益生菌对神经系统疾病作用的研究进展
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摘要
人体肠道内菌群数量巨大且种类丰富,参与机体的多项生理过程,研究显示肠道菌群能够通过肠道菌群-肠-脑轴来调节机体大脑的发育与行为。益生菌是一类对人体有益的活性微生物,可以通过调节人体肠道微生态平衡从而对人体产生有益作用。临床医学研究表明,益生菌对自闭症谱系障碍、阿尔茨海默病、帕金森病、抑郁症和多发性硬化等神经系统疾病具有良好的防治作用。本文总结了近几年来国内外关于益生菌对神经系统疾病作用机制的研究进展,以期为益生菌对此类疾病的干预治疗提供新思路。
The gut microbiome in humans consists of a vast and diverse population of microbes that is involved in many physiological processes. Many studies have demonstrated that the gut microbiome regulates the development and behavior of human brain through the microbiota-gut-brain axis. Probiotics are a group of live microorganisms that are beneficial to the human body by regulating the micro-ecological balance in the human intestinal tract. Clinical studies have shown that probiotics are highly effective in the prevention and treatment of autism spectrum disorders, Alzheimer's disease, Parkinson's disease, depression and multiple sclerosis and other neurological diseases. In this article, recent progress understanding in the mechanism of action of probiotics on nervous system diseases in China and abroad is reviewed in order to provide a new idea for the intervention and treatment of diseases using probiotics.
The gut microbiome in humans consists of a vast and diverse population of microbes that is involved in many physiological processes. Many studies have demonstrated that the gut microbiome regulates the development and behavior of human brain through the microbiota-gut-brain axis. Probiotics are a group of live microorganisms that are beneficial to the human body by regulating the micro-ecological balance in the human intestinal tract. Clinical studies have shown that probiotics are highly effective in the prevention and treatment of autism spectrum disorders, Alzheimer's disease, Parkinson's disease, depression and multiple sclerosis and other neurological diseases. In this article, recent progress understanding in the mechanism of action of probiotics on nervous system diseases in China and abroad is reviewed in order to provide a new idea for the intervention and treatment of diseases using probiotics.
引文
[1]SAMPSON T R,MAZMANIAN S K.Control of brain development,function,and behavior by the microbiome[J].Cell Host&Microbe,2015,17(5):565-576.DOI:10.1016/j.chom.2015.04.011.
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[3]AZIZ Q,THOMPSON D G.Brain-gut axis in health and disease[J].Gastroenterology,1998,114(3):559-578.DOI:10.1016/S0016-5085(98)70540-2.
[4]KENNEDY P J,MURPHY A B,CRYAN J F,et al.Microbiome in brain function and mental health[J].Trends in Food Science&Technology,2016,57:289-301.
[5]KAZEMI A,NOORBALA A A,AZAM K,et al.Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder:a randomized clinical trial[J].Clinical Nutrition,2019,38(2):522-528.DOI:10.1016/j.clnu.2018.04.010.
[6]BRAVO J A,FORSYTHE P,CHEW M V,et al.Ingestion of Lactobacillus strain regulates emotional behavior and central GABAreceptor expression in a mouse via the vagus nerve[J].Proceedings of the National Academy of Sciences of the United States of America,2011,108(38):16050-16055.DOI:10.1073/pnas.1102999108.
[7]ERNY D,HRABěDE ANGELIS A L,JAITIN D,et al.Host microbiota constantly control maturation and function of microglia in the CNS[J].Nature Neuroscience,2015,18(7):965-977.DOI:10.1038/nn.4030.
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[12]HAN A,SUNG Y B,CHUNG S Y,et al.Possible additional antidepressant-like mechanism of sodium butyrate:targeting the hippocampus[J].Neuropharmacology,2014,81(6):292-302.DOI:10.1016/j.neuropharm.2014.02.017.
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[14]PERRY R J,PENG L,BARRY N A,et al.Acetate mediates a microbiome-brain-βcell axis promoting metabolic syndrome[J].Nature,2016,534:213-217.DOI:10.1038/nature18309.
[15]VUONG H E,HSIAO E Y.Emerging roles for the gut microbiome in autism spectrum disorder[J].Biological Psychiatry,2016,81(5):411-423.DOI:10.1016/j.biopsych.2016.08.024.
