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Year : 2020  |  Volume : 8  |  Issue : 1  |  Page : 29-31

The association of bacterial infection with intracranial aneurysm disease

1 City of Tampere - Oral Health Services; Oral and Maxillofacial Unit, Tampere University Hospital; Hemorrhagic Brain Pathology Research Group, University of Tampere, Tampere, Finland
2 Hemorrhagic Brain Pathology Research Group, University of Tampere, Tampere, Finland
3 Hemorrhagic Brain Pathology Research Group, University of Tampere, Tampere; Department of Oral and Maxillofacial Surgery, Kuopio University Hospital, Kuopio, Finland
4 Hemorrhagic Brain Pathology Research Group; Department of Neurosurgery, Tampere University Hospital and University of Tampere, Tampere, Finland

Date of Submission24-Aug-2020
Date of Acceptance31-Aug-2020
Date of Web Publication1-Oct-2020

Correspondence Address:
Dr. Mikko Pyysalo
City of Tampere - Oral Health Services; Oral and Maxillofacial Unit, Tampere University Hospital; Hemorrhagic Brain Pathology Research Group, University of Tampere, Tampere
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcvs.jcvs_20_20

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The human body abounds in micro-organisms that maintain the vital balance of the internal ecosystem. Though it is well known that several benefit the human body while others are linked to disease, how the microbiota affects the pathology of intra-cranial aneurysms is an interesting arena that still requires exploration. Studies have suggested possible association between the excess of bacteria, such as those causing gingivitis, as well the deficit of bacteria, such as loss of gut flora due to antibiotics, to intracranial aneurysms and their subsequent behavior. The authors review existing literature on the subject and outline the scope for further research on the subject.

Keywords: Aneurysm, bacteria, infection, intracranial

How to cite this article:
Pyysalo M, Pessi T, Hallikainen J, Frösen J. The association of bacterial infection with intracranial aneurysm disease. J Cerebrovasc Sci 2020;8:29-31

How to cite this URL:
Pyysalo M, Pessi T, Hallikainen J, Frösen J. The association of bacterial infection with intracranial aneurysm disease. J Cerebrovasc Sci [serial online] 2020 [cited 2022 Aug 14];8:29-31. Available from: http://www.jcvs.com/text.asp?2020/8/1/29/296926

Human beings should no longer be considered as discrete individuals by the classical definitions of the term anymore. The human is a holobiont consisting of host cells and symbiotic microorganisms such as bacteria, archaea, fungi and viruses.[1] The human body consists of approximately 3.8 × 1013 microbial cells and 3.0 × 1013 human cells, of which only 0.3 × 1013 are nucleated.[2] It means that only 10% of all the living cells in our body are human, and 90% are microorganisms. Over 750 bacterial species have been detected from human oral cavity as a part of normal microbiota.[3] Human oral microbiota, mainly comprising bacteria, form biofilms, which are like 'cities of bacteria', on oral surfaces including hard (teeth) and soft (mucosa) tissues. Infectious diseases of the oral cavity are driven by dysbiosis of the biofilm.[4] As a result of normal bacterial growth, dental biofilm forms on the tooth surface supra- and sub-gingivally. If the biofilm (=plaque) is not brushed away with a toothbrush preferably twice a day, early signs of gingivitis develop within 2–4 days.[5]

In the gingival pocket (=subgingivally), there is a continuous struggle between pro-inflammatory and anti-inflammatory conditions.[6] The presence of true risk factors of periodontitis, which include diabetes, smoking and abundance of periodontal pathogens (such as Porphyromonas gingivalis,Treponemadenticola and Tannerellaforsythia) tend to change the balance towards dysbiosis. The network of risk factors of periodontitis is very complex. Obesity, innate immune dysfunction, poor oral hygiene behaviours, poor diet quality, stress disorders, osteoporosis and cognitive disorders have been defined to be possible risk indicators when determining whether the balance between pro- and anti-inflammatory states could be changing towards the dysbiosis.[7] Gingivitis is a very common state and the global age-standardised prevalence of severe periodontitis is approximately 11%.[8]

Patients with gingivitis and periodontitis are exposed to bacteria and their products, such as metabolites and toxins. Oral bacteria have a straight access to the systemic circulation directly through inflamed and bleeding gingival tissues resulting in systemic inflammatory and immunologic responses. It has been shown that clinical periodontitis is associated with an increased risk for cardiovascular diseases through systemic low-grade inflammation and there is continuously increasing evidence, that inflammation in the walls of arteries is associated with clinical periodontitis and dysbiosis of the oral microbiota.[9]

