Microbiomes of Inflammatory Thoracic Aortic Aneurysms Due to Giant Cell Arteritis and Clinically Isolated Aortitis Differ From Those of Non-Inflammatory Aneurysms

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Ted M. Getz
Gary Stuart Hoffman
Roshan Padmanabhan
Alexandra Villa-Forte
Eric E. Roselli
Eugene Blackstone
Douglas Johnston
Gosta Pettersson
Edward Soltesz
Lars G. Svensson
Leonard H. Calabrese
Alison H. Clifford
Charis Eng


Objective: We sought to characterize microbiomes of thoracic aortas from patients with non-infectious aortitis due to giant cell arteritis (GCA) and clinically isolated aortitis (CIA) and to compare them to non-inflammatory aorta aneurysm controls. We also compared microbiomes from concurrently processed and separately reported temporal arteries (TA) and aortas.

Methods: From 220 prospectively enrolled patients undergoing surgery for thoracic aorta aneurysm, 49 were selected. Inflammatory and non-inflammatory cases were selected based on ability to match for age (+/-10 years), gender, and race. Biopsies were collected under aseptic conditions and snap-frozen. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinates analysis.

Results : Forty-nine patients with thoracic aortic aneurysms (12 CIA, 14 GCA, 23 non-inflammatory aneurysms) were enrolled. Alpha (P = 0.018) and beta (P = 0.024) diversity differed between specimens from aortitis cases and controls. There were no significant differences between CIA and GCA (P > 0.7). The largest differential abundances between non-infectious aortitis and non-inflammatory control samples includedEnterobacteriaceae, Phascolarctobacterium, Acinetobactor, Klebsiella, and Prevotella. Functional metagenomic predictions with PICRUSt revealed enrichment of oxidative phosphorylation and porphyrin metabolism pathways and downregulation of transcription factor pathways in aortitis compared to controls. Microbiomes of aortic samples differed significantly from temporal artery samples from a companion study, in both control and GCA groups (P = 0.0002).

Conclusion: Thoracic aorta aneurysms, far from being sterile, contain unique microbiomes that differ from those found in temporal arteries. The aorta microbiomes are most similar between aneurysms that were associated with inflammation, GCA, and CIA, but differed from those associated with non-inflammatory etiologies. These findings are promising in that they indicate that microbes may play a role in the pathogenesis of aortitis-associated aneurysms or non-inflammatory aneurysms by promoting or protecting against inflammation. However, we cannot rule out that these changes are related to alterations in tissue substrate that favor secondary changes in microbial communities.


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Author Biography

Gary Stuart Hoffman, Cleveland Clinic Lerner College of Medicine; Department of Rheumatic and Immunologic Diseases

Professor Emeritus Cleveland Clinic Lerner College of Medicine Center for Vasculitis Care and Research Department of Rheumatic and Immunologic Diseases Cleveland, Ohio


1. Gornik HL, Creager MA. Aortitis. Circulation. 2008;117(23):3039-51. PubMed PMID: 18541754. Pubmed Central PMCID: 2759760. doi: 10.1161/CIRCULATIONAHA.107.760686

2. Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y. Infection and vasculitis. Rheumatology (Oxford). 2009;48(5):475-82. PubMed PMID: 19258377. doi: 10.1093/rheumatology/kep026

3. Stone JR, Bruneval P, Angelini A, Bartoloni G, Basso C, Batoroeva L, Buja LM, Butany J, d'Amati G, Fallon JT, Gittenberger-de Groot AC, Gouveia RH, Halushka MK, Kelly KL, Kholova I, Leone O, Litovsky SH, Maleszewski JJ, Miller DV, Mitchell RN, Preston SD, Pucci A, Radio SJ, Rodriguez ER, Sheppard MN, Suvarna SK, Tan CD, Thiene G, van der Wal AC, Veinot JP. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. Cardiovasc Pathol. 2015;24(5):267-78. PubMed PMID: 26051917. doi: 10.1016/j.carpath.2015.05.001

