肠道菌群与孤独症谱系障碍关系的研究进展
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摘要
随着微生物与大脑相互作用研究的深入,越来越多的科学家认识到肠道菌群对孤独症谱系障碍(ASD)患儿大脑和行为的重要性。目前,主要的研究集中于探究肠道微生物对ASD的致病机制。肠道微生物组与中枢神经系统的双向调节主要通过调节单胺类神经递质、下丘脑-垂体-肾上腺轴激活和神经免疫激活等途径来实现。微生物-肠-脑轴失衡可影响行为表型,导致ASD。因此,通过调节肠道微生物组来治疗ASD是今后的研究热点。本文对ASD肠道微生物组的研究现状进行总结,为肠道微生物组对神经心理的调控寻找更多的证据,以便能更好地理解微生物-肠-脑轴的潜在机制。
It has been increasingly recognized that the presence of a healthy and diverse gut microbiota is important to the development of central nervous system and emotional processing for children with autism spectrum disorders(ASD). The interconnection of gut microbiome and brain function has significantly contributed to establishing the microbiota-gut-brain axis as an extension of the well-accepted gut-brain axis concept. The bidirectional interaction between the gut microbiota and the brain occurs through various pathways including serotonin, hypothalamus-pituitary-adrenal axis, neurotrophin,and the immune system. The microbiota-gut-brain axis has been shown to influence the behaviors associated with neuropsychiatric conditions. Modulation of this gut microbiota as a novel therapy for ASD is gaining interest. This paper summarized the status of neuropsychological microbiome, which provided evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.
It has been increasingly recognized that the presence of a healthy and diverse gut microbiota is important to the development of central nervous system and emotional processing for children with autism spectrum disorders(ASD). The interconnection of gut microbiome and brain function has significantly contributed to establishing the microbiota-gut-brain axis as an extension of the well-accepted gut-brain axis concept. The bidirectional interaction between the gut microbiota and the brain occurs through various pathways including serotonin, hypothalamus-pituitary-adrenal axis, neurotrophin,and the immune system. The microbiota-gut-brain axis has been shown to influence the behaviors associated with neuropsychiatric conditions. Modulation of this gut microbiota as a novel therapy for ASD is gaining interest. This paper summarized the status of neuropsychological microbiome, which provided evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.
引文
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[4] Dinan T G, Borre Y E, Cryan J F. Genomics of schizophrenia:time to consider the gut micbiome?[J]. Mol Psychiatry, 2014,19(12):1252-1257.
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[6] de Theije C G, Wopereis H, Ramadan M, et al. Altered gut mi‐crobiota and activity in a murine model of autism spectrum dis‐orders[J]. Brain Behav Immun, 2014, 37:197-206.
[7] Coretti L, Cristiano C, Florio E, et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of au‐tism spectrum disorder[J]. Sci Rep, 2017, 28:201-208.
[8] Sqritta M, Dooling S W, Buffington S A, et al. Mechanisms Un‐derlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder[J]. Neuron, 2019,101(2):246-259.e6.
[9] Ossenkopp K P, Foley K A, Gibson J, et al. Systemic treatment with the enteric bacterial fermentation product, propionic acid,produces both conditioned taste avoidance and conditioned place avoidance in rats[J]. Behav Brain Res, 2012, 227(1):134-141.
[10] Wall R, Cryan J F, Ross R P, et al. Bacterial neuroactive com‐pounds produced by psychobiotics[J]. Adv Exp Med Biol,2014, 817:221-239.
[11] Nankova B B, Agarwal R, MacFabe D F. Enteric bacterial metabolites propionic and butyric acid modulate gene expres‐sion, including CREB-dependent catecholaminergic neurotrans‐mission, in PC12 cells-possible relevance to autism spectrum disorders[J]. PLoS One, 2014, 9(8):e103740.
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[14] Strati F, Cavalieri D, Albanese D, et al. New evidences on the altered gut microbiota in autism spectrum disorders[J]. Mi‐crobiome, 2017, 5(1):24.
[15] Iovene M R, Bombace F, Maresca R, et al. Intestinal dysbio‐sis and yeast isolation in stool of subjects with autism spectrum disorders[J]. Mycopathologia, 2017, 182(3-4):349-363.
[16] Grossi E, Melli S, Dunca D, et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics[J]. SAGE Open Med Case Rep,2016, 26:4.
[17] Santocchi E, Guiducci L, Fulceri F, et al. Gut to brain interac‐tion in autism spectrum disorders:a randomized controlled trial on the role of probiotics on clinical, biochemical and neuro‐physiological parameters[J]. BMC Psychiatry, 2016, 16:183.