Although a link between periodontitis and cardiovascular diseases other than saccular intracranial aneurysm (sIA) disease has been proposed in the 1980s,[10] the first study regarding the possible association of sIA with bacteria was conducted by Cagli et al. in 2003. In the study, Chlamydiapneumoniae DNA was assessed but not detected from sIA sac tissue samples.[11] Ten years later, in Finnish studies, oral and pharyngeal bacterial DNA, mostly bacterial DNA from the Streptococcus mitis-group and Fusobacterium nucleatum, was detected in 70% of ruptured and unruptured sIA tissue samples along with possibly bacterial-driven inflammation. The patients with sIAs had also significantly more dental infectious foci (≥6 mm gingival pockets) than are generally found in the normal population. In other words, the prevalence of severe periodontitis was significantly higher in sIA patients.[12],[13],[14] Moreover, according to the Finnish studies, abundant amounts of F. nucleatum, which appear to be associated with the progression of periodontitis, were found in the gingival pocket samples from patients with intracranial aneurysms (IAs).[13]

Not only periodontal bacteria and common oral bacteria like S. mitis group but also caries bacteria, Streptococcusmutans have been found to link to sIA disease. In this study, a specific cnm strain of S.mutans was a risk factor for ruptured aneurysm and stroke This strain promotes platelet aggregation inhibition and matrix metalloproteinase-9 activation which could logically be linked with sIA formation and rupturing.[15]

Very recently, in a follow-up study, it was shown that gingival bleeding, gingivitis and periodontitis are clearly associated with sIAs. Severe periodontitis and gingival bleeding at baseline significantly increased the risk of aneurysmal subarachnoid haemorrhage (aSAH) during the follow-up (hazard ratio [HR] 22.5, P = 0.001 and HR 8.3, P = 0.015, respectively). The association of periodontitis and gingival bleeding with the risk of sIA development and aSAH was independent of gender, smoking status, hypertension or alcohol abuse.[16]

To confirm these previously described study results, Shikata et al. demonstrated in a mouse model of IA formation how depletion of the gut microbiota affects the formation of IAs. This effect was related to reduce inflammation at the site of IA formation in the cerebral artery wall. The study by Shikata et al. introduces a novel factor modulating or perhaps even causing this inflammation.[17] After the study was published, aneurysm register data of Kuopio University hospital were coupled with a Finnish national registry for prescribed medications data. It was shown that patients with documented de novo IA formation had used significantly more antibiotics during follow-up than those without de novo IA formation.[18] Thus, not only oral bacteria but also bacteria derived from any of the human microbiotas or environment may induce an inflammation behind remodelling and IA formation of cerebral arteries.

To conclude, the animal model study by Shikata et al. suggests that microbiota or its components can affect the risk of IA formation, growth and rupture. The Finnish studies by Pyysalo et al. and Hallikainen et al. suggest that this finding has a relevance in humans and most importantly, in actual daily clinical practice. Interestingly, a study conducted by Aboukais et al. on French population (contrary to the Finnish studies), did not detect any viable bacterial cells or bacterial DNA in IA wall samples using 478 base pair long universal bacterial primers and probes.[19] However, the use of antibiotics was not recorded, and the laboratory set-up, albeit adequate, is not comparable with the Finnish studies, in which shorter and specific bacterial DNA primers and probes were used to detect bacterial DNA. It is highly recommended to compare these laboratory settings using similar samples. Moreover, not only the prevalence of periodontitis,[20] but also the composition of oral microbiota may differ in different populations. Together these studies also demonstrate the need to investigate further the role of microbiota in the complex pathobiology of IAs. We enthusiastically wait for further studies on the topic.

Possible further study designs are as follows:

  1. Detection of bacterial DNA from aneurysm tissue samples using both laboratory methods reported by Pyysalo et al. and Aboukais et al. and comparing the results
  2. Culturing liquid biopsies taken from sIA sac to detect the possible presence of viable bacteria without antibiotics interferences, for example, in mice
  3. Investigating liquid biopsies taken from sIA sac to detect the possible presence of viable bacteria with microscopy
  4. Assessing the prevalence of severe periodontitis in sIA patients in India.

