An interview with Dr. Masafumi Ihara, MD, PhD; Head, Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan.
Interviewed by Dr. Saurav Das, MD; Fellow in Vascular Neurology, Washington University School of Medicine, St. Louis.
They will be discussing the article “Oral Carriage of Streptococcus mutans Harboring the cnm Gene Relates to an Increased Incidence of Cerebral Microbleeds,” published in the December 2020 issue of Stroke.
Dr. Das: Dr. Ihara, on behalf of the Blogging Stroke team, it is my pleasure to welcome you to this author interview about your publication in Stroke regarding the association between CNM gene-positive Streptococcus mutans and increased incidence of cerebral microbleeds. Given Streptococcus mutans is a common pathogen associated with dental caries, it is a potential treatment target to prevent increase in cerebral microbleeds.
Many of our readers come from a stroke background and may not be as familiar with oral pathology. It will be of interest to start by discussing some common oral pathogens implicated in cerebrovascular disease. Also, what is specific about Streptococcus mutans, and particularly the ones positive for CNM gene?
Dr. Ihara: More than 500 bacterial species have been estimated to exist in the oral cavity, and many remain to be identified and characterized. Of all the known pathogenic oral bacteria, a few have been linked to cerebrovascular diseases. Our co-investigator Prof. Nakano reported that certain strains of Streptococcus mutans (S. mutans) are potential risk factors for intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats and mice with photochemically induced middle cerebral artery occlusion.1 This corresponds with findings showing periodontal infections to be risk factors for stroke, and that S. mutans is detected in 100% of samples of atherosclerotic plaques. S. mutans is a major pathogen in dental caries that can cause bacteremia by dental procedures, such as tooth extraction and periodontal surgery, or even tooth brushing in daily life. S. mutans is well known to be responsible for infective endocarditis. The hemorrhage-causing S. mutans strains express collagen-binding protein Cnm on their cell surface, enabling them to attach to exposed collagen fibers on the surface of damaged blood vessels and prevent platelet activation, thereby, leading to hemorrhages. Another dental bacterium, Porphyromonas gingivalis (P. gingivalis), is also found in atherosclerotic plaques and has been linked to the increased risk of ischemic stroke. P. gingivalis adheres to and infects endothelial cells not only to increase the expression of endothelial adhesion molecules and promote monocyte/macrophage infiltration, but also to produce cysteine proteinase gingipains, which activate protease-activated receptors-1 and -4 on platelets to induce platelet aggregation. Thus, infection from P. gingivalis could cause small vessel disease pathology through thrombotic occlusion and BBB disruption through inflammation.
Dr. Das: In the paper, the authors report increased incidence of cerebral microbleeds in CNM gene positive Streptococcus mutans group, particularly deep microbleeds reaching statistical significance, as opposed to lobar microbleeds. Would it be correct to interpret that the described pathophysiology accelerates hypertensive angiopathy primarily, as opposed to amyloid angiopathy? Also, did these patients have any cognitive assessment?
Dr. Ihara: We would like to propose a 2-hit theory for development of the cerebral microbleeds. Arteriolosclerosis of the perforating arteries is the first hit because such short straight arteries with few branches transmit high blood pressure straight through to end-arterioles and are vulnerable to arterial hypertension. The collagen-binding S. mutans attaches to the damaged vessels with exposed collagen, thereby causing cerebral microbleeds in the deep area (vascular centrencephalon) supplied by the perforating arteries. By contrast, the lobar regions where cerebral amyloid angiopathy occurs are supplied by long artery/arteriole with many branches and with relatively low blood pressure. Therefore, S. mutans may have a lower chance to attach to the exposed collagen in the lobar regions. This may be why the statistical significance was observed in deep microbleeds but not in lobar microbleeds in the current study.
We have not assessed cognitive impairment in our cohort. However, our collaborator previously assessed cognitive function in population cohort and found that cognitive function assessed by letter fluency tasks was lower among subjects with cnm-positive S. mutans.2 So, there is a possibility that cnm-positive S. mutans is associated not only with stroke but also with cognitive impairment.
Dr. Das: Are there any ongoing or upcoming randomized clinical trials addressing this issue?
Dr. Ihara: We are currently conducting a prospective, multi-center cohort study to determine whether cnm-positive S. mutans or other oral bacteria responsible for periodontitis are associated with cerebral microbleeds, cerebral hemorrhage, and cognitive impairment. We have not planned any interventions yet, but Cnm may be specifically targeted to prevent cerebral hemorrhage in subjects harboring cnm-positive S. mutans.
Dr. Das: Based on the findings presented in this paper, what practice recommendations do you have for stroke physicians? For example, would you recommend a blood culture in an inpatient setting and regular dentist visits in an outpatient setting? The increase in microbleeds over months may represent prolonged slow bacteremia. Do you foresee a need for a long course of antibiotic therapy in these patients?
Dr. Ihara: We believe good oral health is very important to decrease the number of S. mutans. A high number of S. mutans in the oral cavity and accompanying dental caries or periodontitis all increase the chance of S. mutans to enter the bloodstream and reach the brain. Unfortunately, there are no antibiotics to get rid of S. mutans from the oral cavity because oral microbiome forms the antibiotics-resistant biofilm. So, oral hygiene would be a top priority. Another point is that S. mutans will not attach to the vascular wall if vascular integrity is maintained and collagen is not exposed. Therefore, prevention or treatment of lifestyle-related diseases such as hypertension and diabetes that can potentially damage the cerebral blood vessels should be another priority even if you have cnm-positive S. mutans.
Dr. Das: This study included 111 Japanese patients admitted with stroke or TIA. Cultural beliefs and lifestyles are known to affect oral health. Does anything come to your mind specific to the Japanese lifestyle that our readers must acknowledge while using these results in the patient population in other countries?
Dr. Ihara: Oral microbiome is established by the age of three, and S. mutans is usually transmitted in a vertical (parent to child) manner. Previously in Japan, saliva-sharing activities between children and parents/caregivers were common, and several decades ago, early childhood caries among 3-year-olds was more than 50%. Recently, Japanese dentists advise parents not to pre-chew food before giving it to babies, and public awareness and parent education about oral health has been raised. The rate of early childhood caries has now decreased to less than 20% in Japan. Oral health consciousness of the parents may matter.
Dr. Das: Thanks for finding time for this interview, Dr. Ihara. It was a pleasure talking to you.
1. Nakano K, Hokamura K, Taniguchi N, Wada K, Kudo C, Nomura R, et al. The collagen-binding protein of Streptococcus mutans is involved in haemorrhagic stroke. Nat Commun. 2011;2:485.
2. Watanabe I, Kuriyama N, Miyatani F, Nomura R, Naka S, Nakano K, et al. Oral Cnm-positive Streptococcus Mutans Expressing Collagen Binding Activity is a Risk Factor for Cerebral Microbleeds and Cognitive Impairment. Sci Rep. 2016;6.