Chronic drinking weakens the blood-brain barrier through the gut

By Vijay Kumar MalesuReviewed by Lauren HardakerNov 27 2025

Scientists trace alcohol’s impact from the gut to the brain, uncovering microbial changes that weaken the blood-brain barrier, and a probiotic that helps repair it.

Study: Chronic alcohol consumption disrupts the integrity of the blood-brain barrier through the gut-brain axis. Image credit: Syda Productions/Shutterstock.com

In a recent study published in Communications Biology, a group of researchers determined whether chronic alcohol consumption disrupts the blood-brain barrier (BBB) via the gut-brain axis and tested whether Faecalibacterium prausnitzii can reduce BBB damage and cognitive decline.

Alcohol’s hidden impact on brain defenses

One in three adults drinks alcohol regularly, yet many underestimate its effects on the brain. Autopsy studies show microvascular changes, while diffusion tensor imaging (DTI) abnormalities can persist even after abstinence, hinting at lasting injury.

The BBB safeguards neural circuits; when weakened, toxins and inflammatory mediators enter the brain, impairing memory and mood. Meanwhile, the gut microbiome, shaped by diet and drink, can signal to the brain through metabolites and immune pathways. Early work links alcohol to microbiome shifts and to BBB dysfunction. Still, human evidence linking these changes to cognitive outcomes remains largely correlational, and causal evidence connecting the two is limited. Further research is needed to establish mechanisms and test microbiome-based interventions.

Linking gut changes to brain vulnerability

The investigators enrolled 30 adult males with Alcohol Use Disorder (AUD) using Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and 30 healthy male controls. Participants with neuropsychiatric, infectious, neoplastic, autoimmune, or digestive diseases and those recently exposed to antibiotics, probiotics, prebiotics, or prolonged abstinence were excluded.

They recorded cognition using Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA), mood using Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD), sleep with Pittsburgh Sleep Quality Index (PSQI), and clinical chemistries including glucose, aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and direct bilirubin (DBIL).

Fecal 16S ribosomal deoxyribonucleic acid (DNA) sequencing profiled taxa; plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA), followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment.

Specific pathogen-free (SPF) and germ-free (GF) male C57BL/6J mice received daily oral gavage of 25 % ethanol (4 g/kg) or water for six weeks. Cognition was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tasks. BBB integrity was assessed by 20-kilodalton (kDa) fluorescein isothiocyanate (FITC)-dextran leakage and by tight-junction proteins zonula occludens-1 (ZO-1), occludin, claudin-5 by western blot and immunofluorescence.

Fecal microbiota transplantation (FMT) from AUD patients or healthy donors was performed in GF mice. Faecalibacterium prausnitzii A2-165 was administered orally; short-chain fatty acids (SCFAs) were quantified by gas chromatography-tandem mass spectrometry (GC-MS/MS) with partial least squares-discriminant analysis (PLS-DA).

Alcohol alters microbes, metabolites, and cognitive scores

Clinically, people with AUD showed worse cognition, higher anxiety and depression, and poorer sleep than controls. MMSE and MoCA scores were lower, while HAMA, HAMD, and PSQI scores were higher. Routine labs reflected alcohol-related stress: red blood cells and platelets were reduced, and liver markers, including AST, GGT, and DBIL, were elevated.

Fecal 16S profiles showed modest alpha-diversity differences but clear beta-diversity separation. Linear Discriminant Analysis Effect Size highlighted reduced Ruminococcaceae and Faecalibacterium with increased Streptococcaceae and Enterobacteriaceae; at the genus level, Faecalibacterium decreased, and Streptococcus increased.

Plasma metabolomics by LC-MS/MS separated groups by PCA, with broad alterations across lipids, amino acids, and bile acids. Correlation networks linked differential taxa, including Faecalibacterium, with several altered metabolites, but did not directly establish relationships with cognitive scores, suggesting microbiome–metabolite patterns that may accompany neurobehavioral differences.

In mice, six weeks of ethanol impaired memory. In the MWM, ethanol-treated animals showed longer escape latencies and fewer platform crossings; in NOR, exploration of the novel object declined. BBB permeability increased, evidenced by greater 20-kDa FITC–dextran leakage in prefrontal cortex (PFC) and hippocampus. Tight-junction integrity was compromised, as evidenced by reduced ZO-1, occludin, and claudin-5 in these regions, as confirmed by immunofluorescence.

Causality along the gut-brain route was supported in GF mice. After FMT, mice receiving AUD donor microbiota showed more FITC-dextran leakage in the PFC and hippocampus than those given healthy microbiota. They also had lower expression of ZO-1, occludin, and claudin-5. Alpha diversity was similar between groups, suggesting that a dysbiotic community alone can weaken the BBB.

Therapeutically, supplementation with Faecalibacterium prausnitzii in ethanol-exposed mice improved behavior and barrier function. Spatial memory improved with shorter probe times and more platform crossings, while object recognition recovered. Permeability decreased, and tight junction proteins were restored to control levels in the PFC and hippocampus.

The microbiome composition shifted, with lower Lactobacillaceae and Helicobacteraceae, and higher Faecalibacterium. SCFAs, measured by GC-MS/MS, increased, including butyric, valeric, and caproic acids; PLS-DA cleanly separated the groups. Because SCFAs can strengthen endothelial junctions, alter nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and reduce neuroinflammation, these metabolite changes offer a plausible mechanism for recovery.

However, the microbial shifts represent alterations rather than complete “restoration” toward healthy community structure.

Microbiome therapies emerge as candidates for AUD care

This study links everyday alcohol exposure to a concrete neurovascular risk: a leakier BBB that tracks with cognitive decline. By demonstrating that AUD microbiota induce barrier breakdown in GF hosts after FMT, it shifts the gut-brain axis from association to causation.

Equally important, Faecalibacterium prausnitzii, a butyrate-producing next-generation probiotic, raised SCFAs, restored tight junctions, and improved memory in ethanol-exposed mice. Future translation to humans will require careful consideration of sex-specific effects, optimal dosing, microbial viability, and how the intervention interacts with strategies such as reducing alcohol intake.

Together, the findings support the use of microbiome-targeted strategies to protect neurovascular health and cognition in at-risk populations.

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