Prevalence, risk factors, and associations of the gut microbiota with neuroimaging markers of cerebral small vessel disease

Abstract

Background. Cerebral small vessel disease (SVD) is a common pathology that affects the small arteries, veins, and capillaries of the brain, and is implicated in vascular dementia, the leading cause of dementia in East Asia, intracerebral hemorrhages, up to 46% of ischemic strokes as lacunar strokes, and other neuropsychiatric and behavioral disorders; SVD may coexist with and exacerbate Alzheimer's disease, the leading cause of dementia worldwide. However, the pathophysiology of and risk factors behind SVD are incompletely understood. Though age and hypertension have been established as the two most important risk factors, the failure of these and other conventional vascular risk factors (e.g., smoking, hyperlipidemia, etc.) to fully explain the pathogenesis of SVD have prompted a search for novel contributors and causative mechanisms. The gut microbiota (GM) has received much attention in recent years for its role in human health and disease, yet the few studies that have been conducted investigating associations of GM with SVD have produced promising but conflicting results. Objectives. A cross-sectional study of community-dwelling Hong Kong Chinese was initiated to investigate the prevalence of vascular risk factors in the community, the prevalence of SVD and especially early subclinical SVD, associations between the two, and the potential role of the GM in SVD. Under the hypothesis that aspects of the GM are associated with a greater severity of SVD independent of conventional vascular risk factors, this work embarked on characterizing these three dimensions and attempts to shed light on their complex relationships with each other. Methods. 313 middle-aged individuals without symptomatic cardiovascular and cerebrovascular diseases meeting this study’s inclusion and exclusion criteria were recruited from the Hong Kong public from 1st July 2018 to 30th June 2023. Interviews and questionnaires characterized each individual’s medical history; estimates of daily sodium intake and lipid profiles were obtained from clinical samples; 24-hour ambulatory monitoring enabled comprehensive assessments of blood pressure parameters; ultrasonography and specialized four-limb blood pressure measurements provided insights into each individual’s vascular health; shotgun sequencing were performed on each individual’s stool samples for true metagenomics study; last but not least, 3 Tesla magnetic resonance imaging revealed each individual’s burden of SVD. Results. Prevalence of deep and periventricular white matter hyperintensities (WMH) (72% and 88% of the study population respectively) and cerebral microbleeds (CMBs) (9% of the study population), which are neuroimaging markers of SVD, were found to be higher than reported in the literature. On the prevalence of vascular risk factors, compared to women, men were found to have higher body mass index (BMI) (25.1±3.3kg/m^2 vs 22.8±3.6kg/m^2, p<0.001), waist-hip ratios (0.90±0.06 vs 0.83±0.07, p<0.001), and daily sodium intake (5.9±1.7g/d vs 5.2±1.6g/d, p=0.003). Various measures of office and ambulatory blood pressures were also higher in men, including office systolic blood pressure (SBP) (126±15mmHg vs 118±15mmHg, p<0.001), office diastolic blood pressure (DBP) (83±10mmHg vs 74±9mmHg, p<0.001), 24-hour SBP (130±14mmHg vs 121±12mmHg, p<0.001), 24-hour DBP (83±10mmHg vs 74±8mmHg, p<0.001), daytime SBP (133±14mmHg vs 123±12mmHg, p<0.001), daytime DBP (85±10mmHg vs 75±9mmHg, p<0.001), nighttime SBP (121±17mmHg vs 109±12mmHg, p<0.001), and nighttime DBP (75±11mmHg vs 66±8mmHg, p<0.001). Men were also found to have higher ankle-brachial index (ABI) (1.21±0.08 vs 1.13±0.08, p<0.001) and carotid intima-media thickness (CIMT) (0.65±0.15mm vs 0.58±0.15mm, p<0.001). The study population on average had higher levels of daily sodium intake (5.6±1.7g/day) than recommended. Associations of conventional vascular risk factors with total SVD score and total WMH volume, both markers of SVD burden, were explored with ordinal and linear regression respectively. Age was associated with both total SVD score (adjusted odds ratio (OR) 1.07 (95% CI 1.03-1.12)) and total WMH volume (adjusted beta 0.13 (95% CI 0.09-0.17)); this association remained significant in subsequent multivariable regression analyses. Waist-hip ratio was also associated with both total SVD score (adjusted OR 115.53 (95% CI 2.07-6450.79)) and total WMH volume (adjusted beta 4.78 (95% CI 0.55-9.01)). However, BMI was not associated with either marker. A previous diagnosis of obstructive sleep apnea (OSA) was associated with higher WMH volume (adjusted beta 1.47 (95% CI 0.23-2.71)), but not OSA risk as determined using the STOP-BANG score. 24h mean systolic blood pressure was associated with total SVD score (adjusted OR 1.02 (95% CI 1.00-1.04), p=0.03). Several other blood pressure parameters and measures of vascular health were found to be associated with markers of SVD but did not retain their associations after adjusting for age and sex. Despite gender differences in exposure to traditional vascular risk factors, men did not have a significantly higher SVD burden than women. Finally, this work is the first in literature to identify Bacteroides coprophilus, Bacteroides salyersiae, and Alistipes shahii were associated with higher WMH volumes in men, independent of conventional vascular risk factors. These species were however not associated with WMH volume in women. This work is also first in reporting Ruminococcus lactaris, Fusicatenibacter saccharivorans, and GGB3277 SGB4327 were positively associated with total SVD score, while Coprococcus SGB4669 and Lachnospiraceae bacterium AM48 27BH were negatively associated with total SVD score. Measures of GM diversity did not show any significant associations with changes in WMH volume, providing contrasting evidence to two smaller cross-sectional studies reported previously in the literature. Conclusions. Overall, this work adds valuable insights into the prevalence, risk factors, and potential role of the gut microbiota in the pathogenesis of cerebral SVD. The findings highlight the higher than reported prevalence of SVD in the community, the importance of considering risk factors and pathophysiological mechanisms beyond conventional vascular risk factors, and the emerging role of the gut microbiota as one of the novel contributors to the pathogenesis of SVD. Further research is warranted to elucidate the underlying mechanisms of these associations and to explore potential therapeutic interventions targeting the microbiota-gut-brain axis in the management of SVD.