Sodium oligomannate modulates the gut-brain axis to alleviate post-stroke cognitive impairment by restoring butyrate metabolism

Nov 29, 2025Microbiome

Sodium oligomannate may improve thinking problems after stroke by restoring gut metabolism linked to brain health

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Abstract

Fecal butyrate levels are significantly reduced in post-stroke cognitive impairment patients and correlate with cognitive scores.

A machine learning model using butyrate levels and clinical factors shows strong predictive performance for cognitive impairment.
In a mouse model of stroke, reduced butyrate-producing bacteria and fecal butyrate levels are linked to neuronal loss and inflammation.
Treatment with sodium oligomannate (GV-971) improves cognitive function and restores butyrate-producing gut bacteria in both sexes.
GV-971 enhances butyrate production by promoting specific metabolic pathways and reduces inflammation in the gut and brain.
Butyrate supplementation inhibits certain enzymatic activity and reduces inflammation in brain cells in laboratory settings.

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BACKGROUND: Post-stroke cognitive impairment (PSCI) affects up to half of stroke survivors, severely impacting their quality of life. Despite its prevalence, the pathogenesis of PSCI remains poorly understood, and no specific pharmacological treatments are currently available.

RESULTS: In PSCI patients, fecal butyrate levels were significantly reduced and correlated with cognitive scores. A machine learning model incorporating butyrate levels, butyrate-producing bacteria, and clinical factors (education, smoking, body mass index [BMI], hemoglobin) demonstrates strong predictive performance (area under the curve [AUC]: 0.793 internal, 0.795 external validation). In a transient middle cerebral artery occlusion (tMCAO) mouse model, both sexes displayed sustained gut microbiota dysbiosis featuring decreased butyrate-producing bacteria and fecal butyrate concentrations, concomitant with hippocampal neuronal loss and microglial activation. Sodium oligomannate (GV-971) treatment ameliorated cognitive impairment in a sex-independent manner and restored butyrate-producing gut bacteria. Metagenomic analysis revealed that GV-971 enhanced butyrate production by promoting D-glucuronate degradation and upregulating butyrate synthesis pathway abundance. The elevated butyrate promoted acetylation of histone H3 at lysines 9 and 14 (Ac-H3K9/K14) in colonic and hippocampal neurons, stimulating neurogenesis, while concurrently reducing gut-derived lipopolysaccharide (LPS) and microglial inflammation. Antibiotic treatment and fecal microbiota transplantation established the essential role of butyrate-producing microbiota in mediating GV-971's effects. In vitro, butyrate supplementation significantly inhibited HDAC3 enzymatic activity in HT22 cells and alleviated LPS-induced inflammatory responses in BV2 microglia.

CONCLUSIONS: Intestinal butyrate levels are significantly associated with PSCI. GV-971 mitigates post-stroke cognitive decline by modulating the gut microbiota to increase butyrate production, highlighting its potential as a therapeutic agent for PSCI.

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Sodium oligomannate modulates the gut-brain axis to alleviate post-stroke cognitive impairment by restoring butyrate metabolism

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