Gamma-aminobutyric acid (GABA) is an amino acid that functions as the main inhibitory neurotransmitter for the central nervous system (CNS), and it is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase. GABA is also involved in fine-tuning the activity of neurons, which is critical for normal brain function. GABA modulates sensory processing, motor control, and cognitive functions [1]. It also plays a role in synaptic plasticity, participating in learning and memory mechanisms [2]. GABAergic signaling is involved in several psychiatric and neurological disorders such as anxiety, depression, epilepsy, and schizophrenia [3].
Deficit in GABA can lead to insomnia, irritability, attention deficit hyperactivity disorder, or epilepsy. This is why the oral ingestion of GABA is done today as a food supplement. There is some evidence supporting the claims made by hundreds of consumers about the calming and beneficial effects of GABA food supplements [4]. However, independent studies are urgently needed to fully assess their efficacy. Moreover, the mechanism by which these food supplements impact the CNS remains to be discovered. Indeed, GABA has long been thought unable to cross the blood–brain barrier (BBB) [5-8] to reach the brain and exert its effects.
Thus, the following questions remain [4]: How do these GABA supplements exert their action? Is the observed effect merely a result of the placebo effect? Do these supplements work through peripheral mechanisms outside the brain? Or can GABA actually cross the BBB?
What is the blood-brain barrier?
The BBB protects the brain from toxins and pathogens that may enter the peripheral vascular system through ingestion or infection [9]. The BBB serves to keep the brain safe from harmful substances by separating the lumen of blood vessels and the CNS parenchyma. However, it also greatly limits the passage of beneficial substances, such as drugs to treat CNS disorders [10]. The BBB regulates nutrients and oxygen passage from the circulatory system into the brain. It also maintains brain homeostasis and regulates the transport of peptides, neurotransmitter precursors, and cytokines [11-13].
The BBB is composed of endothelial cells sealed together by tight junction proteins ensuring its impermeability [14,15], similar to the intestinal or placental barriers [16]. As a result, molecules have to enter the CNS via active uptake by specialized transporters or passive diffusion into the BBB cells [10,17,18].
Can GABA cross the blood-brain barrier?
Contradictory results in animals
Many studies concluded that GABA is unable to cross the BBB due to its impermeability [5-8]. However, others have reported that GABA does cross the BBB, although in very small amounts [19-22]. This discrepancy may result from the significant variations in methods, including chemical compounds, methods of GABA administration, and animal species. For instance, administration of GABA by intravenous injection, intraperitoneal injection, or bilateral brain perfusion. Interestingly, the method of administration did not correlate with the GABA permeability results [4].
Absence of studies in humans
There are no studies of BBB permeability to GABA in humans due to the limited number of methods currently available to measure GABA levels in the human brain. However, magnetic resonance spectroscopy combined with a careful experimental design would enable such an experiment [23].
Discovery of GABA transporters in the blood-brain barrier
In 2001, a study discovered GABA transporters in the BBB of mice [24]. Such transporter expression allows GABA to enter or exit the brain. The influx rate of GABA in the brain (from peripheral blood to CNS) appeared to be 17 times lower than its efflux rate (from CNS to peripheral blood) in rats [25], which greatly complicates the interpretation of GABA concentrations in the CNS. Indeed, some studies may have found little evidence for GABA’s BBB permeability because of its high efflux rate [4].
Are there other alternatives to the blood-brain barrier for GABA signaling to reach the brain?
Interestingly, several bacteria from the gut microbiota can produce neurotransmitters, such as dopamine, 5-HT, acetylcholine, and GABA among others. More specifically, members of the Bacteroides, Bifidobacterium, and Lactobacillus generally synthesize GABA [26], and the abundance of these bacteria is associated with observable behavioral changes.
Effects of gut-secreted GABA on the central nervous system in animals
Intriguingly, manipulating gut microbiota in mice by orally administering L. rhamnosus, a bacteria that produces GABA, can induce anxiolytic behavioral changes [27]. These changes are associated with modifications of GABA-A and GABA-B receptor density and distribution in mice brains [27]. In addition, magnetic resonance spectroscopy showed that mice fed with L. rhamnosus for 4 weeks had elevated levels of GABA in their brain only at 4 weeks and not thereafter [28]. However, the mechanisms driving brain chemistry, receptor expression, and behavior changes are unknown [29].
In Clostridium elegans, gut microbiota-derived GABA showed neuroprotective properties, highlighting its role in keeping brain homeostasis [30]. Additionally, a high-fat diet in rats was associated with lower Bacteroides levels, depressive-like behavior, and reduced GABA levels in the prefrontal cortex of their brain [31]. These findings suggest that gut-secreted GABA has the potential to influence brain chemistry and behavior.
Effects of gut-secreted GABA in human behavior
Preliminary human studies suggest that microbiota-based interventions can alter neurotransmitter levels. A study found a negative correlation between the abundance of fecal Bacteroides and depression-related brain signatures in patients with major depressive disorder [32]. Another one observed that higher levels of Bacteroides in healthy women were linked to increased grey matter and reduced anxiety, distress, and irritability [33]. These findings indicate that gut-secreted GABA might influence CNS function and emotional well-being, although further research with larger cohorts is needed.
The hypothesis of the vagal nerve
The vagus nerve plays a critical role in communication between nerves of the gastrointestinal system, forming the enteric nervous system (ENS) and the CNS. While gut-secreted GABA may not directly cross the BBB, it can potentially influence the CNS through ENS and vagal nerve activation [29], as evidenced by its effects observed in animal studies dependent on vagal integrity [35]. In humans, vagal stimulation has been shown to increase GABA levels in the cerebrospinal fluid of patients with treatment-resistant depression [34], supporting the vagal nerve's role in neurochemical changes and anxiolytic behaviors.
Conclusion
GABA is widely known for its role as a food supplement due to reports of its relaxation and immunity enhancement effects from numerous consumers. However, it is still premature to conclude whether GABA supplementation reaches the brain, and the mechanism by which it impacts the CNS remains unknown [4]. Animal studies led to conflicting results regarding the permeability of the BBB to GABA, necessitating further research. In addition, the vagus nerve is a plausible alternative mechanism for gastrointestinal GABA to influence the CNS, but this hypothesis also requires more research.
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