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Gamma-aminobutyric acid (GABA) plays a critical role in the central nervous system as an inhibitory neurotransmitter. Imbalances of this neurotransmitter are associated with neurological diseases, such as Alzheimer's and Parkinson's disease, and psychological disorders, including anxiety, depression, and stress. Changes in both circulating GABA and brain levels of GABA are associated with changes in the composition of the gut microbiota (gut flora), and changes in GABA levels and microbiota composition play a role in modulating mental health. Recent research has raised the possibility that GABA may be a potent mediator of the gut-brain axis. This article will cover current information on GABA-producing microorganisms isolated from human gut and food sources, explanation of why these microorganisms produce GABA, food factors that induce gut GABA production, evidence suggesting GABA as a mediator linking gut microbiota and mental health, including anxiety, depression, stress, epilepsy, autism spectrum disorder, and ADHD, and new information on homocarnosine - a dominant brain peptide that is a putative downstream mediator of GABA in regulating brain functions. This review will help us understand how the gut microbiota and GABA-homocarnosine metabolism play an important role in brain functions. Nevertheless, it could support further research on the use of GABA production-inducing microorganisms and food factors as agents to treat neurological and psychological disorders.
In the gut, trillions of microbes form a complex community, commonly known as the gut microbiota. The gut microbiota produces thousands of unique small molecules or metabolites that can potentially affect the health of the host (us humans). Commonly identified metabolites include short-chain fatty acids (SCFAs), bile acids, choline metabolites, vitamins, amino acids, and neurotransmitters. The bidirectional communication pathway between the gut microbiota and the gut and their interaction with the central nervous system is called the gut-brain-microbiota axis. The gut microbiota and its metabolites influence the health of the host through the brain and peripheral systems (The peripheral nervous system consists of nerve fibers that extend to different parts of the body. Nerve fibers are found in the arms, legs, and reach all the way to the fingers and toes. The nerve fibers have their cell bodies in the brain or spinal cord.). Metabolites travel by sending signals to the brain via the vagus nerve or the blood-brain barrier after crossing the gut barrier. These metabolites are considered postbiotics because they can ameliorate disease phenotypes and regulate gut microbiota and metabolic pathways. However, dyshomeostasis in gut microbiota and postbiotics leads to a variety of host diseases, such as metabolic, cardiovascular, and neurological diseases.
Dietary factors, including probiotics, prebiotics, fermented foods, and microbial enzymes, positively influence the composition of the gut microbiota and stimulate the release of GABA and other microbial metabolites. When microbial GABA passes through the intestinal barrier, it affects the brain's compound levels via the blood-brain barrier or vagus nerve and improves brain function.
Among recently developed postbiotics, GABA has received much attention. One study showed changes in bacteria with the enzyme gene glutamic acid decarboxylase (which is responsible for converting glutamate to GABA) between control subjects and obese individuals. In addition, another study showed that GABA and GABA-producing bacteria were the most altered plasma metabolites and bacteria in fecal microbiota transplantation from lean individuals to individuals with metabolic syndrome. In addition, the intake of probiotics, such as Lactobacillus and Bifidobacterium , promotes an increase in GABA in both the gut and the brain. These findings indicate that GABA is a possible postbiotic mediator of the gut-brain axis, which in turn regulates our health.
GABA was first discovered in the brain in 1950 and several years later it was recognized as an important inhibitory neurotransmitter. The functional significance of GABA is not limited to the brain; evidence suggests that GABA also has significance in peripheral tissues such as the intestine, bladder, heart, lung, ovaries, and pancreas. In terms of GABA concentration, the brain contains a high concentration of GABA, while most peripheral tissues have low GABA content, accounting for approximately 1% of the GABA amount in the brain. Among peripheral organs, GABA is abundant in the pancreas, and recent research suggests that the pancreatic GABA system plays an important role in protecting the pancreas and regulating insulin metabolism.
GABA is synthesized by various organisms, including humans, plants, and bacteria. In the synthesis process, GABA is produced from glutamate by the glutamic acid decarboxylase (GAD) enzyme, which requires pyridoxal-5′-phosphate (PLP) as a cofactor.
