食品与发酵工业 >

2025 , Vol. 51 >Issue 19: 394 - 402

DOI: https://doi.org/10.13995/j.cnki.11-1802/ts.041795

基于微生物-肠-脑轴治疗的益生菌发酵策略研究进展

  • 荆思思 ,
  • 李曙伟 ,
  • 傅容湛 ,
  • 朱峰 ,
  • 刘亚萍 ,
  • 李红霞 ,
  • 和水祥 ,
  • 田婉怡 ,
  • 范代娣 ,
  • 费强
展开
  • 1(西安交通大学 化学工程与技术学院,陕西 西安,710049)
    2(西安交通大学第一附属医院消化内科,陕西 西安,710061)
    3(西北大学 化工学院,陕西 西安,710069)
    4(西安交通大学第一附属医院转化医学中心,陕西 西安,710061)
    5(陕西省消化系统疾病(肿瘤方向)临床医学研究中心,陕西 西安,710061)
    6(青海大学 农牧学院,青海 西宁,810016)
第一作者:硕士研究生(费强教授和范代娣教授为共同通信作者,E-mail:feiqiang@xjtu.edu.cn;fandaidi@nwu.edu.cn)

收稿日期: 2024-12-07

  修回日期: 2025-03-20

  网络出版日期: 2025-11-03

基金资助

国家自然科学基金项目(22278335);陕西高校青年创新团队项目

收起

Progress in probiotic fermentation strategies for the microbiota-gut-brain axis

  • JING Sisi ,
  • LI Shuwei ,
  • FU Rongzhan ,
  • ZHU Feng ,
  • LIU Yaping ,
  • LI Hongxia ,
  • HE Shuixiang ,
  • TIAN Wanyi ,
  • FAN Daidi ,
  • FEI Qiang
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  • 1(School of Chemical Engineering and Technology, Xi’an Jiaotong University, Xi’an 710049, China)
    2(Department of Gastroenterology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China)
    3(School of Chemical Engineering, Northwest University, Xi’an 710069, China)
    4(Department of Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China)
    5(Clinical Medical Research Center for Digestive Diseases of Shaanxi Province(Oncology), Xi’an 710061, China)
    6(College of Agriculture and Animal Husbandry, Qinghai University, Xining 810016, China)

Received date: 2024-12-07

  Revised date: 2025-03-20

  Online published: 2025-11-03

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摘要

随着对益生菌通过微生物-肠-脑轴(microbiota-gut-brain axis,MGBA)影响神经精神疾病机制的深入理解,益生菌治疗此类疾病的新方法正日益受到临床研究者的关注。MGBA作为一个双向交流的网络,其功能依赖于肠道菌群、神经内分泌系统和免疫系统的协同作用。研究表明,益生菌通过多种机制影响大脑健康,包括调节神经递质合成、调控免疫炎症因子的释放以及维持肠道屏障的完整性。然而,当前益生菌的发酵技术普遍面临成本高和操作复杂等问题,这在一定程度上限制了其临床应用的广泛性。该文首先探讨了益生菌在MGBA中的作用机制及其在神经精神疾病治疗领域的最新研究进展;其次,总结了一系列有助于提高益生菌发酵效率的优化策略,以克服其临床应用中的障碍;最后,针对益生菌制剂效果不明显的问题,提出了多种可行的提升策略,为开发更高浓度和疗效的益生菌制剂提供了新的思路和方向。

关键词： 益生菌; 微生物-肠-脑轴; 神经精神疾病; 发酵工艺优化; 益生菌疗效优化

本文引用格式

荆思思 , 李曙伟 , 傅容湛 , 朱峰 , 刘亚萍 , 李红霞 , 和水祥 , 田婉怡 , 范代娣 , 费强 . 基于微生物-肠-脑轴治疗的益生菌发酵策略研究进展[J]. 食品与发酵工业, 2025 , 51(19) : 394 -402 . DOI: 10.13995/j.cnki.11-1802/ts.041795