[18] Malhi P, Venkatesh L, Bharti B, et al. Feeding problems and nutrient intake in children with and without autism:a compara‐tive study[J]. Indian J Pediatr, 2017, 84(4):283-288.
[19] Pennesi C M, Klein L C. Effectiveness of the gluten-free, ca‐sein-free diet for children diagnosed with autism spectrum dis‐order:based on parental report[J]. Nutr Neurosci, 2012, 15(2):85-91.
[20] Newell C, Bomhof M R, Reimer R A, et al. Ketogenic diet modifies the gut microbiota in a murine model of autism spec‐trum disorder[J]. Mol Autism, 2016, 7(1):37.
[21] Finegold S M. Desulfovibrio species are potentially impor‐tant in regressive autism[J]. Med Hypotheses, 2011, 77(2):270-274.
[22] Petra A I, Panagintidou S, Hatziagelaki E, et al. Gut-microbi‐ota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation[J]. Clin Ther, 2015, 37(5):984-995.
[23] Israelyan N, Margolis K G. Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders[J].Pharmacol Res, 2019, 140:115-120.
[24] Homberg J R, Kolk S M, Schubert D, et al. Editorial perspec‐tive of the research topic"Deciphering Serotonin's Role in Neu‐rodevelopment"[J]. Front Cell Neurosci, 2013, 7:212.
[25] Mulder E J, Anderson G M, Kema I P, et al. Platelet sero‐tonin levels in pervasive developmental disorders and mental retardation:diagnostic group differences, within-group distribu‐tion, and behavioral correlates[J]. J Am Acad Child Adolesc Psychiatry, 2004, 43(4):491-499.
[26] Finegold S M. Desulfovibrio species are potentially impor‐tant in regressive autism[J]. Med Hypotheses, 2011, 77(2):270-274.
[27] Reigstad C S, Salmonson C E, Rainey J F, et al. Gut mi‐crobes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells[J]. FASEB J, 2015, 29(4):1395-1403.
[28] Sj?gren K, Engdahl C, Henning P, et al. The gut microbiota regulates bone mass in mice[J]. J Bone Miner Res, 2012, 27:1357-1367.
[29]白志余,周东蕊,张仁敏,等.肠内代谢物腹腔注射对大鼠神经内分泌和行为学的影响[J].中国现代医学杂志, 2016, 26(19):17-22.
[30]李佳帅,唐强,朱路文,等.肠道菌群功能及其与运动的相关性研究进展[J].中国康复理论与实践, 2018, 24(12):1422-1424.
[31] Takeuchi O, Akira S. Pattern recognition receptors and in‐flammation[J]. Cell, 2010, 140(6):805-820.
[32] Lutgendorff F, Akkermans L M, S?derholm J D. The role of microbiota and probiotics in stress induced gastro-intestinal damage[J]. Curr Mol Med, 2008, 8(4):282-298.
[33] Keita A V, S?derholm J D. The intestinal barrier and its regu‐lation by neuroimmune factors[J]. Neurogastroenterol Motil,2010, 22(7):718-733.
[34] Karczewski J, Troost F J, Konings I, et al. Regulation of hu‐man epithelial tight junction proteins by Lactobacillus planta‐rum in vivo and protective effects on the epithelial barrier[J].Am J Physiol Gastrointest Liver Physiol, 2010, 298(6):G851-G859.
[35] Holmes A S, Blaxill M F, Haley B E. Reduced levels of mer‐cury in first baby haircuts of autistic children[J]. Int J Toxicol,2003, 22(4):277-285.
[36]陈保林,何慕兰,雷雨溪,等.脂多糖诱导孤独症样大鼠的肠道通透性及肠道黏膜免疫系统的变化[J].免疫学杂志, 2019,35(1):12-28.
[37] Ferquson B J, Marler S, Altstein L L, et al. Associations be‐tween cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder[J]. Brain Behav Im‐mun, 2016, 58:57-62.
[38]洪南,湛先保.肠道微生态系统与肠粘膜免疫关系研究进展[J].医学研究学院, 2014, 27(4):444-446.
[39] Gur T L, Bailey M T. Effects of stress on commensal mi‐crobes and immune system activity[J]. Adv Exp Med Biol,2016, 874:289-300.
[40]陆高,孙建华.CRH-NLRP6-微生物轴在肠易激综合征发病机制及其治疗中的作用[J].医学研究生学报, 2016, 29(1):92-96.