Several gastrointestinal (GI) bacteria contain the gene encoding GAD (enzyme), which is responsible for GABA production. Among the human microbiota , Bifidobacterium, Lactobacillus, and Bacteroides are the most well-known GABA producers. GABA production by Bifidobacterium and Lactobacillus has been extensively studied due to their probiotic functions and the need for probiotic and fermented food development. Recent evidence has shown that Bacteroides may be the primary genus of the gut microbiota that influences mental health through the regulation of GABA production. Compared to Bifidobacterium and Lactobacillus, Bacteroides is one of the most abundant and widespread genera in the human gut microbiota. Recent results from animal and human studies have shown a strong association between mental disorders and dysregulation of the gut microbiota linked to glutamate-GABA metabolism, where changes in the composition of Bacteroides were pronounced in the group with mental disorders.
Extensive studies have been conducted to develop GABA-rich dietary supplements and fermented foods that deliver the health benefits of GABA. More recently, GABA production has focused on searching for highly productive GABA strains and optimizing the growth conditions for these bacteria. In Japan, the food industry is primarily interested in GABA production because it is considered a bioactive compound that promotes health and can be utilized in the development of foods for specific health uses.
Fermentation of vegetables, meat and fruits using lactic acid bacteria is a standard method for preserving and improving the nutritional and sensory properties of food raw materials. The complex nutrients in food raw materials are a rich source of vitamins and minerals that are necessary for the growth of lactic acid bacteria strains, which facilitate the microbial production of enzymes and other metabolites. Lactic acid bacteria efficiently and rapidly convert sugars into lactic acid as a primary metabolic product, which contributes to the preservation of fermented foods. There are many different lactic acid bacteria, but the most common are lactobacilli and bifidobacteria. Many of these raw materials contain significant amounts of glutamate, which can be used by lactic acid bacteria to convert glutamate to GABA using the GAD enzyme to increase tolerance to acidic conditions. Several GABA-producing lactic acid bacteria have been isolated from a wide range of fermented foods.
The dominant species of GABA-producing microorganisms are Lactobacillus spp., including L. brevis , L. plantarum , L. paracasei , L. buchneri , and L. helveticus . Among these, Lactobacillus paracasei NFRI 7415, isolated from fermented fish, produces high levels of GABA under appropriate conditions. GABA-producing microorganisms were isolated from a wide range of fermented foods, including cheese, yogurt, tea, and sourdough, as well as various Asian fermented products such as kimchi, jeotgal (Korean fermented fish), nham (fermented Thai sausage, paocai (Chinese fermented vegetables, kung-som (Thai fermented shrimp), and ika-koujizuke (Japanese squid fermented with rice) and ika-kurozukuri (Japanese squid fermented with squid ink).
Despite the wide variety of fermented food products available worldwide from different cultures and traditions, little is known about the microorganisms involved in the fermentation process. There may be undiscovered microorganisms in traditional fermented products that are more efficient producers of GABA and other compounds than those previously identified and documented. In addition, commercially available fermented products, such as kimchi , provide more data and information about the microorganisms involved in the fermentation process.
It is widely known in this field of research that bacteria, especially those with probiotic properties, can produce GABA due to their ability to express GAD genes. However, the reason why these bacteria produce GABA is still unclear. It has been hypothesized that GABA is produced under anaerobic and acidic conditions, which allows bacteria to survive in extreme environments.
In addition to fermented food products that promote GABA production due to the presence of GABA-producing bacteria, several researchers have investigated the potential of other food factors that can induce GABA production in the gut. Probiotics, Bifidobacterium and Lactobacillus , and the dominant gut bacteria Bacteroides are the main GABA producers in the human gut, and food factors that can increase the abundance of these gut bacteria are candidates for GABA production-inducing food factors. In addition to typical well-known prebiotics, such as fructooligosaccharides (FOS), recent research suggests that enzymes derived from microorganisms, such as proteases, lipases, amylases, and cellulases, have the potential to act as prebiotics to increase probiotics in the gut. Recent studies have shown that Aspergillus oryzae-derived protease in the diet significantly increases the abundance of both Bifidobacterium and Lactobacillus in the cecum and induces the production of various postbiotics, including GABA. Taken together with the fact that GABA is a non-proteinogenic amino acid, these findings suggest that GABA was possibly produced from elevated levels of the probiotics Bifidobacterium and Lactobacillus . More recent studies have shown that other dietary factors, such as lipase from Penicillium camemberti , commonly used in cheese production, also induce an increased abundance of Bifidobacterium and Lactobacillus . These studies suggest that the digestive enzymes produced by Aspergillus and Penicillium exert prebiotic-like effects by increasing the abundance of the GABA-producing probiotics Bifidobacterium and Lactobacillus in the gut, possibly making them effective in GABA production. The same is true for inulin , which stimulates GABA production in the gut.
