李晓燕;徐新杰;罗欣;尤欣;
LI Xiaoyan;XU Xinjie;LUO Xin;YOU Xin;Department of Rheumatology and Clinical Immunology,Chinese Academy of Medical Sciences & Peking Union Medical College;Medical Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College;

• 1:中国医学科学院北京协和医院风湿免疫科
• 2:中国医学科学院北京协和医院医学科学研究中心

摘要(Abstract)：

孤独症谱系障碍(autism spectrum disorder, ASD)是发病于儿童早期的神经发育障碍性疾病，目前尚无有效的治愈手段。其发病率近年来明显上升，给患者家庭和社会带来了沉重负担。ASD患者多存在胃肠道症状和肠道菌群失衡，研究发现ASD患者的胃肠道功能障碍与肠道菌群结构变化密切相关，且通过粪菌移植可显著改善ASD相关症状。本文通过总结粪菌移植治疗ASD的最新研究进展，以期为ASD的治疗提供新思路。
Autism spectrum disorder(ASD), a neurodevelopmental disorder during early childhood, currently has no effective treatment. The prevalence of ASD has been increasing, which brings a heavy burden to the family of the patients and the society. Children with ASD are accompanied by gastrointestinal symptoms and have an imbalance of intestinal microbiota. Fecal microbiota transplantation(FMT) can improve autism-related symptoms in children with ASD. This review aims to summarize the research progress of FMT for treating ASD to provide a novel strategy for this untreatable disease.

关键词(KeyWords)： 孤独症;粪菌移植;发育障碍;肠道菌群
autism;fecal microbiota transplantation;developmental disorders;intestinal flora

Abstract:

Keywords:

基金项目(Foundation): 中国医学科学院医学与健康科技创新工程(2017-I2M-3-017);中国医学科学院中央级公益性科研院所基本科研业务费专项资金(2019XK320030)~~

作者(Authors): 李晓燕;徐新杰;罗欣;尤欣;
LI Xiaoyan;XU Xinjie;LUO Xin;YOU Xin;Department of Rheumatology and Clinical Immunology,Chinese Academy of Medical Sciences & Peking Union Medical College;Medical Research Center,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College;

