{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:20:33Z","timestamp":1783426833792,"version":"3.54.6"},"reference-count":40,"publisher":"IMR Press","issue":"2","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Elite Ed)"],"abstract":"<jats:p>Background: Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system and exerts multiple health-promoting effects, including antidepressant, hypotensive, immunomodulatory, and antidiabetic actions. Previous studies have reported a positive correlation between the abundance of Bifidobacterium species in the gut and fecal GABA levels. However, the direct contribution of specific GABA-producing Bifidobacterium strains and the associated interaction with prebiotics remain insufficiently characterized. Methods: This study aimed to elucidate the direct effects of a GABA-producing strain, Bifidobacterium adolescentis 4-2, in combination with the prebiotic mannooligosaccharides (MOS), on fecal GABA concentrations using the Kobe University Human Intestinal Microbiota Model (KUHIMM), an in vitro simulation of the human colonic microbiota. GABA levels were quantified via high-performance liquid chromatography, and changes in microbial composition following oligosaccharide supplementation were assessed by next-generation sequencing of 16S rRNA genes. The presence and activity of the \u03b2-mannosidase producing genes, essential for MOS degradation and present in the B. adolescentis 4-2 genome, were evaluated using enzymatic assays. Results: B. adolescentis 4-2 significantly increased fecal GABA levels within the KUHIMM. MOS supplementation elevated GABA levels, reduced fecal culture pH, and increased the relative abundance of Actinobacteria, particularly the Bifidobacterium species. Notably, the combined application of MOS and B. adolescentis 4-2 produced a synergistic increase in GABA production compared with the individual application of each component. \u03b2-mannosidase activity assays confirmed the effective utilization of MOS by B. adolescentis 4-2, supporting its role in enhancing GABA biosynthesis. Conclusion: These findings demonstrate a synergistic interaction between MOS and B. adolescentis 4-2 in promoting microbial GABA production in the KUHIMM in vitro. This synbiotic combination shows promise for modulating gut-derived GABA levels in vitro and warrants further investigation in animal models and human clinical studies.<\/jats:p>","DOI":"10.31083\/fbe44158","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:01:18Z","timestamp":1783425678000},"source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Enhancement of Fecal GABA Content by Bifidobacterium adolescentis 4-2 and Mannooligosaccharides in a Human Intestinal Flora Model"],"prefix":"10.31083","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1359-3637","authenticated-orcid":true,"given":"Hend","family":"Altaib","sequence":"first","affiliation":[{"name":"The United Graduate School of Agricultural Science, Gifu University, 501-1193 Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Suzuki","sequence":"additional","affiliation":[{"name":"The United Graduate School of Agricultural Science, Gifu University, 501-1193 Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Morioka","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Gifu University, 501-1193 Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuko","family":"Abe","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Gifu University, 501-1193 Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-0822","authenticated-orcid":true,"given":"Yassien","family":"Badr","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Epidemics, Faculty of Veterinary Medicine, Damanhour University, 22511 El-Beheira, Egypt"},{"name":"Faculty of Applied Biological Sciences, Gifu University, 501-1193 Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Rashmi D, Zanan R, John S, Khandagale K, Nadaf A. Chapter 13 - \u03b3-Aminobutyric Acid (GABA): Biosynthesis, Role, Commercial Production, and Applications. Studies in Natural Products Chemistry. 2018; 57: 413\u2013452.","DOI":"10.1016\/B978-0-444-64057-4.00013-2"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Cui Y, Miao K, Niyaphorn S, Qu X. Production of Gamma-Aminobutyric Acid from Lactic Acid Bacteria: A Systematic Review. International Journal of Molecular Sciences. 2020; 21: 995.","DOI":"10.3390\/ijms21030995"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Dhakal R, Bajpai VK, Baek KH. Production of gaba (\u03b3 - Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology. 2012; 43: 1230\u20131241.","DOI":"10.1590\/S1517-83822012000400001"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Nagpal R, Mainali R, Ahmadi S, Wang S, Singh R, Kavanagh K, et al. Gut microbiome and aging: Physiological and mechanistic insights. Nutrition and Healthy Aging. 2018; 4: 267\u2013285.","DOI":"10.3233\/NHA-170030"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Hasan N, Yang H. Factors affecting the composition of the gut microbiota, and its modulation. PeerJ. 