It has been well accepted that gut microbiota dysbiosis is strongly linked to human health, including mental health. Gut microbiota and probiotics influence health through various mechanisms, including the production of metabolites, recently defined as postbiotics, such as short-chain fatty acids, peptides, and amino acids. Among these postbiotics, GABA has received much attention from researchers due to its important role in the nervous system and its strong correlation with the gut microbiota. Studies have suggested that peripheral or circulating GABA is mainly attributed to the gut microbiota.
Neurological disorders such as schizophrenia (SCZ), Alzheimer's disease (AD), and Parkinson's disease (PD) have been linked to dysbiosis due to the strong connection between the gut and the brain.
Recently, altered gut microbiota and decreased function of the GABA system in the prefrontal cortex after chronic ethanol exposure led to anxiety-like behaviors. Administration of Lactobacillus rhamnosus JB-1 improved stress-induced anxiety- and depression-like behaviors in mice by increasing GABA mRNA expression in the hippocampus. Increased GABA levels in the small intestine (0.03–0.04 mM) of mice with metabolic syndrome fed a diet supplemented with Lactobacillus brevis DPC6108 and DSM32386 strains improved depression-like behavior in the forced swim test and resting stress hormone corticosterone levels compared to a high-fat diet. Metagenomic analyses involving datasets collected from children with subclinical symptoms of depression and anxiety revealed high metagenomic reads of GAD in groups with a high abundance of Bifidobacterium adolescentis. Furthermore, the depressed phenotype had a greater prevalence of GABA-consuming microorganisms in the selected strains of Flavonifractor plautii, Pseudomonas spp., and Acinetobacter spp. than the healthy phenotype, favoring GABA degradation. Furthermore, a decreased abundance of Bacteroides eggerthii was found to be associated with a decrease in GABA synthesis in individuals with stress and anxiety, and gut microbiota modulation by probiotic supplementation enriched GABA-synthesizing Bifidobacterium adolescentis and Bifidobacterium longum which alleviated stress-related and anxiety symptoms.
An imbalance in neuroactive compounds, including GABA, and intestinal dysbiosis are two important factors in epilepsy and are frequently observed in humans and dogs. In humans, patients with four or fewer seizures per year were found to have higher fecal bifidobacteria and lactobacilli than those with more than four seizures. This flora promotes GABA synthesis. In dogs, the epileptic group had a significantly reduced abundance of fecal GABA-producing and SCFA-producing bacteria compared to the control group. Despite difficulties with implementation, dietary compliance, and adverse side effects, a ketogenic diet (or low-carbohydrate, high-fat diet) is an effective dietary intervention for treating epilepsy. The ketogenic diet positively altered the gut microbiota by increasing the abundance of Akkermansia muciniphila and Parabacteriodes from 4 to 14 days of treatment, demonstrating an anti-seizure effect in a wide range of anti-epileptic drug-resistant seizure models. Administration of a ketogenic diet together with Akkermansia muciniphila and Parabacteriodes significantly increased hippocampal GABA/glutamate ratio. Probiotic administration (multiple Lactobacillus, Bifidobacterium and Streptococcus strains) to drug-resistant epileptic patients reduced seizure frequency and increased serum GABA concentration after a 12-week treatment.