  References Top

Rosenberg E, Zilber-Rosenberg I. Microbes drive evolution of animals and plants: The hologenome concept. mBio 2016;7:e01395.  Back to cited text no. 1
Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016;14:e1002533.  Back to cited text no. 2
Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner AC, Yu WH, et al. The human oral microbiome. J Bacteriol 2010;192:5002-17.  Back to cited text no. 3
Sanz M, Beighton D, Curtis MA, Cury JA, Dige I, Dommisch H, et al. Role of microbial biofilms in the maintenance of oral health and in the development of dental caries and periodontal diseases. Consensus report of group 1 of the Joint EFP/ORCA workshop on the boundaries between caries and periodontal disease. J Clin Periodontol 2017;44 Suppl 18:S5-11.  Back to cited text no. 4
Payne WA, Page RC, Ogilvie AL, Hall WB. Histopathologic features of the initial and early stages of experimental gingivitis in man. J Periodontal Res 1975;10:51-64.  Back to cited text no. 5
Kurgan S, Kantarci A. Molecular basis for immunohistochemical and inflammatory changes during progression of gingivitis to periodontitis. Periodontol 2000 2018;76:51-67.  Back to cited text no. 6
Bouchard P, Carra MC, Boillot A, Mora F, Rangé H. Risk factors in periodontology: A conceptual framework. J Clin Periodontol 2017;44:125-31.  Back to cited text no. 7
Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of severe periodontitis in 1990-2010: A systematic review and meta-regression. J Dent Res 2014;93:1045-53.  Back to cited text no. 8
Pietiäinen M, Liljestrand JM, Kopra E, Pussinen PJ. Mediators between oral dysbiosis and cardiovascular diseases. Eur J Oral Sci 2018;126 Suppl 1:26-36.  Back to cited text no. 9
Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesäniemi YA, Syrjälä SL, et al. Association between dental health and acute myocardial infarction. BMJ 1989;298:779-81.  Back to cited text no. 10
Cagli S, Oktar N, Dalbasti T, Erensoy S, Ozdamar N, Göksel S, et al. Failure to detect Chlamydia pneumoniae DNA in cerebral aneurysmal sac tissue with two different polymerase chain reaction methods. J Neurol Neurosurg Psychiatry 2003;74:756-9.  Back to cited text no. 11
Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Öhman JE. The connection between ruptured cerebral aneurysms and odontogenic bacteria. J Neurol Neurosurg Psychiatry 2013;84:1214-8.  Back to cited text no. 12
Pyysalo MJ, Pyysalo LM, Pessi T, Karhunen PJ, Lehtimäki T, Oksala N, et al. Bacterial DNA findings in ruptured and unruptured intracranial aneurysms. Acta Odontol Scand 2016;74:315-20.  Back to cited text no. 13
Pyysalo MJ, Pyysalo LM, Hiltunen J, Järnstedt J, Helminen M, Karhunen PJ, et al. The dental infections in patients undergoing preoperative dental examination before surgical treatment of saccular intracranial aneurysm. BMC Res Notes 2018;11:600.  Back to cited text no. 14
Inenaga C, Hokamura K, Nakano K, Nomura R, Naka S, Ohashi T, et al. A potential new risk factor for stroke: Streptococcus mutans with collagen-binding protein. World Neurosurg 2018;113:e77-81.  Back to cited text no. 15
Hallikainen J, Lindgren A, Savolainen J, Selander T, Jula A, Närhi M, et al. Periodontitis and gingival bleeding associate with intracranial aneurysms and risk of aneurysmal subarachnoid hemorrhage. Neurosurg Rev 2020;43:669-79.  Back to cited text no. 16
Shikata F, Shimada K, Sato H, Ikedo T, Kuwabara A, Furukawa H, et al. Potential influences of gut microbiota on the formation of intracranial aneurysm. Hypertension 2019;73:491-6.  Back to cited text no. 17
Frösen J, Hallikainen J, Pyysalo M, Koivisto T, Lindgren A. Letter by Frösen et al. regarding article ”Potential influences of gut microbiota on the formation of intracranial aneurysm”. Hypertension 2019;74:e22-3.  Back to cited text no. 18
Aboukais R, Loiez C, Leclerc X, Bourgeois P, Wallet F, Menovsky T, et al. Absence of bacteria in intracranial aneurysms. Journal of neurosurgery. 2019;132:1197-201.  Back to cited text no. 19
Frösen J, Hallikainen J, Pyysalo M. Letter to the Editor. Periodontitis as a risk factor for formation, progression, and rupture of intracranial aneurysms. Journal of Neurosurgery. 2019;132:1305-6.  Back to cited text no. 20


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