(3):631-643. [16] RACHON D,TEEDE H.Ovarian function and obesity-interrelationship,impact on women's reproductive lifespan and treatment options[J].Mol Cell Endocrinol,2010,316(2):172-179. [17] DEL CHIERICO F,ABBATINI F,RUSSO A,et al.Gut microbiota markers in obese adolescent and adult patients:age-dependent differential patterns[J].Front Microbiol,2018,9:1-12. [18] XIE J,LI L F,DAI T Y,et al.Short-chain fatty acids produced by ruminococcaceae mediate alpha-linolenic acid promote intestinal stem cells proliferation[J/OL].Mol Nutr Food Res,2022,66[2024-07-05]. https://doi.org/10.1002/mnfr.202100408. [19] SALEHI S,ALLAHVERDY J,POURJAFAR H,et al.Gut microbiota and polycystic ovary syndrome(PCOS):understanding the pathogenesis and the role of probiotics as a therapeutic strategy[J/OL].Probiotics Antimicrob Proteins,2024[2024-07-05]. https://doi.org/10.1007/s12602-024-10223-5. [20] MUNOZ M,GUERRERO-ARAYA E,CORTES-TAPIA C,et al.Comprehensive genome analyses of Sellimonas intestinalis,a potential biomarker of homeostasis gut recovery[J].Microb Genom,2020,6(12):1-11. [21] SEO B,YOO J E,LEE Y M,et al.Sellimonas intestinalis gen.nov.,sp.nov.,isolated from human faeces[J].Int J Syst Evol Microbiol,2016,66(2):951-956.