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

被引：57

作者：

Kappel, Ben Arpad ^{[1
,2
]}

De Angelis, Lorenzo ^{[1
]}

Heiser, Michael ^{[3
,4
]}

Ballanti, Marta ^{[1
,5
]}

Stoehr, Robert ^{[2
]}

Goettsch, Claudia ^{[2
]}

Mavilio, Maria ^{[1
]}

Artati, Anna ^{[6
]}

Paoluzi, Omero A. ^{[7
]}

Adamski, Jerzy ^{[6
,8
,9
,10
]}

Mingrone, Geltrude ^{[11
,12
,13
]}

Staels, Bart ^{[14
]}

Burcelin, Remy ^{[15
,16
]}

Monteleone, Giovanni ^{[1
,7
]}

Menghini, Rossella ^{[1
]}

Marx, Nikolaus ^{[2
]}

Federici, Massimo ^{[1
,5
]}

机构：

[1] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy

[2] Rhein Westfal TH Aachen, Univ Hosp Aachen, Dept Internal Med 1, Aachen, Germany

[3] Metab Discoveries GmbH, Potsdam, Germany

[4] Metabolon Inc, Morrisville, NC USA

[5] Policlin Tor Vergata, Ctr Atherosclerosis, Rome, Italy

[6] German Res Ctr Environm Hlth GmbH, Res Unit Mol Endocrinol & Metab, Helmholtz Zentrum Munchen, Neuherberg, Germany

[7] Policlin Tor Vergata, Gastroenterol Unit, Rome, Italy

[8] Tech Univ Munich, Lehrstuhl Expt Genet, Freising Weihenstephan, Germany

[9] German Ctr Diabet Res DZD eV, Neuherberg, Germany

[10] Natl Univ Singapore, Dept Biochem, Yong Loo Lin Sch Med, Singapore, Singapore

[11] Catholic Univ, Dept Internal Med, Rome, Italy

[12] Fdn Policlin Univ A Gemelli IRCCS, Rome, Italy

[13] Kings Coll London, Diabet & Nutr Sci, Hodgkin Bldg,Guys Campus, London, England

[14] Univ Lille, Ctr Hosp Univ Lille, Inst Pasteur Lille, INSERM,U1011 European Genom Inst Diabet, Lille, France

[15] Inst Malad Metab & Cardiovasc, INSERM, U1048, Toulouse, France

[16] Univ Paul Sabatier, Toulouse, France

来源：

MOLECULAR METABOLISM | 2020年 / 36卷

基金：

欧盟第七框架计划;

关键词：

Atherosclerosis; Antibiotics; Gut microbiota; Dysbiosis; Metabolic diversity; Cross-omics; ARYL-HYDROCARBON RECEPTOR; TRIMETHYLAMINE-N-OXIDE; INTIMA-MEDIA THICKNESS; INTESTINAL MICROBIOTA; SEQUENCE DATA; DISEASE RISK; INFLAMMATION; ACTIVATION; PLAQUE; MICE;

D O I：

10.1016/j.molmet.2020.100976

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

引用

页数：18

共 89 条

[1] Metabolic Reconstruction for Metagenomic Data and Its Application to the Human Microbiome [J].

Abubucker, Sahar ;

Segata, Nicola ;

Goll, Johannes ;

Schubert, Alyxandria M. ;

Izard, Jacques ;

Cantarel, Brandi L. ;

Rodriguez-Mueller, Beltran ;

Zucker, Jeremy ;

Thiagarajan, Mathangi ;

Henrissat, Bernard ;

White, Owen ;

Kelley, Scott T. ;

Methe, Barbara ;

Schloss, Patrick D. ;

Gevers, Dirk ;

Mitreva, Makedonka ;

Huttenhower, Curtis .

PLOS COMPUTATIONAL BIOLOGY, 2012, 8 (06)

[2] Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFκB activation [J].

Aguilar, E. C. ;

Leonel, A. J. ;

Teixeira, L. G. ;

Silva, A. R. ;

Silva, J. F. ;

Pelaez, J. M. N. ;

Capettini, L. S. A. ;

Lemos, V. S. ;

Santos, R. A. S. ;

Alvarez-Leite, J. I. .

NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES, 2014, 24 (06) :606-613

[3] Blood Microbiota Dysbiosis Is Associated with the Onset of Cardiovascular Events in a Large General Population: The DESIR Study [J].

Amar, Jacques ;

Lange, Celine ;

Payros, Gaelle ;

Garret, Celine ;

Chabo, Chantal ;

Lantieri, Olivier ;

Courtney, Michael ;

Marre, Michel ;

Charles, Marie Aline ;

Balkau, Beverley ;

Burcelin, Remy .

PLOS ONE, 2013, 8 (01)

[4] Serum Indoxyl Sulfate Is Associated with Vascular Disease and Mortality in Chronic Kidney Disease Patients [J].

Barreto, Fellype C. ;

Barreto, Daniela V. ;

Liabeuf, Sophie ;

Meert, Natalie ;

Glorieux, Griet ;

Temmar, Mohammed ;

Choukroun, Gabriel ;

Vanholder, Raymond ;

Massy, Ziad A. .

CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2009, 4 (10) :1551-1558

[5] Antibiotic Treatment Protocols and Germ-Free Mouse Models in Vascular Research [J].

Bayer, Franziska ;

Ascher, Stefanie ;

Pontarollo, Giulia ;

Reinhardt, Christoph .

FRONTIERS IN IMMUNOLOGY, 2019, 10

[6] Human AHR functions in vascular tissue: Pro- and anti-inflammatory responses of AHR agonists in atherosclerosis [J].

Bock, Karl Walter .

BIOCHEMICAL PHARMACOLOGY, 2019, 159 :116-120

[7] A Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis [J].

Brandsma, Eelke ;

Kloosterhuis, Niels J. ;

Koster, Mirjam ;

Dekker, Daphne C. ;

Gijbels, Marion J. J. ;

van der Velden, Saskia ;

Rios-Morales, Melany ;

van Faassen, Martijn J. R. ;

Loreti, Marco G. ;

de Bruin, Alain ;

Fu, Jingyuan ;

Kuipers, Folkert ;

Bakker, Barbara M. ;

Westerterp, Marit ;

de Winther, Menno P. J. ;

Hofker, Marten H. ;

van de Sluis, Bart ;

Koonen, Debby P. Y. .

CIRCULATION RESEARCH, 2019, 124 (01) :94-100

[8] Random forests [J].

Breiman, L .

MACHINE LEARNING, 2001, 45 (01) :5-32

[9] Microbial modulation of cardiovascular disease [J].

Brown, J. Mark ;

Hazen, Stanley L. .

NATURE REVIEWS MICROBIOLOGY, 2018, 16 (03) :171-181

[10] Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes [J].

Cason, Cori A. ;

Dolan, Kyle T. ;

Sharma, Gaurav ;

Tao, Ming ;

Kulkarni, Rohan ;

Helenowski, Irene B. ;

Doane, Brendan M. ;

Avram, Michael J. ;

McDermott, Mary M. ;

Chang, Eugene B. ;

Ozaki, C. Keith ;

Ho, Karen J. .

JOURNAL OF VASCULAR SURGERY, 2018, 68 (05) :1552-+

← 1 2 3 4 5 6 7 8 9 →