A recent study published in the journal Cell reveals that a bacterial byproduct in the gut may alter immune cells before a stroke, potentially influencing its severity. The findings shed light on the gut-brain axis and its role in neurological disorders, with researchers exploring how gut microbes modulate immune function and the risk of such conditions.
Gut Microbiota and Stroke Severity
Researchers investigated how gut microbial composition affects stroke outcomes through aryl hydrocarbon receptor (AHR) signaling in intestinal dendritic cells (DCs). Using a transient middle cerebral artery occlusion (tMCAO) model, they evaluated microbial profiles associated with stroke severity in mice, employing metagenomic investigations and selective culture techniques.
The study found that 43% of mice developed severe strokes. Ileal microbial diversity and community composition varied with stroke severity, with severe strokes linked to the depletion of obligate anaerobes like Muribaculaceae and Akkermansiaceae, and an increase in E. coli. Although E. coli was more abundant in severe compared to moderate strokes, this difference was not statistically significant.
Indole’s Role in Stroke Severity
The team focused on indole, a byproduct of microbial tryptophan metabolism, measuring its levels in various tissues using Kovács assays and mass spectrometry. In mice, administering indole before a stroke increased infarct volume and neurological deficits, while colonization with an indole-deficient E. coli strain resulted in less severe injuries. Indole also induced AHR-based responses in DCs in vitro, and its detrimental effects on experimental stroke depended on AHR signaling in CD11c+ cells.
In a small human cohort, fecal indole levels were higher in patients with moderate-to-severe strokes, correlating with NIHSS scores. The National Institutes of Health Stroke Scale (NIHSS) scores ≤3.0 represented mild neurological deficit, whereas NIHSS of 13 or greater indicated moderate to severe deficits for selection of the FMT donors. A separate analysis compared fecal indole between patients with NIHSS scores below 5 and those scoring 5 or higher, further supporting an association between indole and stroke severity in humans, though not a causal relationship.
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The study also explored AHR expression across immune cells and organs using flow cytometry, UMAP, scRNA-seq, and PCA. AHR loss increased migratory activity in intestinal DCs, specifically through C-C chemokine receptor type 7 (CCR7)-based mechanisms, and reduced neuroinflammation. CH-223191 administration increased the accumulation of gut-derived DCs in the meninges and mesenteric lymph nodes, leading to higher meningeal Treg frequencies and less neuroinflammation. However, Treg depletion abolished the early neuroprotective effect of AHR inhibition, demonstrating the essential role of Tregs in this protection in mice.
Microbiome-AHR Communication and Stroke Outcomes
Stroke induced limited, time-dependent changes in canonical AHR-responsive genes. Cyp1a1 and Ahrr were transiently reduced throughout the intestine 16 hours after stroke, returning to baseline by 72 hours. Cyp1b1 selectively increased in the ileum at 72 hours, coinciding with the expansion of indole-producing E. coli. In mice lacking AHR in CD11c+ cells, conventional type 2 dendritic cells (cDC2s) and inflammatory macrophages showed reduced expression of several inflammation-associated genes.
Human Relevance and Future Directions
In human metagenomic analyses, E. coli and tnaA were enriched in patients with ischemic stroke compared to controls. Higher tnaA abundance was associated with unfavorable functional outcomes 90 days after stroke in unadjusted analyses. However, after adjusting for clinical factors, tnaA showed a strong trend but no statistically significant independent association with poor outcomes, and E. coli was no longer associated with outcomes. Systemic CH-223191 treatment could affect cell types beyond DCs, whereas the human microbiota findings were correlative.
The researchers emphasize the need for larger prospective human cohorts, studies in female animals, and investigations in other intestinal compartments to determine the broader applicability of these mechanisms. Exploring inter-individual differences in tryptophan metabolism could help assess whether microbial tryptophan metabolism could inform stroke susceptibility and severity. The enrichment of tnaA-encoding bacteria in stroke patients and individuals with obesity or type 2 diabetes supports further study but does not establish microbial tryptophan metabolism as a clinical biomarker or treatment target in humans.