Ischemic Stroke and the Microbiome: Exploring the Gut-Brain Link

Ischemic stroke, in brief

Ischemic stroke occurs when cerebral blood flow is obstructed, depriving neurons of oxygen, glucose, and essential nutrients. This initiates a complex cascade of molecular, biochemical, and structural changes. Central to this process are oxidative stress and inflammation, where reduced blood flow leads to excitotoxicity, mitochondrial dysfunction, and excessive production of reactive oxygen and nitrogen species. These reactive molecules further damage neurons, activate inflammatory pathways, and disrupt the blood-brain barrier.

As a result, stroke often leads to serious complications such as infections, deep vein thrombosis, cognitive and psychological disorders, and long-term disabilities such as limb paralysis and speech impairment. These outcomes contribute to high mortality and morbidity rates, placing significant physical, emotional, and financial strain on patients, families, and society.

Given these consequences, the primary goal of treating ischemic stroke is to restore blood flow to the brain as quickly as possible to minimize long-term damage. This is typically achieved through thrombolytic medications, such as recombinant tissue plasminogen activator (tPA), which dissolves the clot, or through mechanical thrombectomy procedures that physically remove the clot from the blood vessel.

However, because both treatments are only effective within a narrow time window, there is an urgent need for new therapeutic strategies to improve outcomes and expand the treatment options for stroke patients.

Gut microbiota and ischemic stroke

The intricate relationship between the gut microbiota and stroke is best understood through the bidirectional communication of the gut-brain axis. This axis facilitates interaction via multiple pathways, including the immune system, the vagus and enteric nerves, hormonal signaling, and the circulatory system.

Gut microbes play an active role in brain health by producing neuroactive compounds and metabolic byproducts, including short-chain fatty acids (SCFAs) and neurotransmitter precursors. Some of these molecules can cross into the central nervous system, where they modulate brain chemistry, neuroinflammation, and vascular integrity.

In the context of ischemic stroke, this cross-talk is significantly disrupted, setting off a cycle of dysfunction:

Stroke affects gut microbiota

Following a stroke, patients frequently experience reduced gastrointestinal motility, increased gut permeability, and immune dysregulation. These changes can compromise the gut environment, leading to decreased microbial diversity, a loss of beneficial commensal bacteria, and an overgrowth of potentially pathogenic species.

Gut microbiota influences stroke risk and recovery

Conversely, the composition of the gut microbiota also impacts stroke outcomes. Dysbiosis—characterized by an imbalance between beneficial and harmful microbes— has been shown to impair neural repair mechanisms, amplify neuroinflammation, and compromise vascular function, all of which can worsen stroke severity and hinder recovery.

Mechanisms linking gut microbiota to ischemic stroke

Dysbiosis is indeed commonly observed in patients with acute ischemic stroke. A growing body of evidence indicates that most stroke patients exhibit reduced microbial diversity, a hallmark of compromised gut health.

This altered microbial landscape can influence stroke risk, severity, and recovery. In particular, reductions in SCFA-producing bacteria and increases in pro-inflammatory species have been associated with heightened inflammation and poorer clinical outcomes.

Specific bacterial taxa appear to play protective or harmful roles. For example, Bifidobacterium, Lactobacillus, Enterobacter, and Lachnospira have been linked to neuroprotective effects, whereas Clostridium and Escherichia coli may elevate stroke risk by producing endotoxins that promote inflammation and disrupt neural signaling pathways.

Beyond the microbes themselves, their metabolites are increasingly recognized as key mediators in the gut-brain connection. Compounds such as SCFAs, bile acids (BAs), tryptophan (Trp) metabolites, and trimethylamine N-oxide (TMAO) influence a variety of physiological processes relevant to stroke.

• SCFAs may potentially impact ischemic stroke outcomes by supporting gut-brain barrier repair, reducing oxidative stress and neuroinflammation, and limiting autophagy and cell death.
• BAs and Trp metabolites support neurotransmitter balance and brain function.  
• TMAO, in contrast, has been associated with increased stroke risk, heightened neuroinflammation, and worse cognitive outcomes, highlighting its potential as both a biomarker and therapeutic target.

