Lledós Miquel, Prats-Sánchez Luís, Llucià-Carol Laia, Cárcel-Márquez Jara, Muiño Elena, Cullell Natalia, Gallego-Fabrega Cristina, Martín-Campos Jesús M, Aguilera-Simón Ana, Guasch-Jiménez Marina, Guisado-Alonso Daniel, Ramos-Pachón Anna, Martínez-Domeño Alejandro, Izquierdo Artur, Marín Rebeca, Camps-Renom Pol, Martí-Fàbregas Joan, Fernández-Cadenas Israel
Stroke Pharmacogenomics and Genetics Laboratory, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.
Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain.
Eur J Neurol. 2023 Nov;30(11):3497-3506. doi: 10.1111/ene.15931. Epub 2023 Jul 1.
Gut microbiota plays a role in the pathophysiology of ischaemic stroke (IS) through the bidirectional gut-brain axis. Nevertheless, little is known about sex-specific microbiota signatures in IS occurrence.
A total of 89 IS patients and 12 healthy controls were enrolled. We studied the taxonomic differences of the gut microbiota between men and women with IS by shotgun metagenomic sequencing. To evaluate the causal effect of several bacteria on IS risk, we performed a two-sample Mendelian randomisation (MR) with inverse-variance weighting (IVW) using genome-wide association analysis (GWAS) summary statistics from two cohorts of 5959 subjects with genetic and microbiota data and 1,296,908 subjects with genetic and IS data, respectively.
α-Diversity analysis measured using Observed Species (p = 0.017), Chao1 (p = 0.009) and Abundance-based Coverage Estimator (p = 0.012) indexes revealed that IS men have a higher species richness compared with IS women. Moreover, we found sex-differences in IS patients in relation to the phylum Fusobacteria, class Fusobacteriia, order Fusobacteriales and family Fusobacteriaceae (all Bonferroni-corrected p < 0.001). MR confirmed that increased Fusobacteriaceae levels in the gut are causally associated with an increased risk of IS (IVW p = 0.02, β = 0.32).
Our study is the first to indicate that there are gut microbiome differences between men and women with IS, identifying high levels of Fusobacteriaceae in women as a specific risk factor for IS. Incorporating sex stratification analysis is important in the design, analysis and interpretation of studies on stroke and the gut microbiota.
肠道微生物群通过双向肠-脑轴在缺血性中风（IS）的病理生理学中发挥作用。然而，关于IS发生中性别特异性微生物群特征知之甚少。
共纳入89例IS患者和12名健康对照。我们通过鸟枪法宏基因组测序研究了男性和女性IS患者肠道微生物群的分类学差异。为了评估几种细菌对IS风险的因果效应，我们使用来自分别有遗传和微生物群数据的5959名受试者以及有遗传和IS数据的1296908名受试者的两个队列的全基因组关联分析（GWAS）汇总统计数据，进行了带有逆方差加权（IVW）的两样本孟德尔随机化（MR）。
使用观察物种（p = 0.017）、Chao1（p = 0.009）和基于丰度的覆盖度估计器（p = 0.012）指数进行的α多样性分析表明，与女性IS患者相比，男性IS患者的物种丰富度更高。此外，我们发现IS患者在梭杆菌门、梭杆菌纲、梭杆菌目和梭杆菌科方面存在性别差异（所有经Bonferroni校正的p < 0.001）。MR证实，肠道中梭杆菌科水平的升高与IS风险增加存在因果关系（IVW p = 0.02，β = 0.32）。
我们的研究首次表明，男性和女性IS患者之间存在肠道微生物组差异，确定女性中高水平的梭杆菌科是IS的一个特定风险因素。在中风和肠道微生物群研究的设计、分析和解释中纳入性别分层分析很重要。