[41] Crumeyrolle-Arias M, Jaglin M, Bruneau A, et al. Absence of the gut microbiota enhances anxiety-like behavior and neuro‐endocrine response to acute stress in rats[J]. Psychoneuroendo‐crinology, 2014, 42:207-217.
[42] Rook G A, Lowry C A, Raison C L, et al. Lymphocytes in neuroprotection, cognition and emotion:is intolerance really the answer?[J]. Brain Behav Immun, 2011, 25(4):591-601.
[43] Ferguson B J, Marler S, Altstein L L, et al. Associations be‐tween cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder[J]. Brain Behav Im‐mun, 2016, 58:57-62.
[44]潘俊希,谢鹏.神经精神疾病微生物组研究现状和展望[J].生命科学, 2017, 29(7):669-681.
[2] Chaidez V, Hansen R L, Hertz-Picciotto I. Gastrointestinal problems in children with autism, developmental delays or typi‐cal development[J]. J Autism Dev Disord, 2014, 44(5):1117-1127.
[3] Desbonnet L, Clarke G, Shanahan F, et al. Microbiota is essen‐tial for social development in the mouse[J]. Mol Psychiatry,2014, 19(2):146-148.
[4] Dinan T G, Borre Y E, Cryan J F. Genomics of schizophrenia:time to consider the gut micbiome?[J]. Mol Psychiatry, 2014,19(12):1252-1257.
[5] Hsiao E Y, McBride S W, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neu‐rodevelopmental disorders[J]. Cell, 2013, 155(7):1451-1463.
[6] de Theije C G, Wopereis H, Ramadan M, et al. Altered gut mi‐crobiota and activity in a murine model of autism spectrum dis‐orders[J]. Brain Behav Immun, 2014, 37:197-206.
[7] Coretti L, Cristiano C, Florio E, et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of au‐tism spectrum disorder[J]. Sci Rep, 2017, 28:201-208.
[8] Sqritta M, Dooling S W, Buffington S A, et al. Mechanisms Un‐derlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder[J]. Neuron, 2019,101(2):246-259.e6.
[9] Ossenkopp K P, Foley K A, Gibson J, et al. Systemic treatment with the enteric bacterial fermentation product, propionic acid,produces both conditioned taste avoidance and conditioned place avoidance in rats[J]. Behav Brain Res, 2012, 227(1):134-141.
[10] Wall R, Cryan J F, Ross R P, et al. Bacterial neuroactive com‐pounds produced by psychobiotics[J]. Adv Exp Med Biol,2014, 817:221-239.
[11] Nankova B B, Agarwal R, MacFabe D F. Enteric bacterial metabolites propionic and butyric acid modulate gene expres‐sion, including CREB-dependent catecholaminergic neurotrans‐mission, in PC12 cells-possible relevance to autism spectrum disorders[J]. PLoS One, 2014, 9(8):e103740.
[12] Vuong H E, Hsiao E Y. Emerging roles for the gut microbi‐ome in autism spectrum disorder[J]. Biol Psychiatry, 2017, 81(5):411-423.
[13] Wang L, Christophersen C T, Sorich M J, et al. Increased abundance of Sutterella spp. and Rumincoccus torques in feces of children with autism spectrum disorder[J]. Mol Autism,2013, 4(1):42.
[14] Strati F, Cavalieri D, Albanese D, et al. New evidences on the altered gut microbiota in autism spectrum disorders[J]. Mi‐crobiome, 2017, 5(1):24.
[15] Iovene M R, Bombace F, Maresca R, et al. Intestinal dysbio‐sis and yeast isolation in stool of subjects with autism spectrum disorders[J]. Mycopathologia, 2017, 182(3-4):349-363.
[16] Grossi E, Melli S, Dunca D, et al. Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics[J]. SAGE Open Med Case Rep,2016, 26:4.
[17] Santocchi E, Guiducci L, Fulceri F, et al. Gut to brain interac‐tion in autism spectrum disorders:a randomized controlled trial on the role of probiotics on clinical, biochemical and neuro‐physiological parameters[J]. BMC Psychiatry, 2016, 16:183.
[18] Malhi P, Venkatesh L, Bharti B, et al. Feeding problems and nutrient intake in children with and without autism:a compara‐tive study[J]. Indian J Pediatr, 2017, 84(4):283-288.
[19] Pennesi C M, Klein L C. Effectiveness of the gluten-free, ca‐sein-free diet for children diagnosed with autism spectrum dis‐order:based on parental report[J]. Nutr Neurosci, 2012, 15(2):85-91.
[20] Newell C, Bomhof M R, Reimer R A, et al. Ketogenic diet modifies the gut microbiota in a murine model of autism spec‐trum disorder[J]. Mol Autism, 2016, 7(1):37.
