Analysis of Gut Microbiota and Their Metabolites in CADASIL Patients

Abstract

Background and Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a major hereditary small-vessel disease caused by mutations in NOTCH3. We hypothesized that the gut microbiota may serve as an environmental factor influencing disease progression or phenotype diversity among patients. Our previous study identified taxonomic differences between CADASIL patients and controls. In this study, we aimed to replicate our initial findings and further analyze gut microbial metabolites. Methods We performed 16S rRNA sequencing of gut microbiota in the 24 patients and 17 controls. Of these, 15 patients and 13 controls underwent analyses of fecal metabolites. Results Among the 24 CADASIL patients and 17 controls recruited, 16S rRNA sequencing of fecal samples revealed a significant difference in b-diversity (p=0.015), while no significant difference was observed in a-diversity. Taxonomic analysis identified significant differences in specific bacterial genera, particularly Bacteroides dorei. These findings confirm our previous results, demonstrating that gut microbiota composition differs between CADASIL patients and controls. Additionally, metabolite analysis of fecal samples from 15 CADASIL patients and 13 controls showed a significant elevation of the indole concentration in the patients. Moreover, indole levels were positively correlated with the abundance of Streptococcus mutans and Streptococcus parasanguinis. Conclusions Both indole and Streptococcus species have been reported to be associated with atherosclerosis. Our results suggest that alterations in gut microbiota and their metabolites may be associated with the pathophysiology of CADASIL by promoting atherosclerosis.