Abstract

As our understanding of the mechanisms by which probiotics influence neuropsychiatric disorders through the microbiota-gut-brain axis (MGBA) deepens, there is an increasing interest among clinical researchers in developing probiotic-based therapies.The MGBA functions as a bidirectional communication network, with its efficacy relying on the coordinated interactions among gut microbiota, the neuroendocrine system, and immune regulation.Research has demonstrated that probiotics can impact brain health through various mechanisms, including modulation of neurotransmitter synthesis, regulation of immune-inflammatory factors, and maintenance of gut barrier integrity.However, current probiotic fermentation technologies face challenges such as high costs and operational complexity, limiting their widespread clinical application.This review first explores the mechanisms of action of probiotics within the MGBA and summarizes recent advances in research on their therapeutic potential for neuropsychiatric disorders.Additionally, to address the barriers posed by low production efficiency in probiotic applications, we outline several strategies aimed at optimizing fermentation processes.Finally, in light of the often-suboptimal therapeutic effects of probiotic formulations, we propose multiple feasible strategies for enhancing their efficacy, providing new insights and directions for the development of high-concentration and effective probiotic products.

Key words： probiotics; microbiota-gut-brain axis; neuropsychiatric disorders; fermentation process optimization; probiotic efficacy optimization

参考文献

[1] XIAO W P, SU J B, GAO X J, et al.The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids[J].Microbiome, 2022, 10(1):62.
[2] RIBERA C, SÁNCHEZ-ORTÍ J V, CLARKE G, et al.Probiotic, prebiotic, synbiotic and fermented food supplementation in psychiatric disorders:A systematic review of clinical trials[J].Neuroscience & Biobehavioral Reviews, 2024, 158:105561.
[3] TAKADA M, NISHIDA K, KATAOKA-KATO A, et al.Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models[J].Neurogastroenterology and Motility, 2016, 28(7):1027-1036.
[4] QIAN X, LI Q, ZHU H Y, et al.Bifidobacteria with indole-3-lactic acid-producing capacity exhibit psychobiotic potential via reducing neuroinflammation[J].Cell Reports Medicine, 2024, 5(11):101798.
[5] LIU G X, CHONG H X, CHUNG F Y, et al.Lactobacillus plantarum DR7 modulated bowel movement and gut microbiota associated with dopamine and serotonin pathways in stressed adults[J].International Journal of Molecular Sciences, 2020, 21(13):4608.
[6] DALILE B, VAN OUDENHOVE L, VERVLIET B, et al.The role of short-chain fatty acids in microbiota-gut-brain communication[J].Nature Reviews Gastroenterology & Hepatology, 2019, 16(8):461-478.
[7] 董奇奇, 张怡琳, 游春苹.肠道微生物及其代谢产物对血脑屏障的影响及益生菌干预措施研究进展[J].食品工业科技, 2024, 45(22):353-360.
DONG Q Q, ZHANG Y L, YOU C P.Research progress in effects of gut microbiota and their metabolites on the blood-brain barrier and interventions by probiotics[J].Science and Technology of Food Industry, 2024, 45(22):353-360.
[8] XU M S, TIAN P J, ZHU H Y, et al.Lactobacillus paracasei CCFM1229 and Lactobacillus rhamnosus CCFM1228 alleviated depression- and anxiety-related symptoms of chronic stress-induced depression in mice by regulating xanthine oxidase activity in the brain[J].Nutrients, 2022, 14(6):1294.
[9] OU Z H, DENG L L, LU Z, et al.Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease[J].Nutrition & Diabetes, 2020, 10:12.