[21] Finegold S M. Desulfovibrio species are potentially impor‐tant in regressive autism[J]. Med Hypotheses, 2011, 77(2):270-274.
[22] Petra A I, Panagintidou S, Hatziagelaki E, et al. Gut-microbi‐ota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation[J]. Clin Ther, 2015, 37(5):984-995.
[23] Israelyan N, Margolis K G. Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders[J].Pharmacol Res, 2019, 140:115-120.
[24] Homberg J R, Kolk S M, Schubert D, et al. Editorial perspec‐tive of the research topic"Deciphering Serotonin's Role in Neu‐rodevelopment"[J]. Front Cell Neurosci, 2013, 7:212.
[25] Mulder E J, Anderson G M, Kema I P, et al. Platelet sero‐tonin levels in pervasive developmental disorders and mental retardation:diagnostic group differences, within-group distribu‐tion, and behavioral correlates[J]. J Am Acad Child Adolesc Psychiatry, 2004, 43(4):491-499.
[26] Finegold S M. Desulfovibrio species are potentially impor‐tant in regressive autism[J]. Med Hypotheses, 2011, 77(2):270-274.
[27] Reigstad C S, Salmonson C E, Rainey J F, et al. Gut mi‐crobes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells[J]. FASEB J, 2015, 29(4):1395-1403.
[28] Sj?gren K, Engdahl C, Henning P, et al. The gut microbiota regulates bone mass in mice[J]. J Bone Miner Res, 2012, 27:1357-1367.
[29]白志余,周东蕊,张仁敏,等.肠内代谢物腹腔注射对大鼠神经内分泌和行为学的影响[J].中国现代医学杂志, 2016, 26(19):17-22.
[30]李佳帅,唐强,朱路文,等.肠道菌群功能及其与运动的相关性研究进展[J].中国康复理论与实践, 2018, 24(12):1422-1424.
[31] Takeuchi O, Akira S. Pattern recognition receptors and in‐flammation[J]. Cell, 2010, 140(6):805-820.
[32] Lutgendorff F, Akkermans L M, S?derholm J D. The role of microbiota and probiotics in stress induced gastro-intestinal damage[J]. Curr Mol Med, 2008, 8(4):282-298.
[33] Keita A V, S?derholm J D. The intestinal barrier and its regu‐lation by neuroimmune factors[J]. Neurogastroenterol Motil,2010, 22(7):718-733.
[34] Karczewski J, Troost F J, Konings I, et al. Regulation of hu‐man epithelial tight junction proteins by Lactobacillus planta‐rum in vivo and protective effects on the epithelial barrier[J].Am J Physiol Gastrointest Liver Physiol, 2010, 298(6):G851-G859.
[35] Holmes A S, Blaxill M F, Haley B E. Reduced levels of mer‐cury in first baby haircuts of autistic children[J]. Int J Toxicol,2003, 22(4):277-285.
[36]陈保林,何慕兰,雷雨溪,等.脂多糖诱导孤独症样大鼠的肠道通透性及肠道黏膜免疫系统的变化[J].免疫学杂志, 2019,35(1):12-28.
[37] Ferquson B J, Marler S, Altstein L L, et al. Associations be‐tween cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder[J]. Brain Behav Im‐mun, 2016, 58:57-62.
[38]洪南,湛先保.肠道微生态系统与肠粘膜免疫关系研究进展[J].医学研究学院, 2014, 27(4):444-446.
[39] Gur T L, Bailey M T. Effects of stress on commensal mi‐crobes and immune system activity[J]. Adv Exp Med Biol,2016, 874:289-300.
[40]陆高,孙建华.CRH-NLRP6-微生物轴在肠易激综合征发病机制及其治疗中的作用[J].医学研究生学报, 2016, 29(1):92-96.
[41] Crumeyrolle-Arias M, Jaglin M, Bruneau A, et al. Absence of the gut microbiota enhances anxiety-like behavior and neuro‐endocrine response to acute stress in rats[J]. Psychoneuroendo‐crinology, 2014, 42:207-217.
[42] Rook G A, Lowry C A, Raison C L, et al. Lymphocytes in neuroprotection, cognition and emotion:is intolerance really the answer?[J]. Brain Behav Immun, 2011, 25(4):591-601.
[43] Ferguson B J, Marler S, Altstein L L, et al. Associations be‐tween cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder[J]. Brain Behav Im‐mun, 2016, 58:57-62.
[44]潘俊希,谢鹏.神经精神疾病微生物组研究现状和展望[J].生命科学, 2017, 29(7):669-681.