Characterizing the role of the microbiota-gut-brain axis in cerebral small vessel disease: An integrative multi‑omics study

Abstract

• Both depleted and enriched gut microbes were found in CSVD patients. • The differential microbes related to metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. • The affected metabolites related to multi-modal neuroimaging measures in association with cognition and emotion in CSVD patients. • We demonstrated a gut microbiome-metabolome-brain-behavior pathway through which gut microbiota dysbiosis was linked to CSVD. Prior efforts have revealed changes in gut microbiome, circulating metabolome, and multimodal neuroimaging features in cerebral small vessel disease (CSVD). However, there is a paucity of research integrating the multi-omic information to characterize the role of the microbiota-gut-brain axis in CSVD. We collected gut microbiome, fecal and blood metabolome, multimodal magnetic resonance imaging data from 37 CSVD patients with white matter hyperintensities and 46 healthy controls. Between-group comparison was performed to identify the differential gut microbial taxa, followed by performance of multi-stage microbiome-metabolome-neuroimaging-neuropsychology correlation analyses in CSVD patients. Our data showed both depleted and enriched gut microbes in CSVD patients. Among the differential microbes, Haemophilus and Akkermansia were associated with a range of metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. Furthermore, the affected metabolites were associated with neuroimaging measures involving gray matter morphology, spontaneous intrinsic brain activity, white matter integrity, and global structural network topology, which were in turn related to cognition and emotion in CSVD patients. Our findings provide an integrative framework to understand the pathophysiological mechanisms underlying the interplay between gut microbiota dysbiosis and CSVD, highlighting the potential of targeting the microbiota-gut-brain axis as a therapeutic strategy in CSVD patients.