[16]MOLLOY C A,MANNINGCOURTNEY P.Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders[J].Autism the International Journal of Research&Practice,2003,7(2):165-171.DOI:10.1177/1362361303007002004.
[17]NIKOLOV R N,BEARSS K E,LETTINGA J,et al.Gastrointestinal symptoms in a sample of children with pervasive developmental disorders[J].Journal of Autism&Developmental Disorders,2009,39(3):405-413.DOI:10.1007/s10803-008-0637-8.
[18]FINEGOLD S M,DOWD S E,GONTCHAROVA V,et al.Pyrosequencing study of fecal microflora of autistic and control children[J].Anaerobe,2010,16(4):444-453.DOI:10.1016/j.anaerobe.2010.06.008.
[19]HSIAO E Y,MCBRIDE S W,HSIEN S,et al.Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders[J].Cell,2013,155(7):1451-1463.DOI:10.1016/j.cell.2013.11.024.
[20]BUFFINGTON S A,DI P G,AUCHTUNG T A,et al.Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring[J].Cell,2016,165(7):1762-1775.DOI:10.1016/j.cell.2016.06.001.
[21]CESARE M,ROSARIA S.Alzheimer’s disease and gut microbiota modifications:the long way between preclinical studies and clinical evidence[J].Pharmacological Research,2017,129:329-336.DOI:10.1016/j.phrs.2017.12.009.
[22]HARADA R,OKAMURA N,FURUMOTO S,et al.Comparison of the binding characteristics of[18F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology[J].European Journal of Nuclear Medicine&Molecular Imaging,2013,40(1):125-132.DOI:10.1007/s00259-012-2261-2.
[23]HARACH T,MARUNGRUANG N,DUTHILLEUL N,et al.Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota[J].Scientific Reports,2017,7:41802.DOI:10.1038/srep41802.
[24]AKBARI E,ASEMI Z,DANESHVAR R K,et al.Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease:a randomized,double-blind and controlled trial[J].Frontiers in Aging Neuroscience,2016,8:256.DOI:10.3389/fnagi.2016.00256.
[25]TILLISCH K,LABUS J,KILPATRICK L,et al.Consumption of fermented milk product with probiotic modulates brain activity[J].Gastroenterology,2013,144(7):1394-1401.DOI:10.1053/j.gastro.2013.02.043.
[26]王文建,郑跃杰.肠道菌群与中枢神经系统相互作用及相关疾病[J].中国微生态学杂志,2016,28(2):240-245.DOI:10.13381/j.cnki.cjm.201602029.
[27]SAVICA R,CARLIN J M,GROSSARDT B R,et al.Medical records documentation of constipation preceding Parkinson disease:a casecontrol study[J].Neurology,2009,73(21):1752-1758.DOI:10.1212/WNL.0b013e3181c34af5.
[28]NOYCE A J,BESTWICK J P,SILVEIRA-MORIYAMA L,et al.Meta-analysis of early nonmotor features and risk factors for parkinson disease[J].Annals of Neurology,2012,72(6):893-901.DOI:10.1002/ana.23687.
[29]QUIGLEY E M.Gastrointestinal dysfunction in Parkinson’s disease[J].Neurology,1996,42(4):245-250.DOI:10.1055/s-2008-1040981.
[30]SCHEPERJANS F,AHO V,PEREIRA P A B,et al.Gut microbiota are related to Parkinson’s disease and clinical phenotype[J].Movement Disorders,2015,30(3):350-358.DOI:10.1002/mds.26069.
[31]BARICHELLA M,PACCHETTI C,BOLLIRI C,et al.Probiotics and prebiotic fiber for constipation associated with Parkinson disease:an RCT[J].Neurology,2016,87(12):1274-1280.DOI:10.1212/WNL.0000000000003127.
[32]LIN P,LI Q T.Can gut flora changes be new biomarkers for depression?[J].Frontiers in Laboratory Medicine,2017,1(3):129-134.DOI:10.1016/j.flm.2017.08.002.
[33]马燕,郭莉娜,刘漪沦.肠道菌群与抑郁症发生的研究进展[J].实用医学杂志,2018,34(2):324-327.DOI:10.3969/j.issn.1006-5725.2018.02.042.
[34]WANG Yan,KASPER L H.The role of microbiome in central nervous system disorders[J].Brain Behavior&Immunity,2014,38(5):1-12.DOI:10.1016/j.bbi.2013.12.015.