[10] LI T T, CHU C Q, YU L L, et al.Neuroprotective effects of Bifidobacterium breve CCFM1067 in MPTP-induced mouse models of Parkinson’s disease[J].Nutrients, 2022, 14(21):4678.
[11] HATHI Z, METTU S, PRIYA A, et al.Methodological advances and challenges in probiotic bacteria production:Ongoing strategies and future perspectives[J].Biochemical Engineering Journal, 2021, 176:108199.
[12] AGIRMAN G, YU K B, HSIAO E Y.Signaling inflammation across the gut-brain axis[J].Science, 2021, 374(6571):1087-1092.
[13] BREIT S, KUPFERBERG A, ROGLER G, et al.Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders[J].Frontiers in Psychiatry, 2018, 9:44.
[14] KUIJER E J, STEENBERGEN L.The microbiota-gut-brain axis in hippocampus-dependent learning and memory:Current state and future challenges[J].Neuroscience and Biobehavioral Reviews, 2023, 152:105296.
[15] MATSUURA N, MOTOSHIMA H, UCHIDA K, et al.Effects of Lactococcus lactis subsp.cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men[J].European Journal of Clinical Nutrition, 2022, 76(4):574-580.
[16] SMITH C J, EMGE J R, BERZINS K, et al.Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice[J].American Journal of Physiology.Gastrointestinal and Liver Physiology, 2014, 307(8):G793-G802.
[17] DENYSOV Y, PUTYATIN G, MOROZ S, et al.Effects of probiotic supplement Lactobacillus plantarum CECT7485 and Lactobacillus Brevis CECT7480 on sleep quality in patients with anxiety and depression comorbidity[J].European Psychiatry, 2023, 66(S1):S454.
[18] 王秋珍, 邓自腾, 兰静, 等.干酪乳杆菌对DSS诱导结肠炎小鼠焦虑样行为的影响及对结肠的保护作用[J].中国农业大学学报, 2023, 28(4):139-146.
WANG Q Z, DENG Z T, LAN J, et al.Effects of Lactobacillus casei on anxiety like behavior in mice with colitis induced by DSS and its protective effect on colon[J].Journal of China Agricultural University, 2023, 28(4):139-146.
[19] KIM H, KIM H, SUH H J, et al.Lactobacillus brevis-fermented gamma-aminobutyric acid ameliorates depression- and anxiety-like behaviors by activating the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway in BALB/C mice[J].Journal of Agricultural and Food Chemistry, 2024, 72(6):2977-2988.
[20] DONG W Z, WANG Y, LIAO S X, et al.Bifidobacterium animalis subsp.lactis BB-12 improves the state anxiety and sports performance of young divers under stress situations:A single-arm, prospective proof-of-concept study[J].Frontiers in Psychology, 2020, 11:570298.
[21] VICARIOTTO F, MALFA P, TORRICELLI M, et al.Beneficial effects of Limosilactobacillus reuteri PBS072 and Bifidobacterium breve BB077 on mood imbalance, self-confidence, and breastfeeding in women during the first trimester postpartum[J].Nutrients, 2023, 15(16):3513.
[22] TOMITA T, FUKUI H, OKUGAWA T, et al.Effect of Bifidobacterium bifidum G9-1 on the intestinal environment and diarrhea-predominant irritable bowel syndrome (IBS-D)-like symptoms in patients with quiescent Crohn’s disease:A prospective pilot study[J].Journal of Clinical Medicine, 2023, 12(10):3368.
[23] CHENG R R, ZHU H Y, SUN Y, et al.The modified outer membrane protein Amuc_1100 of Akkermansia muciniphila improves chronic stress-induced anxiety and depression-like behavior in mice[J].Food & Function, 2022, 13(20):10748-10758.
[24] MEYNIER M, DAUGEY V, MALLARET G, et al.Pasteurized akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice[J].Gut Microbes, 2024, 16(1):2298026.
