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Gamma aminobutyric acid (GABA) is the principal inhibitory neurotransmitter playing a key role in anxiety and depression disorders in mammals. Recent studies revealed that members of the gut microbiota are able to produce GABA modulating the gut–brain axis response. Among members of the human gut microbiota, bifidobacteria are well known to establish many metabolic and physiologic interactions with the host. In this study, we performed genome analyses of more than 1,000 bifidobacterial strains publicly available revealing that Bifidobacterium adolescentis taxon might represent a model GABA producer in human gastrointestinal tract. Moreover, the in silico screening of human/animal metagenomic datasets showed an intriguing association/correlation between B. adolescentis load and mental disorders such as depression and anxiety. Interestingly, in vitro screening of 82 B. adolescentis strains allowed identifying two high GABA producers, i.e. B. adolescentis PRL2019 and B. adolescentis HD17T2H, which were employed in an in vivo trial in rats. Feeding Groningen rats with a supplementation of B. adolescentis strains, confirmed the ability of these microorganisms to stimulate the in vivo production of GABA highlighting their potential implication in gut–brain axis interactions.

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu 1 – 3 . Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8 + T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses. A paper in Nature demonstrates that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages able to limit anti-tumour T cell cytotoxicity.

Pulmonary neuroendocrine cells (PNECs) are a rare cell type located in airway and alveolar epithelia and are often in contact with sensory nerve fibers. They have a wide phylogenic distribution and are found even in the relatively primitive lungs of amphibia and reptiles, suggesting a critical function. Sui et al. found that mice lacking PNECs have suppressed type 2 (allergic) immune responses. PNECs were observed in close proximity to group 2 innate lymphoid cells (ILC2s) around airway branch points. The PNECs enhanced ILC2 activity by secreting CGRP (calcitonin gene-related peptide). They also induced goblet-cell hyperplasia via the neurotransmitter GABA (γ-aminobutyric acid). Interestingly, human asthma patients were found to have increased PNEC numbers, suggesting a potential therapeutic target for the treatment of asthma. Science , this issue p. eaan8546 PNECs, a rare population of cells in the airways, are critical for amplifying the airway allergen signal into mucosal responses in the lungs. Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1 -mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1 -mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.

The gut microbiome has been shown to regulate the development and functions of the enteric and central nervous systems. Its involvement in the regulation of behavior has attracted particular attention because of its potential translational importance in clinical disorders, however little is known about the pathways involved. We previously have demonstrated that administration of Lactobacillus rhamnosus (JB-1) to healthy male BALB/c mice, promotes consistent changes in GABA-A and -B receptor sub-types in specific brain regions, accompanied by reductions in anxiety and depression-related behaviors. In the present study, using magnetic resonance spectroscopy (MRS), we quantitatively assessed two clinically validated biomarkers of brain activity and function, glutamate+glutamine (Glx) and total N-acetyl aspartate+N-acetyl aspartyl glutamic acid (tNAA), as well as GABA, the chief brain inhibitory neurotransmitter. Mice received 1×109 cfu of JB-1 per day for 4weeks and were subjected to MRS weekly and again 4weeks after cessation of treatment to ascertain temporal changes in these neurometabolites. Baseline concentrations for Glx, tNAA and GABA were equal to 10.4±0.3mM, 8.7±0.1mM, and 1.2±0.1mM, respectively. Delayed increases were first seen for Glx (~10%) and NAA (~37%) at 2weeks which persisted only to the end of treatment. However, Glx was still elevated 4weeks after treatment had ceased. Significantly elevated GABA (~25%) was only seen at 4weeks. These results suggest specific metabolic pathways in our pursuit of mechanisms of action of psychoactive bacteria. They also offer through application of standard clinical neurodiagnostic techniques, translational opportunities to assess biomarkers accompanying behavioral changes induced by alterations in the gut microbiome. •We have shown for the first time that the concentrations of certain metabolites increase in the brain following oral treatment with L. rhamnosus and do so with distinct kinetics.•Both tNAA and Glx increased relatively early after the start of L. rhamnosus die, while GABA was only elevated at four weeks.•These results suggest beneficial bacteria may alter brain function and offer translational approaches into the clinical setting.