[35]GOSHEN I,KREISEL T,BEN-MENACHEM-ZIDON O,et al.Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression[J].Molecular Psychiatry,2008,13(7):717-728.DOI:10.1038/sj.mp.4002055.
[36]ZHENG P,ZENG B,ZHOU C,et al.Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism[J].Molecular Psychiatry,2016,21(6):786-796.DOI:10.1038/mp.2016.44.
[37]GAREAU M G,JURY J,MACQUEEN G,et al.Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation[J].Gut,2007,56(11):1522-1528.DOI:10.1136/gut.2006.117176.
[38]DESBONNET L,GARRETT L,CLARKE G,et al.The probiotic Bifidobacteria infantis:an assessment of potential antidepressant properties in the rat[J].Journal of Psychiatric Research,2008,43(2):164-174.DOI:10.1016/j.jpsychires.2008.03.009.
[39]DESBONNET L,GARRETT L,CLARKE G,et al.Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression[J].Neuroscience,2010,170(4):1179-1188.DOI:10.1016/j.neuroscience.2010.08.005.
[40]MIELCARZ D W,KASPER L H.The gut microbiome in multiple sclerosis[J].Current Treatment Options in Neurology,2015,17(4):344.DOI:10.1007/s11940-015-0344-7.
[41]JOSCELYN J,KASPER L H.Digesting the emerging role for the gut microbiome in central nervous system demyelination[J].Multiple Sclerosis,2014,20(12):1553-1559.DOI:10.1177/1352458514541579.
[42]MIELCARZ D W,KASPER L H.The gut microbiome in multiple sclerosis[J].Current Treatment Options in Neurology,2015,17(4):18.
[43]TREMLETT H,FADROSH D W,FARUQI A A,et al.Gut microbiota in early pediatric multiple sclerosis:a case-control study[J].European Journal of Neurology,2016,23(8):1308-1321.DOI:10.1111/ene.13026.
[44]KWON H K,KIM G C,KIM Y,et al.Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response[J].Clinical Immunology,2013,146(3):217-227.
[45]孙哲,郭力,孔鹏.多发性硬化及EAE动物模型相关信号通路研究进展[J].中国神经免疫学和神经病学杂志,2016,23(1):58-62.DOI:10.3969/j.issn.1006-2963.2016.01.016.
[46]TANKOU S K,REGEV K,HEALY B C,et al.Investigation of probiotics in multiple sclerosis[J].Multiple Sclerosis,2018,24(1):58-63.DOI:10.1177/1352458517737390.
[2]CRYAN J F,DINAN T G.Mind-altering microorganisms:the impact of the gut microbiota on brain and behaviour[J].Nature Reviews Neuroscience,2012,13(10):701-712.DOI:10.1038/nrn3346.
[3]AZIZ Q,THOMPSON D G.Brain-gut axis in health and disease[J].Gastroenterology,1998,114(3):559-578.DOI:10.1016/S0016-5085(98)70540-2.
[4]KENNEDY P J,MURPHY A B,CRYAN J F,et al.Microbiome in brain function and mental health[J].Trends in Food Science&Technology,2016,57:289-301.
[5]KAZEMI A,NOORBALA A A,AZAM K,et al.Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder:a randomized clinical trial[J].Clinical Nutrition,2019,38(2):522-528.DOI:10.1016/j.clnu.2018.04.010.
[6]BRAVO J A,FORSYTHE P,CHEW M V,et al.Ingestion of Lactobacillus strain regulates emotional behavior and central GABAreceptor expression in a mouse via the vagus nerve[J].Proceedings of the National Academy of Sciences of the United States of America,2011,108(38):16050-16055.DOI:10.1073/pnas.1102999108.
[7]ERNY D,HRABěDE ANGELIS A L,JAITIN D,et al.Host microbiota constantly control maturation and function of microglia in the CNS[J].Nature Neuroscience,2015,18(7):965-977.DOI:10.1038/nn.4030.
[8]DINAN T G,STANTON C,CRYAN J F.Psychobiotics:a novel class of psychotropic[J].Biological Psychiatry,2013,74(10):720-726.DOI:10.1016/j.biopsych.2013.05.001.