4. Cinar I, Wang H, Stone JR. Clinically isolated aortitis: pitfalls, progress, and possibilities. Cardiovasc Pathol. 2017;29:23-32. PubMed PMID: 28500877. doi: 10.1016/j.carpath.2017.04.003

5. Miller DV, Isotalo PA, Weyand CM, Edwards WD, Aubry MC, Tazelaar HD. Surgical pathology of noninfectious ascending aortitis: a study of 45 cases with emphasis on an isolated variant. Am J Surg Pathol. 2006;30(9):1150-8. PubMed PMID: 16931960. doi: 10.1097/01.pas.0000213293.04026.ec

6. Wang H, Smith RN, Spooner AE, Isselbacher EM, Cambria RP, MacGillivray TE, Stone JH, Stone JR. Giant cell aortitis of the ascending aorta without signs or symptoms of systemic vasculitis is associated with elevated risk of distal aortic events. Arthritis Rheum. 2012;64(1):317-9. PubMed PMID: 21953530. doi: 10.1002/art.33343

7. Clifford AH, Arafat A, Idrees JJ, Roselli EE, Tan CD, Rene Rodriguez E, Svensson LG, Blackstone E, Johnston D, Pettersson G, Soltesz E, Hoffman GS. Outcomes among 196 patients with non-infectious proximal aortitis. Arthritis Rheumatol. 2019. PubMed PMID: 30730604. doi: 10.1002/art.40855

8. Hoffman GS. Giant Cell Arteritis. Ann Intern Med. 2016;165(9):ITC65-ITC80. PubMed PMID: 27802475. doi: 10.7326/AITC201611010

9. Gordon LK, Goldman M, Sandusky H, Ziv N, Hoffman GS, Goodglick T, Goodglick L. Identification of candidate microbial sequences from inflammatory lesion of giant cell arteritis. Clin Immunol. 2004;111(3):286-96. PubMed PMID: 15183149. doi: 10.1016/j.clim.2003.12.016

10. Hoffman GS, Calabrese LH. Vasculitis: determinants of disease patterns. Nat Rev Rheumatol. 2014;10(8):454-62. PubMed PMID: 24934189. doi: 10.1038/nrrheum.2014.89

11. Clifford A, Hoffman GS. Evidence for a vascular microbiome and its role in vessel health and disease. Curr Opin Rheumatol. 2015;27(4):397-405. PubMed PMID: 26002032. doi: 10.1097/BOR.0000000000000184

12. Hoffman GS, Getz TM, Padmanabhan R, Villa-Forte A, Clifford AH, Funchain P, Sankunny M, Perry JD, Blandford A, Kosmorsky G, Lystad L, Calabrese LH, Eng C. The Microbiome of Temporal Arteries. Pathogens and Immunity. 2019;4(1):21-38. doi: 10.20411/pai.v4i1.270

13. Chakravarti R, Gupta K, Swain M, Willard B, Scholtz J, Svensson LG, Roselli EE, Pettersson G, Johnston DR, Soltesz EG, Yamashita M, Stuehr D, Daly TM, Hoffman GS. 14-3-3 in Thoracic Aortic Aneurysms: Identification of a Novel Autoantigen in Large Vessel Vasculitis. Arthritis Rheumatol. 2015;67(7):1913-21. PubMed PMID: 25917817. Pubmed Central PMCID: 4624269. doi: 10.1002/art.39130

14. Mukherjee PK, Wang H, Retuerto M, Zhang H, Burkey B, Ghannoum MA, Eng C. Bacteriome and mycobiome associations in oral tongue cancer. Oncotarget. 2017;8(57):97273-89. PubMed PMID: 29228609. Pubmed Central PMCID: 5722561. doi: 10.18632/oncotarget.21921

15. Albanese D, Fontana P, De Filippo C, Cavalieri D, Donati C. MICCA: a complete and accurate software for taxonomic profiling of metagenomic data. Sci Rep. 2015;5:9743. PubMed PMID: 25988396. Pubmed Central PMCID: 4649890. doi: 10.1038/srep09743

