Background: Vascular dementia (VaD), linked to chronic cerebral hypoperfusion and metabolic syndrome (MetS), may result from gut–liver–brain axis disruption involving microbiota dysbiosis, hepatic dysfunction, and systemic inflammation. We aim to test whether restoring this axis with Akkermansia muciniphila (AKK) can reduce neurovascular injury, improve cognition, and reveal microbiota-driven mechanisms in VaD with MetS. Methods: In a clinical cohort, 88 patients with chronic internal carotid artery occlusion and 23 age-matched controls underwent cognitive and liver function tests and fecal 16S rDNA sequencing. A murine VaD+MetS model was induced by BCAS+HFD. Mice received oral AKK or vehicle for 42 days. Cognitive tests, liver ultrasound, plasma metabolomics were assessed. Multi-omics included brain single-cell RNA-seq and bulk RNA-seq of brain, liver, and intestine. Results: Clinically, patients with more severe cognitive impairment showed higher AST/ALT ratios and reduced AKK abundance, linking gut dysbiosis and hepatic dysfunction to cognitive decline. BCAS+HFD mice exhibited cognitive deficits, white matter injury, microglial activation, hepatic steatosis, and hypertriglyceridemia. AKK restored microbial balance, reduced systemic/hepatic inflammation, improved gut and BBB integrity, and enhanced cognition. Metabolomics showed AKK lowered oxidative stress (allantoin) and pro-inflammatory metabolites while increasing lipid metabolism, antioxidants (3-indolepropionic acid), and sphingolipids. Brain scRNA-seq revealed AKK reduced neuroinflammatory, foam-cell–like microglia and increased remyelinating oligodendrocytes, with gene enrichment for myelin formation, synaptic plasticity, and antioxidant defense. Bulk RNA-seq confirmed upregulation of myelin-repair and synaptic genes (Arc, Mbp) and downregulation of inflammatory mediators (Pdlim2). Liver transcriptomics showed reduced chemokines (Ccl2, Ccl7) and lipid droplet genes (Cidec), with increased lipid metabolism (Msmo1, Fdft1) and anti-inflammatory regulators (Zfp36). Intestinal RNA-seq indicated enhanced barrier function (ACE2, Lpcat3) and reduced chemotaxis (Ccl5). Conclusion: AKK depletion associates with VaD severity, and supplementation restores gut–liver–brain axis homeostasis, reduces systemic/neuroinflammation, and improves cognition in VaD+MetS. AKK is a promising microbiota-based therapy for vascular cognitive impairment, particularly in patients with metabolic comorbidities.
Cui et al. (Thu,) studied this question.