The presence of high levels of Clostridium spp. in the gut is associated with ASD in patients with gastrointestinal diseases. Specifically, 76–87% of beta2-toxin-producing Clostridium perfringens was significantly higher in children with ASD compared to control children, indicating that these opportunistic pathogens thrive in immature or compromised immune systems. A recent study has shown that infants with an increased likelihood of ASD have a decreased abundance of Bifidobacterium but an increased abundance of Clostridium and Klebsiella compared to those with a lower likelihood of ASD. In addition, fecal GABA levels in infants with an increased likelihood of ASD were lower than those with a lower likelihood of ASD, with fecal GABA levels being positively correlated with Bifidobacterium but negatively correlated with Clostridium. A lower abundance of Prevotella copri, Feacalibacterium prausnitzii, and Haemophilus parainfluenzae and decreased concentrations of fecal GABA were found in children with ADS compared to healthy children.
In contrast, an increased fecal GABA/glutamate ratio was found with a higher prevalence of Escherichia/Shigella and a lower prevalence of Bacteroides in mild ASD children than in healthy children. Dialists, Escherichia/Shigella and Bifidobacterium were more common in ASD children, while Prevotella, Megamonas and Ruminococcus were more common in healthy children, where GABA precursors, such as N-carboxyethyl-g-aminobutyric acid, glutamylproline, pyroglutamic acid and gamma-glutamylglycine were higher in children with ASD.
In ADHD, magnetic resonance spectroscopy showed a significant decrease in GABA concentration in the brain of children with ADHD. In contrast, increased cortical GABA concentration was observed in adults with ADHD, suggesting that GABA levels may be correlated with the age of patients with ADHD. A recent study has shown that the top five depleted bacterial families in infants (6 months old) with ADHD are Lachnospiraceae, Ruminococcus, Bacteroides, Lachnospiraceae, and Enterococcus, while the top five enriched bacterial families are Bacteroides, Dorea, Erysipelotrichaceae, Ruminococcaceae, and Dialister. Interestingly, 50% of the depleted families belong to the order Lactobacillales, or lactic acid bacteria. Due to the fact that lactic acid bacteria are strong GABA producers, this may indicate that the depletion of lactic acid bacteria in the gut of infants with ADHD may be related to a decrease in GABA. On the other hand, in a case study, an adult with ADHD was found to have a high abundance of Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium longum, Bacteroides ovatus, Bacteroides uniformis, Fusobacterium ulcerans, Enterocococcus avecoccus and gallinarumterioccus but transplantation of fecal microbiota significantly reduced the abundance of these bacteria with relief of ADHD symptoms. Since most of these bacteria (Bifidobacterium, Bacteroides and Enterocococcus) are well-known GABA producers, this may support a positive correlation between GABA and ADHD in adults as previously reported. It seems likely that GABA may play a role in the pathogenesis of ADHD in children and adults, but possibly in different ways.
Homocarnosine (GABA-l-histidine) is a GABA-containing dipeptide found predominantly in the brain. It is an analogue of the dominant muscle dipeptide carnosine (β-alanine-l-histidine). Homocarnosine is synthesized from GABA and histidine by carnosine synthase in neurons and is degraded by carnosinase. The occipital cortex, basal ganglia, and cervical cord have the highest human homocarnosine synthase (currently known as carnosine synthase) activity, while the cerebellar cortex has the lowest. It is found in greater amounts in the human brain than in the brains of other mammals. Homocarnosine concentrations in the autopsied brain range from 0.4 mmol/kg in the corpus callosum and temporal cortex to 1.0 mmol/kg in the thalamus and basal ganglia and vary independently of GABA concentrations. Homocarnosine concentrations are three to six times higher in adults than in infants. Recently, areas of the human central nervous system, particularly the olfactory bulb, spinal cord, medulla oblongata, thalamus, cerebellum, white matter, and frontal cortex, have been found to have a significant amount of homocarnosine, while human CSF contains abundant homocarnosine.
Although its concentration in the brain is high, the function of homocarnosine in the brain remains underexplored, leading to a limited understanding of its high sustained concentrations in the brain. However, several biochemical properties of homocarnosine have been reported.
For example, homocarnosine acts as a protective agent against a wide range of disease states, including protection of brain endothelial cells from amyloid peptide-induced toxicity and anti-inflammatory action in ischemic brain injury. Homocarnosine exhibits similar properties to carnosine in protecting Cu and Zn superoxide dismutase from oxidative damage through a combination of copper chelation and peroxyl radical scavenging. Furthermore, homocarnosine, in combination with carnosine and anserine, reduces oxidative damage by reducing lipid peroxidation and increasing antioxidant levels in the brain. Many studies have investigated the biological role of homocarnosine in the brain and other neurological diseases. Therefore, a thorough investigation is required to better understand the role of homocarnosine.