Modulating gut microbiota in stroke

Given the emerging role of the gut-brain axis in stroke pathophysiology, researchers have begun exploring whether targeted modulation of the gut microbiota could help restore microbial balance.

These approaches include supplementation with probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary adjustments. Each of these seeks to recalibrate the gut environment and is being explored for its potential to attenuate neuroinflammation and support recovery-related pathways. While clinical evidence is still limited, early findings suggest that microbiota-based therapies may represent a promising frontier in stroke management.

Probiotics

Modulating the gut microbiota with probiotics has shown potential in both preclinical and clinical settings for improving outcomes after ischemic stroke.

Animal studies

A recent systematic review of animal models of stroke reported that probiotic supplementation was associated with improved neurological function, reduced infarct volume, and enhanced cognitive performance. These benefits were accompanied by anti-inflammatory effects, reduced oxidative stress, and decreased neuronal apoptosis, indicating their potential to support recovery through multiple neuroprotective pathways.

Clinical studies

It’s important to note that while preclinical studies show encouraging results, most human clinical trials to date have focused on secondary outcomes such as gastrointestinal health, infection rates, and inflammatory markers.

A meta-analysis of 26 randomized controlled trials involving 2,216 stroke patients found that early enteral nutrition combined with probiotics significantly reduced gastrointestinal complications, lowered infection rates, and shortened hospital stays when compared to those receiving only enteral nutrition.

Additionally, one retrospective study found that Bifidobacterium bifidum supplementation in elderly ischemic stroke patients led to significant improvements in neurological status, as indicated by reduced National Institutes of Health Stroke Scale (NIHSS) scores, and lower levels of inflammatory markers over four weeks.

Prebiotics

Prebiotics are also being investigated for their potential role in stroke recovery.

Animal studies

Preclinical research has demonstrated that prebiotics such as inulin and resistant starches can positively modulate the gut microbiota, reduce neuroinflammation, and improve outcomes following stroke. These effects appear to be mediated through enhanced gut-brain axis signaling, highlighting a potential neuroprotective role for prebiotics in limiting brain injury and supporting post-stroke recovery.

While prebiotics have shown benefits in general cognitive enhancement in clinical studies, research focusing on stroke-specific outcomes is needed to evaluate the efficacy of prebiotics.

FMT

FMT, which involves transferring gut microbiota from a healthy donor to a recipient, has gained attention as a novel strategy for modulating the gut-brain axis in neurological diseases, including ischemic stroke.

Animal studies

Multiple animal-based studies have highlighted the role of FMT as a potential treatment for acute ischemic stroke and its complications.

A recent systematic review indicated that FMT in preclinical stroke models affects brain infarct volume, survival rate, neurological and behavioral outcomes, and inflammatory pathways.

Clinical studies

Despite promising results in animal models, as of now, there are no registered clinical trials on ClinicalTrials.gov evaluating the safety or efficacy of FMT in stroke patients.

Dietary adjustments

Healthy eating habits, by modulating the gut microbiota, may play a beneficial role in stroke risk and progression. Diets such as the Mediterranean diet and those rich in fiber, polyphenols, and omega-3 fatty acids have been shown to modulate gut microbiota, protect nerve cells, and enhance cognitive and motor recovery, while unhealthy diets high in salt, sugar, fat, or alcohol can increase stroke risk.

Takeaway

Growing evidence suggests that the gut microbiota plays a critical role in ischemic stroke risk, progression, and recovery through its effects on inflammation, oxidative stress, and neurovascular health. Stroke can disrupt the gut microbial balance, while pre-existing dysbiosis may exacerbate brain injury and hinder repair. Emerging interventions—such as probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary strategies—aim to restore microbial equilibrium and enhance stroke outcomes. Although clinical research is still in its early stages, gut-targeted therapies represent a promising area of investigation.

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Key references

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