Gut Microbiota–Brain Axis Emerges as Key Regulator of Post-Stroke Cognitive Impairment Through Epigenetic Mechanisms
Key Insights
Gut microbiota dysbiosis after stroke drives post-stroke cognitive impairment (search) (PSCI) through altered microbial metabolites including short-chain fatty acids (search), B vitamins, and tryptophan derivatives.
Microbiota-derived metabolites such as butyrate regulate epigenetic processes—DNA methylation, histone modification, and non-coding RNA—affecting neuroinflammation and synaptic plasticity.
PSCI patients exhibit distinct gut microbiota profiles with reduced α-diversity, depleted SCFAs, and elevated Enterobacteriaceae, offering potential diagnostic biomarkers.
Stroke remains the leading cause of death and disability worldwide, with approximately 13 million new cases reported annually, and survivors face a 5- to 8-fold higher risk of developing cognitive impairment compared with the general population. Post-stroke cognitive impairment (search) (PSCI), one of the most common neuropsychiatric complications after stroke, is characterized by deficits in memory, attention, executive function, and learning ability, yet its underlying mechanisms remain incompletely understood and current treatments are largely derived from general stroke management strategies with limited effectiveness.
A comprehensive review published in Frontiers in Cellular and Infection Microbiology now synthesizes emerging evidence that gut microbiota (GM) and their metabolites play a critical role in the pathogenesis of PSCI through the microbiota-gut-brain (MGB) axis, with epigenetic regulation serving as a central mechanistic link.
Gut microbiota dysbiosis defines PSCI
Clinical studies have identified distinctive GM profiles in PSCI patients. Liu et al. (2020) reported reduced α-diversity, compositional dysbiosis, and metabolite depletion—particularly diminished short-chain fatty acids (search) (SCFAs)—alongside elevated Fusobacterium abundance compared with non-PSCI controls. Wang et al. (2022) further demonstrated that PSCI cohorts display exacerbated peripheral inflammation and elevated Enterobacteriaceae levels. These findings were validated through fecal microbiota transplantation (FMT) experiments, wherein mice colonized with GM from PSCI donors exhibited elevated Enterobacteriaceae abundance, impaired cognitive performance, intestinal barrier dysfunction, reduced fecal butyrate concentrations, and upregulated TLR4 expression.
Additional studies revealed enrichment of Actinobacterota phylum (e.g., Bifidobacterium and Alloscardovia) and specific Bacillota species (e.g., Anaerostipes hadrus and Lactobacillus gasseri) in PSCI patients. A meta-analysis corroborated phylum-level dysbiosis, showing increased Pseudomonadota and Bacteroidaceae, Lachnospiraceae, and Veillonellaceae at the family level, though Enterobacteriaceae depletion contrasted with Wang's observations—a discrepancy that underscores the need for longitudinal studies.
Microbial metabolites as epigenetic regulators
The review highlights how GM-derived metabolites mediate epigenetic reprogramming involved in neuroinflammation, oxidative stress, and neuronal apoptosis. SCFAs, particularly butyrate, have been identified as potent histone deacetylase (HDAC (search)) inhibitors. Treatment with sodium butyrate enhanced acetylation levels of histone H3 and H4 by inhibiting HDAC, elevated BDNF levels in brain tissues, and improved cognitive deficits in stroke rats.
"Pharmacological treatment with butyrate has been found to potentially create an enriched epigenetic platform in the hippocampus and to improve stroke-induced cognitive dysfunction," the authors note, citing Okamura et al. (2023).
Beyond histone modification, SCFAs also influence DNA methylation processes. Butyrate has been shown to prevent α-synuclein-induced DNA damage by upregulating DNA repair genes in a mouse model of Parkinson's disease. SCFAs and protocatechuic acid produced by GM can inhibit the activity of DNMT1 and DNMT3B, enzymes critical for CNS synaptic plasticity and cognitive memory formation.
B vitamins represent another key metabolite class. Nearly all B vitamins participate in one-carbon metabolism, which produces S-adenosylmethionine (SAM)—the sole methyl donor for DNA, RNA, histones, and protein methyltransferases. A cross-sectional study showed that low blood folate levels are an important cause of cognitive impairment in stroke survivors. Sandvig et al. (2024) carried out the first study of biomarkers of vitamin B6 status in PSCI, encouraging further research into potential preventive effects of vitamin B6 supplementation.
Non-coding RNA and chromatin remodeling
The review also addresses non-coding RNA regulation in PSCI. miRNA-532-5p expression levels were significantly reduced in a mouse model of cerebral ischemia, and its overexpression attenuated neuronal damage and apoptosis by inhibiting PTEN and activating the PI3K/Akt signaling pathway. miRNA-511-3p has been suggested as a potential novel biomarker to predict PSCI occurrence in stroke patients.
Chromatin remodeling and RNA modifications, particularly N6-methyladenosine (m6A), represent additional layers of epigenetic regulation. m6A modifications play vital roles in learning and memory, with modulation of RNA methylation shown to improve hippocampus-dependent cognitive function.
TMAO and neurotransmitters
Trimethylamine-N-oxide (search) (TMAO), produced from dietary choline via gut microbial metabolism, accelerates brain aging and cognitive decline by promoting neuronal senescence, damaging synapses, and downregulating synaptic plasticity-associated proteins. TMAO can directly interfere with the methionine cycle by inhibiting S-adenosylhomocysteine hydrolase (SAHH), leading to accumulation of S-adenosylhomocysteine and reduced overall methylation capacity. Notably, the cerebral cortex and hippocampus are more sensitive to these TMAO-induced epigenetic changes compared to the liver.
Therapeutic implications and future directions
The review proposes a new regulatory network model integrating findings from microbiomics, epigenetics, and neuroscience. Therapeutic strategies under investigation include microbiota modulation through probiotics or FMT, metabolite supplementation (particularly SCFAs and butyrate), and epigenetic interventions.
However, the authors caution that most current studies are based on animal models, and cases of direct treatment of clinical PSCI patients using probiotics have not been reported with limited clinical data. "Due to the difficulty of isolation and cultivation of specific strains, the means of faecal transplantation used in therapeutic animal models are mostly with mixed strains, which cannot clarify the effective strains in different diseases," they note.
The authors emphasize that preventive and therapeutic strategies should not be uniform across all post-stroke stages. In the acute phase, strategies may focus on reducing neuroinflammation and stabilizing the blood-brain barrier; during the subacute phase, approaches may aim to promote neuroplasticity and synaptic remodeling; and in the chronic phase, interventions may focus on long-term cognitive rehabilitation and maintenance of microbiota homeostasis.
Future research directions include integrating multi-omics approaches such as metagenomics combined with single-bacteria transcriptomics and epigenomics, implementing personalized treatment protocols, and conducting longitudinal cohort studies to observe the evolution of the entire disease process.