Since homocarnosine is a GABA-containing peptide, changes in GABA levels may contribute to changes in homocarnosine homeostasis. This hypothesis is supported by the notion that homocarnosine is a possible GABA reservoir, as approximately 40% of GABA measured in human CSF is homocarnosine. Furthermore, it has been hypothesized that the release of homocarnosine contributes to the glutamate-GABA cycle and reflects an adaptive response to excess extracellular glutamate, with a strong linear correlation between GABA and homocarnosine concentrations observed in healthy CSF (GABA concentration being higher than homocarnosine concentration).
Homocarnosine homeostasis in the brain plays a crucial role in clinical studies of neurological diseases, such as Alzheimer's disease and epilepsy. Low homocarnosine levels may reflect reduced fractional volumes of homocarnosine-containing neurons, and homocarnosine deficits may indicate either loss or dysfunction of GABA neurons. Drugs can be given to improve homocarnosine levels in the brain. Vigabatrin and gabapentin, known antiepileptic drugs, improve seizures by increasing brain GABA and homocarnosine levels. Topiramate, another anticonvulsant drug, improves brain homocarnosine and GABA levels, contributing to its potent antiepileptic effects in patients with complex partial seizures. In addition, isoniazid supplementation in healthy patients increases homocarnosine and GABA concentrations. As mentioned above, homocarnosine could possibly be a good reservoir of GABA in the brain, and other neurological disorders, such as AD, ASD and SCZ, may be associated with homocarnosine because they are characterized by low GABA levels, and GABA can induce homocarnosine production .
It is worth mentioning that the above-mentioned neurological disorders alter the GABA-producing microorganisms in the gut, which affects the GABA homeostasis in the gut and brain. An increase in the abundance of the well-known probiotics Lactobacillus and Bifidobacterium induces GABA production in the gut. However, to date, the direct interaction and correlation between homocarnosine and the gut microbiota influenced by diet is still unknown. Recently (unpublished data), a group discovered the ability of Aspergillus -derived enzymes together with FOS to show a tendency to increase brain GABA levels. Furthermore, dietary intake of these prebiotic-coupled enzymes and FOS increases brain homocarnosine levels. These findings suggest that dietary factors may act as one of the modulators of GABA and homocarnosine levels in the gut and brain.
In summary, GABA has long been the subject of rigorous research, and its health benefits have been proven through in vitro and in vivo experiments. Although circulating GABA has long been thought not to cross the blood-brain barrier, the permeability of GABA through the blood-brain barrier is still questioned due to conflicting evidence. Recent research has shown that GABA may be a potent mediator of the gut-brain axis, as it is circulating and brain levels are regulated by the microbiota, and that changes in GABA levels and microbiota composition play a role in modulating mental health. Generally, GABA is present at trace concentrations in the bloodstream. Recent studies have suggested that circulating GABA is mainly attributed to the gut microbiota. Several studies have isolated GABA-producing bacteria from the human gut such as Lactobacillus , Bifidobacterium , and Bacteroides , and from fermented foods, such as Lactobacillus , Streptococcus , Leuconostoc , and Weisella . In addition to probiotics, non-typical prebiotic food factors, such as Aspergillus- and Penicillium-derived enzymes, have been shown to stimulate increased abundance of probiotics and GABA production in the gut. Dietary supplementation with probiotics and probiotic-rich products improves cognitive function in patients with neurological disorders; alleviates anxiety, depression, and stress; and increases circulation and brain GABA availability. In addition to GABA, a dominant GABA-containing brain peptide, homocarnosine, has recently been shown to be a possible downstream mediator of GABA in the gut-brain axis. Currently, there is limited information on the relationships between homocarnosine, gut microbiota, and brain function. Therefore, it is of great importance to further investigate this issue as this information may help to clarify how the gut microbiota and GABA-homocarnosine metabolism play a role in brain function.