参考文献(References)：

• [1] American Psychiatric Association.Diagnostic and statistical manual of mental disorders:DSM- 5 [M].5th ed.Washington DC:American Psychiatric Association,2013:50- 59.
• [2] Maenner MJ,Shaw KA,Bakian AV,et al.Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years-Autism and Developmental Disabilities Monitoring Network,11 Sites,United States,2018[J].MMWR Surveill Summ,2021,70:336- 346.
• [3] Sun X,Allison C,Matthews FE,et al.Exploring the Underdiagnosis and Prevalence of Autism Spectrum Conditions in Beijing[J].Autism Res,2015,8:250- 260.
• [4] Roberts EM,English PB,Grether JK,et al.Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley[J].Environ Health Perspect,2007,115:1482- 1489.
• [5] Karimi P,Kamali E,Mousavi SM,et al.Environmental factors influencing the risk of autism[J].J Res Med Sci,2017,22:27.
• [6] Lord C,Elsabbagh M,Baird G,et al.Autism spectrum disorder[J].Lancet,2018,392:508- 520.
• [7] Lord C,Brugha TS,Charman T,et al.Autism spectrum disorder[J].Nat Rev Dis Primers,2020,6:5.
• [8] Yu Y,Zhang B,Ji P,et al.Changes to gut amino acid transporters and microbiome associated with increased E/I ratio in Chd8 mouse model of ASD-like behavior[J].Nat Commun,2022,13:1151.
• [9] Mannion A,Leader G.Gastrointestinal Symptoms in Autism Spectrum Disorder:A Literature Review[J].Rev J Autism Dev Disord,2013,1:11- 17.
• [10] Buie T,Campbell DB,Fuchs GJ,et al.Evaluation,diagnosis,and treatment of gastrointestinal disorders in individuals with ASDs:a consensus report[J].Pediatrics,2010,125:S1-S18.
• [11] Restrepo B,Angkustsiri K,Taylor SL,et al.Developmental-behavioral profiles in children with autism spectrum disorder and co-occurring gastrointestinal symptoms[J].Autism Res,2020,13:1778- 1789.
• [12] Srikantha P,Mohajeri MH.The Possible Role of the Microbiota-Gut-Brain-Axis in Autism Spectrum Disorder[J].Int J Mol Sci,2019,20:2115.
• [13] Stewart CJ,Ajami NJ,O'Brien JL,et al.Temporal development of the gut microbiome in early childhood from the TEDDY study[J].Nature,2018,562:583- 588.
• [14] Tamburini S,Shen N,Wu HC,et al.The microbiome in early life:implications for health outcomes[J].Nat Med,2016,22:713- 722.
• [15] Sharon G,Sampson TR,Geschwind DH,et al.The Central Nervous System and the Gut Microbiome[J].Cell,2016,167:915- 932.
• [16] Planer JD,Peng Y,Kau AL,et al.Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice[J].Nature,2016,534:263- 266.
• [17] Lou M,Cao A,Jin C,et al.Deviated and early unsustainable stunted development of gut microbiota in children with autism spectrum disorder[J].Gut,2022,71:1588- 1599.
• [18] Blanton LV,Charbonneau MR,Salih T,et al.Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children[J].Science,2016,351:10.1126/science.aad3311 aad3311.
• [19] Strati F,Cavalieri D,Albanese D,et al.New evidences on the altered gut microbiota in autism spectrum disorders[J].Microbiome,2017,5:24.
• [20] Dan Z,Mao X,Liu Q,et al.Altered gut microbial profile is associated with abnormal metabolism activity of Autism Spectrum Disorder[J].Gut Microbes,2020,11:1246- 1267.
• [21] Iglesias-Vázquez L,Van Ginkel Riba G,Arija V,et al.Composition of Gut Microbiota in Children with Autism Spectrum Disorder:A Systematic Review and Meta-Analysis[J].Nutrients,2020,12:792.
• [22] Kandeel WA,Meguid NA,Bj?rklund G,et al.Impact of Clostridium Bacteria in Children with Autism Spectrum Disorder and Their Anthropometric Measurements[J].J Mol Neurosci,2020,70:897- 907.
• [23] Wang L,Christophersen CT,Sorich MJ,et al.Increased abundance of Sutterella spp.and Ruminococcus torques in feces of children with autism spectrum disorder[J].Mol Autism,2013,4:42.
• [24] Liu S,Li E,Sun Z,et al.Altered gut microbiora and short chain fatty acids in Chinese children with autism spectrum disorder[J].Sci Rep,2019,9:287.
• [25] Hamer HM,Jonkers D,Venema K,et al.Review article:the role of butyrate on colonic function[J].Aliment Pharmacol Ther,2008,27:104- 119.
• [26] Tomova A,Husarova V,Lakatosova S,et al.Gastrointestinal microbiota in children with autism in Slovakia[J].Physiol Behav,2015,138:179- 187.
• [27] Adams JB,Johansen LJ,Powell LD,et al.Gastrointestinal flora and gastrointestinal status in children with autism--comparisons to typical children and correlation with autism severity[J].BMC Gastroenterol,2011,11:22.
• [28] Kang DW,Ilhan ZE,Isern NG,et al.Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders[J].Anaerobe,2018,49:121- 131.
• [29] Luna RA,Oezguen N,Balderas M,et al.Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder[J].Cell Mol Gastroenterol Hepatol,2017,3:218- 230.
• [30] Yap CX,Henders AK,Alvares GA,et al.Autism-related dietary preferences mediate autism-gut microbiome associations[J].Cell,2021,184:5916- 5931.
