INTRODUCTION The number of smokers worldwide increased greatly during the past decades and reached 1.14 billion in 2019, becoming a leading risk factor for human health. Tobacco smoking has wide effects on human genetics, epigenetics, transcriptome, and gut microbiome. Although many studies have revealed effects of smoking on host transcriptome, research on the relationship among smoking, host gene expression, and the gut microbiome is limited. METHODS We first explored transcriptome and metagenome profile differences between smokers and non-smokers. To evaluate the relationship between host gene expression and gut microbiome, we then applied bi-directional mediation analysis to infer causal relationships between smoking, gene expression, and gut microbes. RESULTS Metagenome and transcriptome analyses revealed 71 differential species and 324 differential expressed genes between smokers and non-smokers. With smoking as an exposure variable, we identified 272 significant causal relationships between gene expression and gut microbes, among which there were 247 genes that mediate the effect of smoking on gut microbes. Pathway-based enrichment analysis showed that these genes were significantly enriched in heme metabolic pathway, which mainly mediated the changes of Bacteroides finegoldii and Lachnospiraceae bacterium 9_1_43BFAA. Additionally, by performing metabolome data analysis in the Integrated Human Microbiome project (iHMP) database, we verified the correlation between the intermediate products of the heme metabolism pathway (porphobilinogen, bilirubin, and biliverdin) and gut microbiome. CONCLUSIONS By investigating the bi-directional interaction between smoking-related host gene expression and gut microbes, this study provided evidence for the mediation of smoking on gut microbes through co-involvement or interaction of heme metabolism. IMPLICATIONS By comparing the metagenome and transcriptome sequencing profiles between 34 smokers and 33 age- and gender-matched non-smokers, we are the first to reveal causal relationships among tobacco smoking, host gene expression and gut microbes. These findings offer insight into how smoking affects gut microbes through host gene expression and metabolism, which highlights the importance of heme metabolism in modulating the effects of smoking on gut microbiome.

中文翻译：

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血红素代谢介导吸烟对肠道微生物组的影响。

简介 过去几十年来，全球吸烟者数量大幅增加，2019 年达到 11.4 亿，成为人类健康的主要风险因素。吸烟对人类遗传学、表观遗传学、转录组和肠道微生物组有广泛影响。尽管许多研究揭示了吸烟对宿主转录组的影响，但对吸烟、宿主基因表达和肠道微生物组之间关系的研究仍然有限。方法我们首先探讨了吸烟者和非吸烟者之间转录组和宏基因组谱的差异。为了评估宿主基因表达与肠道微生物组之间的关系，我们应用双向中介分析来推断吸烟、基因表达和肠道微生物之间的因果关系。结果 宏基因组和转录组分析揭示了吸烟者和非吸烟者之间的 71 个差异物种和 324 个差异表达基因。以吸烟作为暴露变量，我们确定了基因表达与肠道微生物之间的 272 个显着因果关系，其中有 247 个基因介导吸烟对肠道微生物的影响。Pathway-based富集分析显示，这些基因在血红素代谢途径中显着富集，主要介导Bacteroides Finegoldii和Lachnospiraceae细菌9_1_43BFAA的变化。此外，通过在综合人类微生物组项目（iHMP）数据库中进行代谢组数据分析，我们验证了血红素代谢途径的中间产物（胆色素原、胆红素和胆绿素）与肠道微生物组之间的相关性。结论通过研究吸烟相关宿主基因表达与肠道微生物之间的双向相互作用，本研究为吸烟通过血红素代谢的共同参与或相互作用介导肠道微生物提供了证据。通过比较 34 名吸烟者和 33 名年龄和性别匹配的非吸烟者的宏基因组和转录组测序图谱，我们首次揭示了吸烟、宿主基因表达和肠道微生物之间的因果关系。这些发现提供了关于吸烟如何通过宿主基因表达和代谢影响肠道微生物的见解，这凸显了血红素代谢在调节吸烟对肠道微生物组影响方面的重要性。