2019; 7: e7502.","DOI":"10.7717\/peerj.7502"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Turroni F, van Sinderen D, Ventura M. Bifidobacteria: insights into the biology of a key microbial group of early life gut microbiota. Microbiome Research Reports. 2021; 1: 2.","DOI":"10.20517\/mrr.2021.02"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Altaib H, Badr Y, Suzuki T. Bifidobacteria and Psychobiotic Therapy: Current Evidence and Future Prospects. Reviews in Agricultural Science. 2021; 9: 74\u201391.","DOI":"10.7831\/ras.9.0_74"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Savignac HM, Kiely B, Dinan TG, Cryan JF. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB\/c mice. Neurogastroenterology and Motility. 2014; 26: 1615\u20131627.","DOI":"10.1111\/nmo.12427"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Braga JD, Thongngam M, Kumrungsee T. Gamma-aminobutyric acid as a potential postbiotic mediator in the gut-brain axis. NPJ Science of Food. 2024; 8: 16.","DOI":"10.1038\/s41538-024-00253-2"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Mazzoli R, Pessione E. The Neuro-endocrinological Role of Microbial Glutamate and GABA Signaling. Frontiers in Microbiology. 2016; 7: 1934.","DOI":"10.3389\/fmicb.2016.01934"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Wang H, Huang X, Tan H, Chen X, Chen C, Nie S. Interaction between dietary fiber and bifidobacteria in promoting intestinal health. Food Chemistry. 2022; 393: 133407.","DOI":"10.1016\/j.foodchem.2022.133407"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Monteagudo-Mera A, Arthur JC, Jobin C, Keku T, Bruno-Barcena JM, Azcarate-Peril MA. High purity galacto-oligosaccharides enhance specific Bifidobacterium species and their metabolic activity in the mouse gut microbiome. Beneficial Microbes. 2016; 7: 247\u2013264.","DOI":"10.3920\/BM2015.0114"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Collins MD, Gibson GR. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. The American Journal of Clinical Nutrition. 1999; 69: 1052S\u20131057S.","DOI":"10.1093\/ajcn\/69.5.1052s"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. The Journal of Nutrition. 1995; 125: 1401\u20131412.","DOI":"10.1093\/jn\/125.6.1401"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Bedu-Ferrari C, Biscarrat P, Langella P, Cherbuy C. Prebiotics and the Human Gut Microbiota: From Breakdown Mechanisms to the Impact on Metabolic Health. Nutrients. 2022; 14: 2096.","DOI":"10.3390\/nu14102096"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Pudlo NA, Pereira GV, Parnami J, Cid M, Markert S, Tingley JP, et al. Diverse events have transferred genes for edible seaweed digestion from marine to human gut bacteria. Cell Host & Microbe. 2022; 30: 314\u2013328.e11.","DOI":"10.1016\/j.chom.2022.02.001"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Kosuwon P, Lao-Araya M, Uthaisangsook S, Lay C, Bindels J, Knol J, et al. A synbiotic mixture of scGOS\/lcFOS and Bifidobacterium breve M-16V increases faecal Bifidobacterium in healthy young children. Beneficial Microbes. 2018; 9: 541\u2013552.","DOI":"10.3920\/BM2017.0110"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Cheng W, Lu J, Li B, Lin W, Zhang Z, Wei X, et al. Effect of Functional Oligosaccharides and Ordinary Dietary Fiber on Intestinal Microbiota Diversity. Frontiers in Microbiology. 2017; 8: 1750.","DOI":"10.3389\/fmicb.2017.01750"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Ngo DH, Vo TS. An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid. Molecules. 2019; 24: 2678.","DOI":"10.3390\/molecules24152678"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Altaib H, Nakamura K, Abe M, Badr Y, Yanase E, Nomura I, et al. Differences in the Concentration of the Fecal Neurotransmitters GABA and Glutamate Are Associated with Microbial Composition among Healthy Human Subjects. Microorganisms. 2021; 9: 378.","DOI":"10.3390\/microorganisms9020378"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Hoshi N, Inoue J, Sasaki D, Sasaki K. The Kobe University Human Intestinal Microbiota Model for gut intervention studies. Applied Microbiology and Biotechnology. 2021; 105: 2625\u20132632.","DOI":"10.1007\/s00253-021-11217-x"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Oba S, Sunagawa T, Tanihiro R, Awashima K, Sugiyama H, Odani T, et al. Prebiotic effects of yeast mannan, which selectively promotes Bacteroides thetaiotaomicron and Bacteroides ovatus in a human colonic microbiota model. Scientific Reports. 2020; 10: 17351.","DOI":"10.1038\/s41598-020-74379-0"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Lindroth P, Mopper K. High performance liquid chromatographic determination of subpicomole amounts of amino acids by precolumn fluorescence derivatization with o-phthaldialdehyde. Analytical Chemistry. 1979; 51: 1667\u20131674.","DOI":"10.1021\/ac50047a019"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Estaki M, Jiang L, Bokulich NA, McDonald D, Gonz\u00e1lez A, Kosciolek T, et al. QIIME 2 Enables Comprehensive End-to-End Analysis of Diverse Microbiome Data and Comparative Studies with Publicly Available Data. Current Protocols in Bioinformatics. 