The glutamate decarboxylase (GAD) system catalyzed the conversion of L-glutamate to gamma-aminobutyric acid (GABA) in a proton-consuming reaction, which played a critical role to maintain intracellular pH homeostasis. However, the genetic organization and functional roles of GAD system in Lactiplantibacillus plantarum remain incompletely understood. In this study, L. plantarum ZR79, a GABA-producing strain, was successfully screened from 120 L. plantarum strains based on gas production and pH increase after 48-h fermentation. Comparative genomic analysis revealed that only L. plantarum ZR79 harbors two glutamate decarboxylases encoded by gadA and gadB , respectively. Insertional inactivation of the gadB gene abolished the ability to synthesize GABA, suggesting that the gadB gene plays a critical role in GABA biosynthesis in L. plantarum ZR79. The complete genome sequencing analysis combined with RT-PCR revealed that the gadB gene was located on the plasmid pZR79, which was co-transcribed with gadR and gadC . Plasmid stability assays revealed that pZR79 was stably maintained in ZR79 over 200 generations. Furthermore, acid stress survival assays confirmed that gadB -mediated GABA production contributes to the acid tolerance of L. plantarum ZR79. This study provides the first evidence of a plasmid-encoded gadRCB operon in L. plantarum , offering new insights into the strain-specific genetic basis of GABA biosynthesis and its physiological role in acid stress resistance. Key points • L. plantarum ZR79 harbors two distinct glutamate decarboxylase-encoding genes, gadA and gadB, with the gadB gene cluster located on its plasmid pZR79. • Insertional inactivation of the gadB gene abolished the ability of L. plantarum ZR79 to synthesize GABA. • The gadB gene increased the survival ability in L. plantarum ZR79 under acidic conditions.

The operation of a glutamine–glutamate/GABA cycle in the brain consisting of the transfer of glutamine from astrocytes to neurons and neurotransmitter glutamate or GABA from neurons to astrocytes is a well-known concept. In neurons, glutamine is not only used for energy production and protein synthesis, as in other cells, but is also an essential precursor for biosynthesis of amino acid neurotransmitters. An excellent tool for the study of glutamine transfer from astrocytes to neurons is [ 14 C]acetate or [ 13 C]acetate and the glial specific enzyme inhibitors, i.e. the glutamine synthetase inhibitor methionine sulfoximine and the tricarboxylic acid cycle (aconitase) inhibitors fluoro-acetate and -citrate. Acetate is metabolized exclusively by glial cells, and [ 13 C]acetate is thus capable when used in combination with magnetic resonance spectroscopy or mass spectrometry, to provide information about glutamine transfer. The present review will give information about glutamine trafficking and the tools used to map it as exemplified by discussions of published work employing brain cell cultures as well as intact animals. It will be documented that considerably more glutamine is transferred from astrocytes to glutamatergic than to GABAergic neurons. However, glutamine does have an important role in GABAergic neurons despite their capability of re-utilizing their neurotransmitter by re-uptake.

Neural activation patterns in the ventral visual cortex in response to different categories of visual stimuli (e.g., faces vs. houses) are less selective, or distinctive, in older adults than in younger adults, a phenomenon known as age-related neural dedifferentiation. In this study, we investigated whether neural dedifferentiation extends to the auditory cortex. Inspired by previous animal work, we also investigated whether individual differences in GABA are associated with individual differences in neural distinctiveness in humans. 20 healthy young adults (ages 18–29) and 23 healthy older adults (over 65) completed a functional magnetic resonance imaging (fMRI) scan, during which neural activity was estimated while they listened to music and foreign speech. GABA levels in the auditory, ventrovisual and sensorimotor cortex were estimated in the same individuals in a separate magnetic resonance spectroscopy (MRS) scan. Relative to the younger adults, the older adults exhibited both (1) less distinct activation patterns for music vs. speech stimuli and (2) lower GABA levels in the auditory cortex. Also, individual differences in auditory GABA levels (but not ventrovisual or sensorimotor GABA levels) were associated with individual differences in neural distinctiveness in the auditory cortex in the older adults. These results demonstrate that age-related neural dedifferentiation extends to the auditory cortex and suggest that declining GABA levels may play a role in neural dedifferentiation in older adults. •Older adults have less distinct activation patterns for music vs. foreign speech in auditory cortex than young adults.•Older adults also exhibit lower levels of the neurotransmitter GABA in the auditory cortex.•Individual differences in auditory GABA levels are associated with distinctiveness in the auditory cortex of older adults.