16. Magoc T, Salzberg SL. FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics. 2011;27(21):2957-63. PubMed PMID: 21903629. Pubmed Central PMCID: 3198573. doi: 10.1093/bioinformatics/btr507

17. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335-6. PubMed PMID: 20383131. Pubmed Central PMCID: 3156573. doi: 10.1038/nmeth.f.303

18. Rognes T, Flouri T, Nichols B, Quince C, Mahe F. VSEARCH: a versatile open source tool for metagenomics. PeerJ. 2016;4:e2584. PubMed PMID: 27781170. Pubmed Central PMCID: 5075697. doi: 10.7717/peerj.2584

19. Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007;73(16):5261-7. PubMed PMID: 17586664. Pubmed Central PMCID: 1950982. doi: 10.1128/AEM.00062-07

20. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32(5):1792-7. PubMed PMID: 15034147. Pubmed Central PMCID: 390337. doi: 10.1093/nar/gkh340

21. Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. 2004;5:113. PubMed PMID: 15318951. Pubmed Central PMCID: PMC517706. doi: 10.1186/1471-2105-5-113

22. DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, Huber T, Dalevi D, Hu P, Andersen GL. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol. 2006;72(7):5069-72. PubMed PMID: 16820507. Pubmed Central PMCID: 1489311. doi: 10.1128/AEM.03006-05

23. Price MN, Dehal PS, Arkin AP. FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol Biol Evol. 2009;26(7):1641-50. PubMed PMID: 19377059. Pubmed Central PMCID: 2693737. doi: 10.1093/molbev/msp077

24. Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, Beiko RG, Huttenhower C. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013;31(9):814-21. PubMed PMID: 23975157. Pubmed Central PMCID: 3819121. doi: 10.1038/nbt.2676

25. Parks DH, Beiko RG. Identifying biologically relevant differences between metagenomic communities. Bioinformatics. 2010;26(6):715-21. PubMed PMID: 20130030. doi: 10.1093/bioinformatics/btq041

26. Elling P, Olsson AT, Elling H. Synchronous variations of the incidence of temporal arteritis and polymyalgia rheumatica in different regions of Denmark; association with epidemics of Mycoplasma pneumoniae infection. J Rheumatol. 1996;23(1):112-9. PubMed PMID: 8838518.

27. Wagner AD, Gerard HC, Fresemann T, Schmidt WA, Gromnica-Ihle E, Hudson AP, Zeidler H. Detection of Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating dendritic cells. Arthritis Rheum. 2000;43(7):1543-51. PubMed PMID: 10902759. doi: 10.1002/1529-0131(200007)43:7<1543::AID-ANR19>3.0.CO;2-8

28. Koening CL, Katz BJ, Hernandez-Rodriguez J, Corbera-Bellata M, Cid MC, Schweizer HP, Li D, Kaplan J, Hoffman GS, De Domenico I. Identification of a Burkholderia-Like Strain From Temporal Arteries of Subjects with Giant Cell Arteritis. 2012 ACR/ARHP Annual Meeting, 2012.

29. Bhatt AS, Manzo VE, Pedamallu CS, Duke F, Cai D, Bienfang DC, Padera RF, Meyerson M, Docken WP. In search of a candidate pathogen for giant cell arteritis: sequencing-based characterization of the giant cell arteritis microbiome. Arthritis Rheumatol. 2014;66(7):1939-44. PubMed PMID: 24644069. Pubmed Central PMCID: 4113339. doi: 10.1002/art.38631

30. Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, Andoh A. Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol. 2018;11(1):1-10. PubMed PMID: 29285689. doi: 10.1007/s12328-017-0813-5

31. Scher JU, Joshua V, Artacho A, Abdollahi-Roodsaz S, Ockinger J, Kullberg S, Skold M, Eklund A, Grunewald J, Clemente JC, Ubeda C, Segal LN, Catrina AI. The lung microbiota in early rheumatoid arthritis and autoimmunity. Microbiome. 2016;4(1):60. PubMed PMID: 27855721. Pubmed Central PMCID: 5114783. doi: 10.1186/s40168-016-0206-x