• [31] Akins RS,Angkustsiri K,Hansen RL.Complementary and alternative medicine in autism:an evidence-based approach to negotiating safe and efficacious interventions with families[J].Neurotherapeutics,2010,7:307- 319.
• [32] Anon.The brain-gut axis:a new frontier.Proceedings of an international symposium.Florence Italy,June 29-July 1,1981[J].Peptides,1981,2:1- 299.
• [33] Bove C,Travagli RA.Neurophysiology of the brain stem in Parkinson's disease[J].J Neurophysiol,2019,121:1856- 1864.
• [34] Cryan JF,O'Riordan KJ,Cowan CSM,et al.The Microbiota-Gut-Brain Axis[J].Physiol Rev,2019,99:1877- 2013.
• [35] Margolis KG,Cryan JF,Mayer EA.The Microbiota-Gut-Brain Axis:From Motility to Mood[J].Gastroenterology,2021,160:1486- 1501.
• [36] Cryan JF,Dinan TG.Mind-altering microorganisms:the impact of the gut microbiota on brain and behaviour[J].Nat Rev Neurosci,2012,13:701- 712.
• [37] Eiseman B,Silen W,Bascom GS,et al.Fecal enema as an adjunct in the treatment of pseudomembranous entero-colitis[J].Surgery,1958,44:854- 859.
• [38] Kelly CR,Fischer M,Allegretti JR,et al.ACG Clinical Guidelines:Prevention,Diagnosis,and Treatment of Clostridioides difficile Infections[J].Am J Gastroenterol,2021,116:1124- 1147.
• [39] Haifer C,Paramsothy S,Kaakoush NO,et al.Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS):a randomised,double-blind,placebo-controlled trial[J].Lancet Gastroenterol Hepatol,2022,7:141- 151.
• [40] Holvoet T,Joossens M,Vázquez-Castellanos JF,et al.Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating:Short-and Long-term Results From a Placebo-Controlled Randomized Trial[J].Gastroenterology,2021,160:145- 157.
• [41] Kim MS,Kim Y,Choi H,et al.Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model[J].Gut,2020,69:283- 294.
• [42] Hazan S.Rapid improvement in Alzheimer's disease symptoms following fecal microbiota transplantation:a case report[J].J Int Med Res,2020,48:300060520925930.
• [43] Xiao L,Yan J,Yang T,et al.Fecal Microbiome Transplantation from Children with Autism Spectrum Disorder Modulates Tryptophan and Serotonergic Synapse Metabolism and Induces Altered Behaviors in Germ-Free Mice[J].MSystems,2021,6:e01343- 20.
• [44] Sharon G,Cruz NJ,Kang DW,et al.Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice[J].Cell,2019,177:1600- 1618.
• [45] Goo N,Bae HJ,Park K,et al.The effect of fecal microbiota transplantation on autistic-like behaviors in Fmr1 KO mice[J].Life Sci,2020,262:118497.
• [46] Li Y,Luo ZY,Hu YY,et al.The gut microbiota regulates autism-like behavior by mediating vitamin B homeostasis in EphB6-deficient mice[J].Microbiome,2020,8:120.
• [47] Kang DW,Adams JB,Gregory AC,et al.Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms:an open-label study[J].Microbiome,2017,5:10.
• [48] Kang DW,Adams JB,Coleman DM,et al.Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota[J].Sci Rep,2019,9:5821.
• [49] Li N,Chen H,Cheng Y,et al.Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study[J].Front Cell Infect Microbiol,2021,11:759435.
• [50] Kang DW,Adams JB,Vargason T,et al.Distinct Fecal and Plasma Metabolites in Children with Autism Spectrum Disorders and Their Modulation after Microbiota Transfer Therapy[J].mSphere,2020,5:e00314- 20.
• [51] Qureshi F,Adams J,Hanagan K,et al.Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy[J].J Pers Med,2020,10:152.
• [52] Ye C,Zhang XY,Cui JQ,et al.FTACMT study protocol:a multicentre,double-blind,randomised,placebo-controlled trial of faecal microbiota transplantation for autism spectrum disorder[J].BMJ Open,2022,12:e051613.
• [53] Tariq R,Pardi DS,Bartlett MG,et al.Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection:A Systematic Review and Meta-analysis[J].Clin Infect Dis,2019,68:1351- 1358.
• [54] Fecal Microbiota Transplantation-standardization Study Group.Nanjing consensus on methodology of washed microbiota transplantation[J].Chin Med J,2020,133:2330- 2332.
• [55] Aggarwala V,Mogno I,Li Z,et al.Precise quantification of bacterial strains after fecal microbiota transplantation delineates long-term engraftment and explains outcomes[J].Nat Microbiol,2021,6:1309- 1318.
• [56] Haifer C,Saikal A,Paramsothy R,et al.Response to faecal microbiota transplantation in ulcerative colitis is not sustained long term following induction therapy[J].Gut,2021,70:2210- 2211.
• [57] DeFilipp Z,Bloom PP,Torres Soto M,et al.Drug-Resistant Bacteremia Transmitted by Fecal Microbiota Transplant[J].N Engl J Med,2019,381:2043- 2050.
• [58] Marcella C,Cui B,Kelly CR,et al.Systematic review:the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020[J].Aliment Pharmacol Ther,2021,53:33- 42.
• [59] Papanicolas LE,Gordon DL,Wesselingh SL,et al.Improv-ing Risk-Benefit in Faecal Transplantation through Microbiome Screening[J].Trends Microbiol,2020,28:331- 339.