Emerging evidence suggests that the gut microbiota influences neurovascular injury through modulation of host metabolism and immune signaling. We investigated how changes in gut microbial diversity and tryptophan (TRP) metabolism affect lesion burden in a murine model of neurovascular unit damage and microhemorrhage induced by focal irradiation. Mice were treated with broad-spectrum antibiotics (ABX) to deplete gut microbiota, and lesion burden was subsequently assessed radiographically. Microbial composition was profiled using 16S rRNA sequencing, and functional predictions were generated using PICRUSt2 with KEGG ortholog mapping. As ABX treatment suggested altered host–microbiome competition for TRP and its metabolites, stool and plasma metabolomics were performed to quantify TRP metabolite levels, and a separate cohort was fed a high-TRP diet to assess microbiome-dependent effects on lesion burden. ABX-treated mice exhibited reduced microbial diversity and significantly decreased lesion burden. This protective phenotype was associated with increased circulating plasma TRP metabolites. In contrast, ABX-naive mice fed with high TRP showed increased lesion burden, despite similarly elevated plasma TRP levels. These opposing effects suggest the microbiome alters the impact of TRP and its metabolites on brain injury. Functional predictions based on 16S rRNA sequencing revealed downregulation of phenylalanine, tyrosine, and TRP biosynthesis/metabolism in ABX-treated mice. Stool metabolomics confirmed elevated TRP levels in ABX-treated mice (log2FC = 1.4, p = 0.03), indicating reduced microbial utilization and supporting competition between host and microbiota for essential amino acids. The contrasting lesion outcomes in ABX-treated versus high TRP-fed ABX-naive mice underscore the role of microbial metabolism in shaping host responses to dietary components. We hypothesize that microbiota-derived TRP metabolites—not TRP itself—may drive blood-brain barrier (BBB) disruption via immune activation and T cell polarization. TRP and its metabolites have been identified in other diseases of the BBB and neurovascular unit physiology. Collectively, our data reveal a complex interaction between gut ecology, amino acid metabolism, and neurovascular unit injury that may inform future microbiome-targeted therapies. These findings offer a mechanistic framework to interpret its clinical significance.
Yuan et al. (Thu,) studied this question.