32. Allen-Vercoe E, Jobin C. Fusobacterium and Enterobacteriaceae: important players for CRC? Immunol Lett. 2014;162(2 Pt A):54-61. PubMed PMID: 24972311. Pubmed Central PMCID: 4259803. doi: 10.1016/j.imlet.2014.05.014

33. Larsen JM. The immune response to Prevotella bacteria in chronic inflammatory disease. Immunology. 2017;151(4):363-74. PubMed PMID: 28542929. Pubmed Central PMCID: 5506432. doi: 10.1111/imm.12760

34. Larsen JM, Musavian HS, Butt TM, Ingvorsen C, Thysen AH, Brix S. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology. Immunology. 2015;144(2):333-42. PubMed PMID: 25179236. Pubmed Central PMCID: 4298427. doi: 10.1111/imm.12376

35. Debarry J, Garn H, Hanuszkiewicz A, Dickgreber N, Blumer N, von Mutius E, Bufe A, Gatermann S, Renz H, Holst O, Heine H. Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties. J Allergy Clin Immunol. 2007;119(6):1514-21. PubMed PMID: 17481709. doi: 10.1016/j.jaci.2007.03.023

36. Schaller M, Loewenstein M, Borelli C, Jacob K, Vogeser M, Burgdorf WH, Plewig G. Induction of a chemoattractive proinflammatory cytokine response after stimulation of keratinocytes with Propionibacterium acnes and coproporphyrin III. Br J Dermatol. 2005;153(1):66-71. PubMed PMID: 16029328. doi: 10.1111/j.1365-2133.2005.06530.x

37. de la Fuente R, Schleifer KH, Götz F, Köst H-P. Accumulation of porphyrins and pyrrole pigments by Staphylococcus aureus ssp. anaerobius and its aerobic mutant. FEMS Microbiology Letters. 1986;35(2‐3):183-8. doi: 10.1111/j.1574-6968.1986.tb01524.x

38. McClary JS, Boehm AB. Transcriptional Response of Staphylococcus aureus to Sunlight in Oxic and Anoxic Conditions. Front Microbiol. 2018;9:249. PubMed PMID: 29599752. Pubmed Central PMCID: 5863498. doi: 10.3389/fmicb.2018.00249

39. Marques da Silva R, Caugant DA, Eribe ER, Aas JA, Lingaas PS, Geiran O, Tronstad L, Olsen I. Bacterial diversity in aortic aneurysms determined by 16S ribosomal RNA gene analysis. J Vasc Surg. 2006;44(5):1055-60. PubMed PMID: 17098542. doi: 10.1016/j.jvs.2006.07.021

40. Ramirez JA. Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group. Ann Intern Med. 1996;125(12):979-82. PubMed PMID: 8967709.

41. Mosorin M, Surcel HM, Laurila A, Lehtinen M, Karttunen R, Juvonen J, Paavonen J, Morrison RP, Saikku P, Juvonen T. Detection of Chlamydia pneumoniae-reactive T lymphocytes in human atherosclerotic plaques of carotid artery. Arterioscler Thromb Vasc Biol. 2000;20(4):1061-7. PubMed PMID: 10764674.

42. Choi J, Chung SW, Kim SJ, Kim SJ. Establishment of Porphyromonas gingivalis-specific T-cell lines from atherosclerosis patients. Oral Microbiol Immunol. 2001;16(5):316-8. PubMed PMID: 11555310.

43. Lalla E, Lamster IB, Hofmann MA, Bucciarelli L, Jerud AP, Tucker S, Lu Y, Papapanou PN, Schmidt AM. Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2003;23(8):1405-11. PubMed PMID: 12816879. doi: 10.1161/01.ATV.0000082462.26258.FE

44. Mougeot JC, Stevens CB, Paster BJ, Brennan MT, Lockhart PB, Mougeot FK. Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries. J Oral Microbiol. 2017;9(1):1281562. PubMed PMID: 28326156. Pubmed Central PMCID: 5328378. doi: 10.1080/20002297.2017.1281562

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