Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.,Molecular Metabolism

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Cross-omics analysis revealed gut microbiome-related metabolic pathways underlying atherosclerosis development after antibiotics treatment.
Molecular Metabolism ( IF 7.0 ) Pub Date : 2020-03-13 , DOI: 10.1016/j.molmet.2020.100976
Ben Arpad Kappel ₁ , Lorenzo De Angelis ₂ , Michael Heiser ₃ , Marta Ballanti ₄ , Robert Stoehr ₅ , Claudia Goettsch ₅ , Maria Mavilio ₂ , Anna Artati ₆ , Omero A Paoluzi ₇ , Jerzy Adamski ₈ , Geltrude Mingrone ₉ , Bart Staels ₁₀ , Remy Burcelin ₁₁ , Giovanni Monteleone ₁₂ , Rossella Menghini ₂ , Nikolaus Marx ₅ , Massimo Federici ₄

Affiliation

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Department of Internal Medicine 1, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Metabolomic discoveries GmbH, Potsdam, Germany; Metabolon Inc., Morrisville, NC, USA.
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Center for Atherosclerosis, Policlinico Tor Vergata, Rome, Italy.
Department of Internal Medicine 1, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
Gastroenterology Unit, Policlinico Tor Vergata, Rome, Italy.
Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technical University of Munich, Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Internal Medicine, Catholic University, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Diabetes and Nutritional Sciences, Hodgkin Building, Guy's Campus, King's College London, London, United Kingdom.
Université Lille, INSERM, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Toulouse, France; Université Paul Sabatier, Toulouse, France.
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Gastroenterology Unit, Policlinico Tor Vergata, Rome, Italy.

Objective

The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity, and long-term usage has been identified as an independent risk factor for atherosclerosis-driven events. The aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with the impact on atherosclerosis development.

Methods

We combined oral antibiotics with different diets in an Apolipoprotein E-knockout mouse model linking gut microbiota to atherosclerotic lesion development via an integrative cross-omics approach including serum metabolomics and cecal 16S rRNA targeted metagenomic sequencing. We further investigated patients with carotid atherosclerosis compared to control subjects with comparable cardiovascular risk.

Results

Here, we show that increased atherosclerosis by antibiotics was connected to a loss of intestinal diversity and alterations of microbial metabolic functional capacity with a major impact on the host serum metabolome. Pathways that were modulated by antibiotics and connected to atherosclerosis included diminished tryptophan and disturbed lipid metabolism. These pathways were related to the reduction of certain members of Bacteroidetes and Clostridia by antibiotics in the gut. Patients with atherosclerosis presented a similar metabolic signature as those induced by antibiotics in our mouse model.

Conclusion

Taken together, this work provides insights into the complex interaction between intestinal microbiota and host metabolism. Our data highlight that detrimental effects of antibiotics on the gut flora are connected to a pro-atherogenic metabolic phenotype beyond classical risk factors.

中文翻译：

跨组学分析显示，抗生素治疗后，肠道微生物群相关的代谢途径成为动脉粥样硬化发展的基础。

目的

肠道菌群的代谢影响在心脏代谢疾病的发病机理中起着关键作用。抗生素影响肠道细菌的多样性，长期使用已被确定为动脉粥样硬化驱动事件的独立危险因素。这项研究的目的是探讨通过抗生素肠道代谢和代谢途径之间的相互作用对动脉粥样硬化发展的影响。

方法

我们通过载脂蛋白E基因敲除小鼠模型将口服抗生素与不同饮食相结合，通过整合的交叉组学方法（包括血清代谢组学和盲肠16S rRNA靶向宏基因组测序）将肠道菌群与动脉粥样硬化病变发展联系起来。我们与具有可比较的心血管风险的对照组相比，进一步研究了颈动脉粥样硬化患者。

结果

在这里，我们表明，由抗生素引起的动脉粥样硬化增加与肠道多样性的丧失和微生物代谢功能能力的改变有关，对宿主血清代谢组的影响最大。受抗生素调节并与动脉粥样硬化有关的途径包括色氨酸减少和脂质代谢紊乱。这些途径与肠道中的抗生素减少了拟杆菌和梭状芽胞杆菌的某些成员有关。在我们的小鼠模型中，动脉粥样硬化患者的代谢特征与抗生素诱导的相似。