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. Graphical Abstract Post-stroke reduction of intestinal butyrate-producing bacteria leads to decreased butyrate levels and compromised intestinal barrier integrity, facilitating the translocation of gut-derived LPS into systemic circulation. GV-971 treatment modulates the gut microbiota to restore butyrate-producing populations, thereby increasing intestinal butyrate levels and enhancing its availability in brain tissue. This elevated cerebral butyrate promotes neuronal histone H3 acetylation and subsequent neurogenesis. Concurrently, GV-971-mediated suppression of intestinal LPS production attenuates hippocampal microglial activation, ultimately ameliorating post-stroke cognitive impairment <MediaObject ID="MOESM2"> <VideoObject FileRef="MediaObjects/40168_2025_2257_MOESM2_ESM.mp4" VideoID="B8PJWdhYcj2Lo_1TKuURRW"> <Caption Language="En" xml:lang="en"> <CaptionContent> Video Abstract </CaptionContent> </Caption> </VideoObject> </MediaObject>

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

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2025年11月29日

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Yueran Ren,
Jingru Liang,
Jiahui Xie,
Weike Hu,
Minlin Lai,
Xiao Li,
Jiafeng Zhang,
Yifeng Zheng,
Qiheng Wu,
Hongwei Zhou,
Jia Yin

摘要

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.

Graphical Abstract

Post-stroke reduction of intestinal butyrate-producing bacteria leads to decreased butyrate levels and compromised intestinal barrier integrity, facilitating the translocation of gut-derived LPS into systemic circulation. GV-971 treatment modulates the gut microbiota to restore butyrate-producing populations, thereby increasing intestinal butyrate levels and enhancing its availability in brain tissue. This elevated cerebral butyrate promotes neuronal histone H3 acetylation and subsequent neurogenesis. Concurrently, GV-971-mediated suppression of intestinal LPS production attenuates hippocampal microglial activation, ultimately ameliorating post-stroke cognitive impairment

Video Abstract