Integrated gut microbiota and metabolome signatures revealed by deep metagenomic sequencing in post-stroke cognitive impairment with type 2 diabetes.

UNLABELLED: Post-stroke cognitive impairment (PSCI) is significantly exacerbated in individuals with type 2 diabetes mellitus (T2DM), yet the underlying gut microbial and metabolic mechanisms remain unclear. In this study, baseline fecal samples from 28 diabetic PSCI (PSCI-DM) patients and 29 matched non-PSCI non-diabetic controls were subjected to deep metagenomic sequencing and untargeted metabolomics. Although alpha diversity was preserved, subtle but meaningful shifts were observed in bacterial and fungal composition. The PSCI-DM group exhibited depletion of beneficial butyrate-producing taxa, including Lachnospira spp. and Butyribacter intestini, and enrichment of Butyricimonas virosa. Five fungal species, including Torulaspora globosa and Pichia kudriavzevii, were significantly reduced. Metabolomic profiling identified 45 differentially abundant metabolites, with decreases in neuroprotective compounds, such as 9-oxononanoic acid, C16-ceramide, and nootkatone, and increases in metformin and bile acid derivatives. Abundances of microbial functional pathways linked to energy metabolism were elevated, while those involved in cofactor and neurotransmitter precursor synthesis were reduced. Significant correlations were found between specific microbes and metabolites, suggesting coordinated dysregulation across kingdoms. However, only a limited subset of microbial features remained independently associated with cognitive performance. Specifically, metabolites Nb-palmitoyltryptamine and pipecolic acid, and fungal species Pichia kudriavzevii showed significant correlations with Montreal cognitive assessment (MoCA) scores for cognitive impairment. These findings reveal a tripartite gut ecosystem signature in PSCI-DM and provide a mechanistic foundation for microbiota-targeted therapeutic strategies.

IMPORTANCE: In the context of type 2 diabetes, post-stroke cognitive impairment represents a clinically prevalent yet mechanistically underexplored condition with limited therapeutic options. This study combined metagenomic sequencing with non-targeted metabolomics to reveal the coordinated dysregulation of bacteria, fungi, and host-related metabolites in the gut of type 2 diabetes mellitus with post-stroke cognitive impairment (PSCI-DM) patients. The research indicates that cognitive impairment is not solely related to the overall decline in microbial diversity, but also involves the targeted reduction of neuroprotective butyrate-producing bacteria, the absence of specific gut fungi, and the corresponding reduction in neural activity and lipid metabolites. These findings collectively establish the gut microbiota-metabolite characteristics of PSCI-DM patients, providing a theoretical basis for targeted probiotic intervention measures to prevent or alleviate cognitive decline in diabetic patients after stroke.