γ-Aminobutyric acid (GABA) activates neuronal cells by inducing the secretion of exosomes from intestinal cells

Inotsuka, Ryo; Uchimura, K.; Yasuda, Atsushi; Kim, Mujo; Katakura, Yoshinori

doi:10.1039/d0fo01184c

Cited by 20 publications

(16 citation statements)

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“…We assumed that exosomes are involved in the activation of cell–cell interactions. Exosomes are an important component of paracrine signaling and can mediate communication between distant cells by directly transferring various biomolecules, including miRNAs, from donor cells to recipient cells [ 10 , 19 , 20 ]. However, the potential of exosomes as modulators of hair follicle dynamics has not received widespread attention.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion

et al. 2021

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Enhanced telomerase reverse transcriptase (TERT) levels in dermal keratinocytes can serve as a novel target for hair growth promotion. Previously, we identified fisetin using a system for screening food components that can activate the TERT promoter in HaCaT cells (keratinocytes). In the present study, we aimed to clarify the molecular basis of fisetin-induced hair growth promotion in mice. To this end, the dorsal skin of mice was treated with fisetin, and hair growth was evaluated 12 days after treatment. Histochemical analyses of fisetin-treated skin samples and HaCaT cells were performed to observe the effects of fisetin. The results showed that fisetin activated HaCaT cells by regulating the expression of various genes related to epidermogenesis, cell proliferation, hair follicle regulation, and hair cycle regulation. In addition, fisetin induced the secretion of exosomes from HaCaT cells, which activated β-catenin and mitochondria in hair follicle stem cells (HFSCs) and induced their proliferation. Moreover, these results revealed the existence of exosomes as the molecular basis of keratinocyte-HFSC interaction and showed that fisetin, along with its effects on keratinocytes, caused exosome secretion, thereby activating HFSCs. This is the first study to show that keratinocyte-derived exosomes can activate HFSCs and consequently induce hair growth.

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Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion

et al. 2021

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“…After washing with PBS, the cells were stained with Alexa Fluor 555 goat anti-rabbit IgG antibody (Thermo Fisher Scientific, Inc., Waltham, MA, USA) for 1 h at 25 °C. After washing with PBS, cells were further stained with Hoechst 33342 (Dojindo, Kumamoto, Japan) for 15 min, and neurite length was measured using the IN Cell Analyzer 2200 (GE Healthcare, Amersham Place, UK), as previously described [ 24 ]. The total neurite length for each cell is shown in the figure.…”

Section: Methodsmentioning

confidence: 99%

“…SH-SY5Y cells were seeded onto a µClear fluorescence black plate (Greiner-Bio One, Tokyo, Japan), fixed with 4% paraformaldehyde for 15 min, and blocked with blocking buffer (1 × PBS, 5% goat serum, and 0.3% Triton X-100) for 1 h. The cells were subsequently incubated with Milli-Mark Pan Neuronal Marker (Merck Millipore, Billerica, MA, USA) at 25 • C overnight. After washing with PBS, the cells were stained with Alexa Fluor 555 goat anti-rabbit IgG antibody (Thermo Fisher Scientific, Inc., Waltham, MA, USA) for 1 h at 25 • C. After washing with PBS, cells were further stained with Hoechst 33342 (Dojindo, Kumamoto, Japan) for 15 min, and neurite length was measured using the IN Cell Analyzer 2200 (GE Healthcare, Amersham Place, UK), as previously described [24]. The total neurite length for each cell is shown in the figure.…”

Section: Quantitative Evaluation Of Neurite Growthmentioning

confidence: 99%

“…In our previous study, we clarified the molecular basis of GABA-induced gut–brain interactions and reported that exosomes derived from GABA-treated intestinal cells serve as signal transducers that mediate brain–gut interactions [ 24 ]. Exosomes are a family of particles released from the cell that are delimited by a lipid bilayer, and attention has recently been focused on the role of exosomes as biomarker candidates for diagnosis, prognosis and even therapeutic tools of various diseases [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Exosome-Mediated Activation of Neuronal Cells Triggered by γ-Aminobutyric Acid (GABA)

Inotsuka

Udono

Yasuda³

et al. 2021

Nutrients

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γ-Aminobutyric acid (GABA) is a potent bioactive amino acid, and several studies have shown that oral administration of GABA induces relaxation, improves sleep, and reduces psychological stress and fatigue. In a recent study, we reported that exosomes derived from GABA-treated intestinal cells serve as signal transducers that mediate brain–gut interactions. Therefore, the purpose of this study was to verify the functionality of GABA-derived exosomes and to examine the possibility of improving memory function following GABA administration. The results showed that exosomes derived from GABA-treated intestinal cells (Caco-2) activated neuronal cells (SH-SY5Y) by regulating genes related to neuronal cell functions. Furthermore, we found that exosomes derived from the serum of GABA-treated mice also activated SH-SY5Y cells, indicating that exosomes, which are capable of activating neuronal cells, circulate in the blood of mice orally administered GABA. Finally, we performed a microarray analysis of mRNA isolated from the hippocampus of mice that were orally administered GABA. The results revealed changes in the expression of genes related to brain function. Gene Set Enrichment Analysis (GSEA) showed that oral administration of GABA affected the expression of genes related to memory function in the hippocampus.

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“…Moreover, GABAB receptors are expressed along the gastrointestinal tract [ 283 , 284 ], and co-localized with 5-HT-producing cells identified as morphologically similar to EECs [ 284 ], probably inhibiting 5-HT-release by ECs [ 285 ]. Second, GABA transmits sensory information by activating GABAA [ 205 ] and GABAB receptors [ 206 ] expressed in vagal afferents or by secreting exosomes from GABA-stimulated intestinal cells that, in turn, activate neurons [ 207 ]. Nonetheless, specific studies are needed to understand the contribution of gut microbiota-derived GABA to nutrient sensing from the gut to the brain and, thus, to the control energy homeostasis in both lean and obese subjects.…”

Section: Microbial Ligands Mediating Gut–brain Communication and Energy Homeostasismentioning

confidence: 99%

The Microbiota and the Gut–Brain Axis in Controlling Food Intake and Energy Homeostasis

Romaní-Pérez

Bullich-Vilarrubias

López-Almela

et al. 2021

IJMS

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Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota–diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota–brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut–endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota–diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut–brain axis function and, thus, combat obesity.

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γ-Aminobutyric acid (GABA) activates neuronal cells by inducing the secretion of exosomes from intestinal cells

Abstract: The oral administration of γ-aminobutyric acid (GABA) has been shown to affect brain functions. However, the molecular mechanisms underlying GABA-induced gut-brain interactions have not yet been fully elucidated. As the...

Cited by 20 publications

References 19 publications

Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion

Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion

Exosome-Mediated Activation of Neuronal Cells Triggered by γ-Aminobutyric Acid (GABA)

The Microbiota and the Gut–Brain Axis in Controlling Food Intake and Energy Homeostasis

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