Gut microbial histamine and serotonin promote cerebrovascular angiogenesis: Evidence from moyamoya disease

Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by arterial stenosis and compensatory neovascularization, but its upstream drivers remain poorly defined. Here, we identify Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), a traditionally probiotic species, as a context-dependent pathobiont. Integrated metagenomic and metabolomic analyses revealed enrichment of B. pseudocatenulatum in MMD, closely associated with elevated microbial-derived histamine and serotonin. In mice, chronic oral administration of B. pseudocatenulatum disrupted intestinal barrier integrity and increased gut microbial production and systemic levels of histamine and serotonin. These changes were accompanied by systemic inflammation and activation of angiogenic pathways, which together promoted MMD-relevant cerebrovascular remodeling in experimental models. Notably, direct administration of histamine or serotonin to mice reproduced key MMD-like vascular phenotypes, supporting the conclusion that these microbial metabolites are sufficient to induce selected MMD-relevant vascular changes in experimental models. Our findings propose a microbial-metabolite-vascular axis and suggest that the role of specific Bifidobacterium strains may be more nuanced than previously recognized. These results provide a mechanistic framework for understanding the gut-brain axis in neurovascular pathology and nominate the microbiome and its metabolic products as potential targets for non-invasive diagnostics and precision therapeutic interventions in MMD.