In everyday life we are confronted with inputs of multisensory stimuli that need to be integrated across our senses. Individuals vary considerably in how they integrate multisensory information, yet the neurochemical foundations underlying this variability are not well understood. Neural oscillations, especially in the gamma band (>30Hz) play an important role in multisensory processing. Furthermore, gamma-aminobutyric acid (GABA) neurotransmission contributes to the generation of gamma band oscillations (GBO), which can be sustained by activation of metabotropic glutamate receptors. Hence, differences in the GABA and glutamate systems might contribute to individual differences in multisensory processing. In this combined magnetic resonance spectroscopy and electroencephalography study, we examined the relationships between GABA and glutamate concentrations in the superior temporal sulcus (STS), source localized GBO, and illusion rate in the sound-induced flash illusion (SIFI). In 39 human volunteers we found robust relationships between GABA concentration, GBO power, and the SIFI perception rate (r-values=0.44 to 0.53). The correlation between GBO power and SIFI perception rate was about twofold higher when the modulating influence of the GABA level was included in the analysis as compared to when it was excluded. No significant effects were obtained for glutamate concentration. Our study suggests that the GABA level shapes individual differences in audiovisual perception through its modulating influence on GBO. GABA neurotransmission could be a promising target for treatment interventions of multisensory processing deficits in clinical populations, such as schizophrenia or autism. •We combined magnetic resonance spectroscopy and electroencephalography in 39 humans.•Glutamate and GABA concentration were obtained from superior temporal sulcus (STS).•Gamma band oscillations (GBO) in sound-induced flash illusion were localized in STS.•GABA level in STS was positively correlated with source localized GBO power.•GABA level in STS mediated correlation between GBO and audiovisual perception

Γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, has been shown to alleviate various physiological disorders including insomnia, hypertension, depression, and memory loss. Lactic acid bacteria (LAB), recognized as safe GABA producers, have attracted increasing attention. This study aimed to screen GABA-producing LAB from naturally fermented dairy products and evaluate their probiotic potential, antioxidant and neuromodulatory activities, while optimizing GABA production. GABA-producing LAB were screened using the Berthelot method and thin-layer chromatography. The safety of  Lactiplantibacillus plantarum  SY1 was assessed through hemolysin production and drug sensitivity tests.  L. plantarum  SY1 demonstrated high tolerance to acidic conditions and low bile salt concentrations, along with significant antioxidant capacity (49 ± 0.2% DPPH radical scavenging rate, 86.1 ± 0.14% hydroxyl radical scavenging rate, and 32.7 ± 1.6% superoxide radical anion scavenging rate). In vivo experiments revealed that  L. plantarum  SY1 extended the lifespan of  C. elegans  N2, enhanced oxidative stress resistance, and delayed paralysis in transgenic  C. elegans  (CL4176) by 23.53%. Through OFAT strategy and RSM optimization, GABA production reached 1.49 g/L under optimal conditions (37℃, pH 4.44, 96 h fermentation, and 4.16% inoculum). These findings demonstrate that  L. plantarum  SY1 is a promising GABA-producing strain with antioxidant and neuromodulatory effects, suggesting its potential as an anti-aging and neuroprotective probiotic.

Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has been believed to be involved in dopamine degradation, which supports the idea that the therapeutic efficacy of MAO-B inhibitors in Parkinson’s disease can be attributed to an increase in extracellular dopamine concentration. However, this belief has been controversial. Here, by utilizing in vivo phasic and basal electrochemical monitoring of extracellular dopamine with fast-scan cyclic voltammetry and multiple-cyclic square wave voltammetry and ex vivo fluorescence imaging of dopamine with GRAB DA2m , we demonstrate that MAO-A, but not MAO-B, mainly contributes to striatal dopamine degradation. In contrast, our whole-cell patch-clamp results demonstrated that MAO-B, but not MAO-A, was responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum. We conclude that, in contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels. Parkinson’s disease: rewriting the roles of a critical enzyme The inhibition of two forms of an enzyme that modulate key processes in the brain has different benefits for patients with Parkinson’s disease than previously thought. Monoamine oxidase (MAO) is present in the brain as MAO-A and MAO-B, both of which were thought to be involved in dopamine degradation. MAO inhibitors are used to limit dopamine degradation in Parkinson’s disease and depression, improving symptoms by increasing levels of usable dopamine. In experiments on rats, Hyun-U Cho at Hanyang University, Seoul, South Korea, and coworkers have shown that MAO-A, but not MAO-B, affects dopamine degradation. The team found that MAO-B instead mediates the synthesis of a key neurotransmitter, GABA, the upregulation of which is linked to Parkinson’s motor symptoms. Taking MAO-B inhibitors may be addressing these symptoms, explaining why patients show improvement.