The current study demonstrated that oral carriage of Cnm-positive S. mutans was independently associated with a greater number of all, deep, and lobar, but not infratentorial, CMBs. The similar frequencies of CAA and strictly lobar CMBs between patients with Cnm-positive and those with Cnm-negative S. mutans suggests that Cnm-positive S. mutans does not accelerate the pathophysiology of CAA.
S. mutans is an anaerobic Gram-positive coccus that is detected in the oral cavity of approximately 90% of the general population15. Bacteremia caused by S. mutans is almost inevitable in daily life because of toothbrushing, flossing, or tooth extraction10. The major sources of S. mutans are mothers or caregivers18. S. mutans is vertically transmitted and colonizes the mouths of infants18 and is rarely implanted during adulthood19. However, it frequently disappears from the oral cavity of edentulous people because S. mutans resides on the tooth surface20. We therefore excluded patients from whom no S. mutans was detected and compared those with Cnm-positive and Cnm-negative S. mutans in this study.
Cnm-positive S. mutans is characterized by its binding to components of the vascular basement membrane, such as collagen-IV and laminin12,16,21, while Cnm-negative S. mutans cannot attach to soft tissues16,21. Aging and vascular risk factors including hypertension induce endothelial injury and increase the thickness of the basement membranes, resulting in collagen-IV and laminin exposure in small cerebral arteries22,23. Once Cnm-positive S. mutans adheres to the basement membrane21, infiltration of neutrophils may aggravate local inflammation, resulting in increased permeability of the blood-brain barrier and increased production of enzymes, such as matrix metalloproteinase-913, that accelerate endothelial damage, leading to CMBs (Figure 3)11.
Our previous cross-sectional9 and retrospective longitudinal studies11 showed a strong association of Cnm-positive S. mutans with deep, but not lobar, CMBs. The seemingly different results regarding lobar CMBs may stem from the different sample sizes between the previous and current studies. Twenty-one or fewer stroke patients with Cnm-positive S. mutans were registered in the previous studies9,11. Hachinski described the “vascular centrencephalon” as the phylogenetically ancient part of the brain that is perfused by short straight arteries with few branches, transmitting pressure directly from the large arteries to small arterioles24,25. However, the cortex is supplied by long arteries with many branches, resulting in a large blood pressure decrement in the brain26. In a computational hemodynamics model of hypertension patients with a blood pressure of 192/113 mmHg in the brachial artery, the small arterial pressure was 169/101 mmHg in the lenticulostriate bed but only 117/68 mmHg in the posterior parietal artery bed26. This marked difference in the arterial pressure between the deep and cortical regions could explain why lacunar infarcts related to vasculopathies induced by high blood pressure preferentially occur in the vascular centrencephalon rather than in the cortex25.
However, stroke-prone SHRs, a rat model of systemic hypertension, exhibit endothelial damage not only in the deep arteries but also in the cortical arteries23. Furthermore, cerebrovascular integrity is more severely damaged in stroke-prone SHRs than in SHRs, even though stroke-prone SHRs and SHRs show similar degrees of hypertension27. Hypertensive patients who have achieved target blood pressure levels still display autonomic dysfunction28 and a high residual cardiovascular risk29. These findings suggest that factors other than high blood pressure also contribute to endothelial injury in patients with systemic hypertension10, which may explain the increased numbers of lobar and deep CMBs in patients with Cnm-positive S. mutans. Furthermore, patients with a high-salt diet exhibit impaired endothelium-dependent vasodilation even without any blood pressure changes30. The age of onset of hypertension is associated with end organ damage, independent of the measured blood pressure31. Hence, several known and unknown factors other than hypertension may contribute to endothelial injury in small arteries, enabling Cnm-positive S. mutans to attach to the basement membranes and induce both deep and lobar CMBs.
There are some limitations to this study. First, this study was retrospectively performed, posing a potential risk of selection bias. Second, only 428 patients (13.6%) of the total 3154 stroke patients underwent an oral bacterial evaluation. We attempted to widely recruit stroke patients, but older and severe stroke patients tended not to participate in the study, largely because of difficulties in explaining the research to those with impaired consciousness or various disabilities including dementia and advanced frailty. This resulted in a younger age and lower NIHSS scores in patients who underwent bacterial assessments. Third, the proportion of patients with ICH and the frequencies of patients with a history of hypertension or atrial fibrillation were different between those who did and did not undergo oral bacterial examination. We previously reported that Cnm-positive S. mutans is more closely associated with hypertensive ICH than ischemic stroke9, which might have influenced participation in the research or affected the success rate of informed consent acquisition. Fourth, while cognitive function was not assessed in this study, we are now performing a prospective observational study to evaluate the effects of Cnm-positive S. mutans on cognition.
In conclusion, we found that Cnm-positive S. mutans was associated with a higher number of both lobar and deep CMBs. The close association between Cnm-positive S. mutans and CMBs suggests that reduction of Cnm-positive S. mutans in the oral cavity may serve as a novel therapeutic approach for improving the long-term prognosis of stroke patients.