[9]LYTE M.Probiotics function mechanistically as delivery vehicles for neuroactive compounds:microbial endocrinology in the design and use of probiotics[J].BioEssays,2011,33(8):574-581.DOI:10.1002/bies.201100024.
[10]BARRETT E,ROSS R P,O’TOOLE P W,et al.γ-Aminobutyric acid production by culturable bacteria from the human intestine[J].Journal of Applied Microbiology,2012,113(2):411-417.DOI:10.1111/j.1365-2672.2012.05344.x.
[11]MAC FARLANE S,MACFARLANE G T.Regulation of short-chain fatty acid production[J].Proceedings of the Nutrition Society,2003,62(1):67-72.DOI:10.1079/PNS2002207.
[12]HAN A,SUNG Y B,CHUNG S Y,et al.Possible additional antidepressant-like mechanism of sodium butyrate:targeting the hippocampus[J].Neuropharmacology,2014,81(6):292-302.DOI:10.1016/j.neuropharm.2014.02.017.
[13]MORETTI M,VALVASSORI S S,VARELA R B,et al.Behavioral and neurochemical effects of sodium butyrate in an animal model of mania[J].Behavioural Pharmacology,2011,22(8):766-772.DOI:10.1097/FBP.0b013e32834d0f1b.
[14]PERRY R J,PENG L,BARRY N A,et al.Acetate mediates a microbiome-brain-βcell axis promoting metabolic syndrome[J].Nature,2016,534:213-217.DOI:10.1038/nature18309.
[15]VUONG H E,HSIAO E Y.Emerging roles for the gut microbiome in autism spectrum disorder[J].Biological Psychiatry,2016,81(5):411-423.DOI:10.1016/j.biopsych.2016.08.024.
[16]MOLLOY C A,MANNINGCOURTNEY P.Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders[J].Autism the International Journal of Research&Practice,2003,7(2):165-171.DOI:10.1177/1362361303007002004.
[17]NIKOLOV R N,BEARSS K E,LETTINGA J,et al.Gastrointestinal symptoms in a sample of children with pervasive developmental disorders[J].Journal of Autism&Developmental Disorders,2009,39(3):405-413.DOI:10.1007/s10803-008-0637-8.
[18]FINEGOLD S M,DOWD S E,GONTCHAROVA V,et al.Pyrosequencing study of fecal microflora of autistic and control children[J].Anaerobe,2010,16(4):444-453.DOI:10.1016/j.anaerobe.2010.06.008.
[19]HSIAO E Y,MCBRIDE S W,HSIEN S,et al.Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders[J].Cell,2013,155(7):1451-1463.DOI:10.1016/j.cell.2013.11.024.
[20]BUFFINGTON S A,DI P G,AUCHTUNG T A,et al.Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring[J].Cell,2016,165(7):1762-1775.DOI:10.1016/j.cell.2016.06.001.
[21]CESARE M,ROSARIA S.Alzheimer’s disease and gut microbiota modifications:the long way between preclinical studies and clinical evidence[J].Pharmacological Research,2017,129:329-336.DOI:10.1016/j.phrs.2017.12.009.
[22]HARADA R,OKAMURA N,FURUMOTO S,et al.Comparison of the binding characteristics of[18F]THK-523 and other amyloid imaging tracers to Alzheimer’s disease pathology[J].European Journal of Nuclear Medicine&Molecular Imaging,2013,40(1):125-132.DOI:10.1007/s00259-012-2261-2.
[23]HARACH T,MARUNGRUANG N,DUTHILLEUL N,et al.Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota[J].Scientific Reports,2017,7:41802.DOI:10.1038/srep41802.
[24]AKBARI E,ASEMI Z,DANESHVAR R K,et al.Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease:a randomized,double-blind and controlled trial[J].Frontiers in Aging Neuroscience,2016,8:256.DOI:10.3389/fnagi.2016.00256.
[25]TILLISCH K,LABUS J,KILPATRICK L,et al.Consumption of fermented milk product with probiotic modulates brain activity[J].Gastroenterology,2013,144(7):1394-1401.DOI:10.1053/j.gastro.2013.02.043.
[26]王文建,郑跃杰.肠道菌群与中枢神经系统相互作用及相关疾病[J].中国微生态学杂志,2016,28(2):240-245.DOI:10.13381/j.cnki.cjm.201602029.