[25] WANG L, ZHAO Z J, ZHAO L, et al.Lactobacillus plantarum DP189 reduces α-SYN aggravation in MPTP-induced Parkinson’s disease mice via regulating oxidative damage, inflammation, and gut microbiota disorder[J].Journal of Agricultural and Food Chemistry, 2022, 70(4):1163-1173.
[26] TAN F H P, LIU G, LAU S A, et al.Lactobacillus probiotics improved the gut microbiota profile of a Drosophila melanogaster Alzheimer’s disease model and alleviated neurodegeneration in the eye[J].Beneficial Microbes, 2020, 11(1):79-89.
[27] ZHU G S, ZHAO J X, WANG G, et al.Bifidobacterium breve HNXY26M4 attenuates cognitive deficits and neuroinflammation by regulating the gut-brain axis in APP/PS1 mice[J].Journal of Agricultural and Food Chemistry, 2023, 71(11):4646-4655.
[28] ZUBAREVA O E, DYOMINA A V, KOVALENKO A A, et al.Beneficial effects of probiotic Bifidobacterium longum in a lithium-pilocarpine model of temporal lobe epilepsy in rats[J].International Journal of Molecular Sciences, 2023, 24(9):8451.
[29] MENSI M M, ROGANTINI C, MARCHESI M, et al.Lactobacillus plantarum PS128 and other probiotics in children and adolescents with autism spectrum disorder:A real-world experience[J].Nutrients, 2021, 13(6):2036.
[30] WU S, WU C C, TSAI P J, et al.Psychobiotic supplementation of PS128TM improves stress, anxiety, and insomnia in highly stressed information technology specialists:A pilot study[J].Frontiers in Nutrition, 2021, 8:614105.
[31] KONG Q M, CHEN Q, MAO X H, et al.Bifidobacterium longum CCFM1077 ameliorated neurotransmitter disorder and neuroinflammation closely linked to regulation in the kynurenine pathway of autistic-like rats[J].Nutrients, 2022, 14(8):1615.
[32] 朱铮, 李兰娟, 王保红.新一代益生菌:肠道微生态疗法的新机遇[J].中国医学前沿杂志(电子版), 2024, 16(1):92.
ZHU Z, LI L J, WANG B H.New generation probiotics:A new opportunity for gut microecology[J].Therapy Chinese Journal of the Frontiers of Medical Science(Electronic Version), 2024, 16(1):92.
[33] CANI P D, DEPOMMIER C, DERRIEN M, et al.Akkermansia muciniphila:Paradigm for next-generation beneficial microorganisms[J].Nature Reviews Gastroenterology & Hepatology, 2022, 19(10):625-637.
[34] OLSON C A, VUONG H E, YANO J M, et al.The gut microbiota mediates the anti-seizure effects of the ketogenic diet[J].Cell, 2018, 174(2):497.
[35] SANMARCO L M, RONE J M, POLONIO C M, et al.Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells[J].Nature, 2023, 620(7975):881-889.
[36] KAZEMI A, ALI NOORBALA A, AZAM K, et al.Effect of prebiotic and probiotic supplementation on circulating pro-inflammatory cytokines and urinary Cortisol levels in patients with major depressive disorder:A double-blind, placebo-controlled randomized clinical trial[J].Journal of Functional Foods, 2019, 52:596-602.
[37] 邹仁英, 朱慧越, 许梦舒, 等.“精神益生菌” 对慢性应激诱导的抑郁和便秘症状的缓解及机制研究[J].食品与发酵工业, 2021, 47(3):1-9.
ZOU R Y, ZHU H Y, XU M S, et al.Effect and mechanism of psychobiotics in regulating chronic stress induced depression and constipation[J].Food and Fermentation Industries, 2021, 47(3):1-9.
[38] 张腾霄, 王斌, 蔡宏达, 等.蔬菜液体培养基用于发酵培养青春双歧杆菌的研究[J].河南工业大学学报(自然科学版), 2020, 41(6):74-79.
ZHANG T X, WANG B, CAI H D, et al.Research on the application of vegetable liquid media in fermentation and culture of Bifidobacterium adolescentis[J].Journal of Henan University of Technology (Natural Science Edition), 2020, 41(6):74-79.
[39] 王超凡, 王慧慧, 胡世伟, 等.鼠李糖乳杆菌TCCC 10035的培养条件优化[J].饲料研究, 2024, 47(22):116-122.
WANG C F, WANG H H, HU S W, et al.Optimization of cultivation conditions for Lactobacillus rhamnosus TCCC 10035[J].Feed Research, 2024, 47 (22):116-122.