2020; 70: e100.","DOI":"10.1002\/cpbi.100"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Duranti S, Ruiz L, Lugli GA, Tames H, Milani C, Mancabelli L, et al. Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABA. Scientific Reports. 2020; 10: 14112.","DOI":"10.1038\/s41598-020-70986-z"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Ruiz E, Gull\u00f3n B, Moura P, Carvalheiro F, Eibes G, Cara C, et al. Bifidobacterial growth stimulation by oligosaccharides generated from olive tree pruning biomass. Carbohydrate Polymers. 2017; 169: 149\u2013156.","DOI":"10.1016\/j.carbpol.2017.04.014"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Altaib H, El-Nouby MAM, Badr Y. An Overview of GABA Production by Microorganisms. Microbial Nutraceuticals: Products and Processes. Microbial Nutraceuticals: Products and Processes (pp. 365\u2013398). Wiley Book: Hoboken, New Jersey, USA. 2025.","DOI":"10.1002\/9781394241538.ch17"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Leser T, Baker A. Bifidobacterium adolescentis - a beneficial microbe. Beneficial Microbes. 2023; 14: 525\u2013551.","DOI":"10.1163\/18762891-20230030"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Li J, Li Y, Zhao J, Li L, Wang Y, Chen F, et al. Effects of Bifidobacterium breve 207-1 on regulating lifestyle behaviors and mental wellness in healthy adults based on the microbiome-gut-brain axis: a randomized, double-blind, placebo-controlled trial. European Journal of Nutrition. 2024; 63: 2567\u20132585.","DOI":"10.1007\/s00394-024-03447-2"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Aas JA, Griffen AL, Dardis SR, Lee AM, Olsen I, Dewhirst FE, et al. Bacteria of dental caries in primary and permanent teeth in children and young adults. Journal of Clinical Microbiology. 2008; 46: 1407\u20131417.","DOI":"10.1128\/JCM.01410-07"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Hidalgo-Cantabrana C, Delgado S, Ruiz L, Ruas-Madiedo P, S\u00e1nchez B, Margolles A. Bifidobacteria and Their Health-Promoting Effects. Microbiology Spectrum. 2017; 5:  https:\/\/doi.org\/10.1128\/microbiolspec.BAD-0010-2016.","DOI":"10.1128\/microbiolspec.bad-0010-2016"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Strandwitz P, Kim KH, Terekhova D, Liu JK, Sharma A, Levering J, et al. GABA-modulating bacteria of the human gut microbiota. Nature Microbiology. 2019; 4: 396\u2013403.","DOI":"10.1038\/s41564-018-0307-3"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Yunes RA, Poluektova EU, Dyachkova MS, Klimina KM, Kovtun AS, Averina OV, et al. GABA production and structure of gadB\/gadC genes in Lactobacillus and Bifidobacterium strains from human microbiota. Anaerobe. 2016; 42: 197\u2013204.","DOI":"10.1016\/j.anaerobe.2016.10.011"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Yogeswara IBA, Maneerat S, Haltrich D. Glutamate Decarboxylase from Lactic Acid Bacteria-A Key Enzyme in GABA Synthesis. Microorganisms. 2020; 8: 1923.","DOI":"10.3390\/microorganisms8121923"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Saito Y, Shigehisa A, Watanabe Y, Tsukuda N, Moriyama-Ohara K, Hara T, et al. Multiple Transporters and Glycoside Hydrolases Are Involved in Arabinoxylan-Derived Oligosaccharide Utilization in Bifidobacterium pseudocatenulatum. Applied and Environmental Microbiology. 2020; 86: e01782-20.","DOI":"10.1128\/AEM.01782-20"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Jadhav A, Bajaj A, Xiao Y, Markandey M, Ahuja V, Kashyap PC. Role of Diet-Microbiome Interaction in Gastrointestinal Disorders and Strategies to Modulate Them with Microbiome-Targeted Therapies. Annual Review of Nutrition. 2023; 43: 355\u2013383.","DOI":"10.1146\/annurev-nutr-061121-094908"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. Microbial degradation of complex carbohydrates in the gut. Gut Microbes. 2012; 3: 289\u2013306.","DOI":"10.4161\/gmic.19897"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"Bisht D, Pal D, Shrestha R. Introduction to Probiotics, Prebiotics, and Synbiotics: A Holistic Approach. Probiotics (pp. 1\u201328). CRC Press: Boca Raton, Florida, USA. 2024.","DOI":"10.1201\/9781003452249-1"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Wei X, Yu L, Zhang C, Ni Y, Zhang H, Zhai Q, et al. Genetic-Phenotype Analysis of Bifidobacterium bifidum and Its Glycoside Hydrolase Gene Distribution at Different Age Groups. Foods. 2023; 12: 922.","DOI":"10.3390\/foods12050922"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Research. 2018; 1693: 128\u2013133.","DOI":"10.1016\/j.brainres.2018.03.015"}],"container-title":["Frontiers in Bioscience-Elite"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBE\/18\/2\/10.31083\/FBE44158","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T12:02:27Z","timestamp":1783425747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBE\/18\/2\/10.31083\/FBE44158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026]]}},"alternative-id":["S1945-0494(26)02967-0"],"URL":"https:\/\/doi.org\/10.31083\/fbe44158","relation":{},"ISSN":["1945-0494","1945-0508"],"issn-type":[{"value":"1945-0494","type":"print"},{"value":"1945-0508","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]},"article-number":"44158"}}