[27]SAVICA R,CARLIN J M,GROSSARDT B R,et al.Medical records documentation of constipation preceding Parkinson disease:a casecontrol study[J].Neurology,2009,73(21):1752-1758.DOI:10.1212/WNL.0b013e3181c34af5.
[28]NOYCE A J,BESTWICK J P,SILVEIRA-MORIYAMA L,et al.Meta-analysis of early nonmotor features and risk factors for parkinson disease[J].Annals of Neurology,2012,72(6):893-901.DOI:10.1002/ana.23687.
[29]QUIGLEY E M.Gastrointestinal dysfunction in Parkinson’s disease[J].Neurology,1996,42(4):245-250.DOI:10.1055/s-2008-1040981.
[30]SCHEPERJANS F,AHO V,PEREIRA P A B,et al.Gut microbiota are related to Parkinson’s disease and clinical phenotype[J].Movement Disorders,2015,30(3):350-358.DOI:10.1002/mds.26069.
[31]BARICHELLA M,PACCHETTI C,BOLLIRI C,et al.Probiotics and prebiotic fiber for constipation associated with Parkinson disease:an RCT[J].Neurology,2016,87(12):1274-1280.DOI:10.1212/WNL.0000000000003127.
[32]LIN P,LI Q T.Can gut flora changes be new biomarkers for depression?[J].Frontiers in Laboratory Medicine,2017,1(3):129-134.DOI:10.1016/j.flm.2017.08.002.
[33]马燕,郭莉娜,刘漪沦.肠道菌群与抑郁症发生的研究进展[J].实用医学杂志,2018,34(2):324-327.DOI:10.3969/j.issn.1006-5725.2018.02.042.
[34]WANG Yan,KASPER L H.The role of microbiome in central nervous system disorders[J].Brain Behavior&Immunity,2014,38(5):1-12.DOI:10.1016/j.bbi.2013.12.015.
[35]GOSHEN I,KREISEL T,BEN-MENACHEM-ZIDON O,et al.Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression[J].Molecular Psychiatry,2008,13(7):717-728.DOI:10.1038/sj.mp.4002055.
[36]ZHENG P,ZENG B,ZHOU C,et al.Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism[J].Molecular Psychiatry,2016,21(6):786-796.DOI:10.1038/mp.2016.44.
[37]GAREAU M G,JURY J,MACQUEEN G,et al.Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation[J].Gut,2007,56(11):1522-1528.DOI:10.1136/gut.2006.117176.
[38]DESBONNET L,GARRETT L,CLARKE G,et al.The probiotic Bifidobacteria infantis:an assessment of potential antidepressant properties in the rat[J].Journal of Psychiatric Research,2008,43(2):164-174.DOI:10.1016/j.jpsychires.2008.03.009.
[39]DESBONNET L,GARRETT L,CLARKE G,et al.Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression[J].Neuroscience,2010,170(4):1179-1188.DOI:10.1016/j.neuroscience.2010.08.005.
[40]MIELCARZ D W,KASPER L H.The gut microbiome in multiple sclerosis[J].Current Treatment Options in Neurology,2015,17(4):344.DOI:10.1007/s11940-015-0344-7.
[41]JOSCELYN J,KASPER L H.Digesting the emerging role for the gut microbiome in central nervous system demyelination[J].Multiple Sclerosis,2014,20(12):1553-1559.DOI:10.1177/1352458514541579.
[42]MIELCARZ D W,KASPER L H.The gut microbiome in multiple sclerosis[J].Current Treatment Options in Neurology,2015,17(4):18.
[43]TREMLETT H,FADROSH D W,FARUQI A A,et al.Gut microbiota in early pediatric multiple sclerosis:a case-control study[J].European Journal of Neurology,2016,23(8):1308-1321.DOI:10.1111/ene.13026.
[44]KWON H K,KIM G C,KIM Y,et al.Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response[J].Clinical Immunology,2013,146(3):217-227.
[45]孙哲,郭力,孔鹏.多发性硬化及EAE动物模型相关信号通路研究进展[J].中国神经免疫学和神经病学杂志,2016,23(1):58-62.DOI:10.3969/j.issn.1006-2963.2016.01.016.
[46]TANKOU S K,REGEV K,HEALY B C,et al.Investigation of probiotics in multiple sclerosis[J].Multiple Sclerosis,2018,24(1):58-63.DOI:10.1177/1352458517737390.