[40] 郭艳荣. 格氏乳杆菌体外筛选及高密度培养工艺研究[D].呼和浩特:内蒙古农业大学, 2020.
GUO Y R.The in vitro sereening of Lactobacillus gasseri and the research of high cell density culture[D].Hohhot:Inner Mongolia Agricultural University, 2020.
[41] 田睿. 两歧双歧杆菌F35高密度发酵培养基的优化及应用[D].无锡:江南大学, 2024.
TIAN R.Optimization of high-density fermentation medium for Bifidobacterium bifidum F35 and its application[D].Wuxi:Jiangnan University, 2024.
[42] 刘福东, 桑跃, 葛绍阳.乳双歧杆菌BL-99高密度发酵培养工艺的优化研究[J].中国奶牛, 2023 (12):32-36.
LIU F D, SANG Y, GE S Y.Optimization of high cell density fermentation for Bifidobacterium lactis BL-99[J].China Dairy Cattle, 2023 (12):32-36.
[43] 毕长富, 曾思恒, 何娟, 等.产γ-氨基丁酸酵母菌高密度培养条件优化[J].四川轻化工大学学报(自然科学版), 2022, 35(6):26-34.
BI C F, ZENG S H, HE J, et al.Optimization of high density culture conditions for γ-GABA producing yeast[J].Journal of Sichuan University of Science & Engineering (Natural Science Edition), 2022, 35(6):26-34.
[44] 彭奎耀, 关成冉, 王伟军, 等.嗜热链球菌937增殖培养基及发酵条件的优化[J].现代食品科技, 2024, 40(5):24-33.
PENG K Y, GUAN C R, WANG W J, et al.Optimization of enrichment culture medium and fermentation conditions for Streptococcus thermophilus 937[J].Modern Food Science and Technology, 2024, 40(5):24-33.
[45] WANG T, LU Y Y, YAN H, et al.Fermentation optimization and kinetic model for high cell density culture of a probiotic microorganism:Lactobacillus rhamnosus LS-8[J].Bioprocess and Biosystems Engineering, 2020, 43(3):515-528.
[46] SUN Y R, PENG C T, WANG J C, et al.Mesopic fermentation contributes more to the formation of important flavor compounds and increased growth of Lactobacillus casei Zhang than does high temperature during milk fermentation and storage[J].Journal of Dairy Science, 2022, 105(6):4857-4867.
[47] CUI S M, SADIQ F A, MAO B Y, et al.High-density cultivation of Lactobacillus and Bifidobacterium using an automatic feedback feeding method[J].LWT, 2019, 112:108232.
[48] METTU S, HATHI Z, ATHUKORALALAGE S, et al.Perspective on constructing cellulose-hydrogel-based gut-like bioreactors for growth and delivery of multiple-strain probiotic bacteria[J].Journal of Agricultural and Food Chemistry, 2021, 69(17):4946-4959.
[49] JU J H, JEON S G, HEO S Y, et al.Synbiotics production using Lactobacillus reuteri EC01, a strain that produces alternan-type exopolysaccharide[J].LWT, 2023, 182:114814.
[50] WANG X L, SUN Y Q, PAN D T, et al.Kinetics-based development of two-stage continuous fermentation of 1, 3-propanediol from crude glycerol by Clostridium butyricum[J].Biotechnology for Biofuels and Bioproducts, 2024, 17(1):38.
[51] WU H, ZHANG Y L, LI L, et al.Positive regulation of the DLT operon by TCSR7 enhances acid tolerance of Lactococcus lactis F44[J].Journal of Dairy Science, 2022, 105(10):7940-7950.
[52] KIM Y Y, KIM J C, KIM S, et al.Heterotypic stress-induced adaptive evolution enhances freeze-drying tolerance and storage stability of Leuconostoc mesenteroides WiKim33[J].Food Research International, 2024, 175:113731.
[53] 高娉娉, 刘汉清, 张凤, 等.益生菌遗传育种方法研究进展[J].食品与发酵工业, 2023, 49(22):302-310.
GAO P P, LIU H Q, ZHANG F, et al.Research progress in genetic breeding methods for probiotics[J].Food and Fermentation Industries, 2023, 49(22):302-310.
[54] 魏笑莲, 钱智玲, 陈巧巧, 等.遗传改造微生物制造食品和饲料的监管要求及欧盟授权案例分析[J].合成生物学, 2021, 2(1):121-133.
WEI X L, QIAN Z L, CHEN Q Q, et al.Regulatory requirements for food and feed produced with genetically modified microorganisms and case studies for EU authorization[J].Synthetic Biology Journal, 2021, 2(1):121-133.
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