A Segatella Copri-centered Gut Microbiota-mediated Metabolic Dysregulation Associated with Transition from Asymptomatic to Symptomatic Intracranial Atherosclerosis.

Five robust biomarkers were identified as associated with the transition from asymptomatic to symptomatic intracranial atherosclerosis using machine learning.

• The study used fecal shotgun metagenomics and untargeted plasma metabolomics in a case-control study of 63 iLAA-IS cases and 56 aICAS controls.
• Machine learning with 10-fold nested cross-validation was used to identify biomarkers.
• One risk-associated biomarker was identified: Alistipes putredinis.
• Four protective biomarkers were identified: Segatella copri, Gln-Gly, Methionine Sulfoxide, and N6-Acetyl-L-Lysine.

Integrated models incorporating the identified microbiota-metabolite biomarkers significantly improved predictive performance compared to conventional risk factors.

• The mean AUC for Gln-Gly was 0.9104 versus 0.7188 for conventional risk factors.
• This improvement was demonstrated across integrated models incorporating the five identified biomarkers.
• Conventional risk factors alone showed substantially lower discriminatory ability (mean AUC 0.7188).

Depletion of Segatella copri coincided with a broad loss of anabolic metabolic pathways in the transition from asymptomatic to symptomatic intracranial atherosclerosis.

• The affected anabolic pathways included BCAA biosynthesis, folate-SAM-methionine metabolism, and tRNA charging.
• These pathways were positively linked to amino acid-related metabolites.
• The metabolic dysregulation was described as 'Segatella copri-centered,' indicating a coordinated functional collapse associated with this species' depletion.
• In contrast, pathways associated with Alistipes putredinis showed no such coupling to amino acid-related metabolites.

The aICAS-to-iLAA-IS transition is characterized by chronic metabolic dysregulation involving a gut microbiota-metabolite axis rather than acute changes.

• The study design compared 63 symptomatic ischemic stroke (iLAA-IS) cases to 56 asymptomatic intracranial atherosclerotic stenosis (aICAS) controls.
• The findings suggest the dysregulation is chronic in nature, reflecting a continuum from asymptomatic to symptomatic disease.
• The multi-omic signature involved both microbial species and plasma metabolites as interconnected components.
• The mechanistic analyses indicated that microbial depletion (particularly Segatella copri) was functionally linked to downstream metabolite changes.

Alistipes putredinis was identified as a risk-associated gut microbiota species in the transition to symptomatic intracranial large-artery atherosclerotic ischemic stroke.

• Alistipes putredinis was the sole microbial risk factor identified among the five robust biomarkers.
• Unlike Segatella copri, the pathways of Alistipes putredinis showed no coupling to amino acid-related metabolites.
• Alistipes putredinis was identified through machine learning with 10-fold nested cross-validation applied to shotgun metagenomic data.