Oral microbiota dysbiosis related to the cortical thinning and cognitive impairment in cerebral small vessel disease

Background: Prior studies have linked the microbiota to brain diseases, whereas the longitudinal effects of the oral microbiota on cortical thinning and cognitive impairments in cerebral small vessel disease (CSVD) remain unexplored. Methods: We recruited 120 CSVD patients and 40 healthy controls (HCs). The subgingival plaque microbiota was sequenced by a metagenomic approach. Cortical thickness was assessed using GM-centile, an age- and sex-normalized MRI metric. Differential microbial taxa and KEGG orthologs (KOs) between groups were identified using MaAsLin2. Associations between key differential taxa with CSVD-specific cortical thinning were examined using the Spearman test, and those with MoCA score and plasma inflammatory markers (CRP and lymphocyte counts) were examined by linear regression models. Mediation models evaluated the indirect role of cortical thinning in the relationship between microbial abundance and cognitive function. Generalized estimation equations validated the longitudinal effects of the microbiota on cortical thinning progression. Result: We identified distinct oral microbiota dysbiosis in CSVD, including depletion of g_Selenomonas and g_Leptotrichia and enrichment of g_Treponema. The abundance of these microbes was correlated with longitudinal cortical thinning in the frontal gyrus, insular lobes, and inferotemporal gyrus. Enrichment analysis revealed that CSVD-enriched KOs were linked to the upregulation of LPS-mediated pro-inflammatory pathways, while those depleted were associated with the reduced biosynthesis of neuroprotective short-chain fatty acids (SCFAs). g_Leptotrichia abundance showed negatively correlation with CRP (p = 0.045). Mediation analyses indicated that the association between g_Leptotrichia depletion and baseline cognitive impairment was mediated by bilateral insular cortical thinning (both p < 0.05). Additionally, the association between g_Leptotrichia depletion and one-year cognitive decline was mediated by superior frontal cortical thinning (p = 0.033). Conclusions: Oral microbiota dysbiosis in CSVD patients reflects a pro-inflammatory state, characterized by enhanced LPS synthesis and reduced SCFAs production. This dysbiosis is associated with CSVD-specific cortical thinning in regions vulnerable to neuroinflammation, which in turn mediates cognitive impairment.