Correlation of Gut Microbiome Between ASD Children and Mothers and Potential Biomarkers for Risk Assessment
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摘要
Variation of maternal gut microbiota may increase the risk of autism spectrum disorders(ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in mouse offspring, while it is unclear whether there is a correlation between gut microbiota of ASD children and their mothers. We examined the relationships between gut microbiome profiles of ASD children and those of their mothers, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. Gut microbiome was profiled and evaluated by 16S ribosomal RNA gene sequencing in stool samples of 59 mother–child pairs of ASD children and 30 matched mother–child pairs of healthy children. Significant differences were observed in the gut microbiome composition between ASD and healthy children in our Chinese cohort. Several unique bacterial biomarkers, such as Alcaligenaceae and Acinetobacter, were identified. Mothers of ASD children had more Proteobacteria, Alphaproteobacteria, Moraxellaceae, and Acinetobacter than mothers of healthy children. There was a clear correlation between gut microbiome profiles of children and their mothers; however, children with ASD still had unique bacterial biomarkers, such as Alcaligenaceae, Enterobacteriaceae, and Clostridium. Candidate biomarkers discovered in this study had remarkable discriminatory power. The identified patterns of mother–child gut microbiome profiles may be important for assessing risks during the early stage and planning of personalized treatment and prevention of ASD via microbiota modulation.
Variation of maternal gut microbiota may increase the risk of autism spectrum disorders(ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in mouse offspring, while it is unclear whether there is a correlation between gut microbiota of ASD children and their mothers. We examined the relationships between gut microbiome profiles of ASD children and those of their mothers, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. Gut microbiome was profiled and evaluated by 16S ribosomal RNA gene sequencing in stool samples of 59 mother–child pairs of ASD children and 30 matched mother–child pairs of healthy children. Significant differences were observed in the gut microbiome composition between ASD and healthy children in our Chinese cohort. Several unique bacterial biomarkers, such as Alcaligenaceae and Acinetobacter, were identified. Mothers of ASD children had more Proteobacteria, Alphaproteobacteria, Moraxellaceae, and Acinetobacter than mothers of healthy children. There was a clear correlation between gut microbiome profiles of children and their mothers; however, children with ASD still had unique bacterial biomarkers, such as Alcaligenaceae, Enterobacteriaceae, and Clostridium. Candidate biomarkers discovered in this study had remarkable discriminatory power. The identified patterns of mother–child gut microbiome profiles may be important for assessing risks during the early stage and planning of personalized treatment and prevention of ASD via microbiota modulation.
Variation of maternal gut microbiota may increase the risk of autism spectrum disorders(ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in mouse offspring, while it is unclear whether there is a correlation between gut microbiota of ASD children and their mothers. We examined the relationships between gut microbiome profiles of ASD children and those of their mothers, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. Gut microbiome was profiled and evaluated by 16S ribosomal RNA gene sequencing in stool samples of 59 mother–child pairs of ASD children and 30 matched mother–child pairs of healthy children. Significant differences were observed in the gut microbiome composition between ASD and healthy children in our Chinese cohort. Several unique bacterial biomarkers, such as Alcaligenaceae and Acinetobacter, were identified. Mothers of ASD children had more Proteobacteria, Alphaproteobacteria, Moraxellaceae, and Acinetobacter than mothers of healthy children. There was a clear correlation between gut microbiome profiles of children and their mothers; however, children with ASD still had unique bacterial biomarkers, such as Alcaligenaceae, Enterobacteriaceae, and Clostridium. Candidate biomarkers discovered in this study had remarkable discriminatory power. The identified patterns of mother–child gut microbiome profiles may be important for assessing risks during the early stage and planning of personalized treatment and prevention of ASD via microbiota modulation.
引文
[1]Jeste SS,Geschwind DH.Disentangling the heterogeneity of autism spectrum disorder through genetic findings.Nat Rev Neurol 2014;10:74-81.
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[36]Kesli R,Gokcen C,Bulug U,Terzi Y.Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children.J Immunoassay Immunochem2014;35:101-9.
[37]Finegold SM,Molitoris D,Song Y,Liu C,Vaisanen ML,Bolte E,et al.Gastrointestinal microflora studies in late-onset autism.Clin Infect Dis 2002;35:S6-16.
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[39]Ding HT,Taur Y,Walkup JT.Gut microbiota and autism:key concepts and findings.J Autism Dev Disord 2017;47:480-9.
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[41]Kang DW,Ilhan ZE,Isern NG,Hoyt DW,Howsmon DP,Shaffer M,et al.Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders.Anaerobe2018;49:121-31.
[42]Hung YM,Chang YT,Kao CH.Polymicrobial bacteremia involving comamonas testosteroni in a patient on dialysis with acute appendicitis.Ther Apher Dial 2017;21:637-8.
[43]Ba¨ckhed F,Roswall J,Peng Y,Feng Q,Jia H,Kovatchevadatchary P,et al.Dynamics and stabilization of the human gut microbiome during the first year of life.Cell Host Microbe2015;17:690.
[44]MacFabe DF,Cain DP,Rodriguez-Capote K,Franklin AE,Hoffman JE,Boon F,et al.Neurobiological effects of intraventricular propionic acid in rats:possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders.Behav Brain Res2007;176:149-69.
[45]Sandler RH,Finegold SM,Bolte ER,Buchanan CP,Maxwell AP,Vaisanen ML,et al.Short-term benefit from oral vancomycin treatment of regressive-onset autism.J Child Neurol2000;15:429-35.
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[47]Carvalho FA,Koren O,Goodrich JK,Johansson ME,Nalbantoglu I,Aitken JD,et al.Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice.Cell Host Microbe 2012;12:139-52.
[48]Velden LBJVD,Jong ASD,Jong HD,Gier RPED.Rentenaar RJ.First report of a Wautersiella falsenii isolated from the urine of an infant with pyelonephritis.Diagn Microbiol Infect Dis2012;74:404-5.
[49]Jr DW,Tillman J,Murray JC.Recovery of a strain of Agrobacterium radiobacter with a mucoid phenotype from an immunocompromised child with bacteremia.J Clin Microbiol1993;31:2541-3.
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[53]Ng PC,Herrington RA,Beane CA,Ghoneim AT,Dear PR.An outbreak of acinetobacter septicaemia in a neonatal intensive care unit.J Hosp Infect 1989;14:363-8.
[54]Kang DW,Jin GP,Ilhan ZE,Wallstrom G,Labaer J,Adams JB,et al.Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.PLoS One 2013;8:e68322.
[55]Dawson TM,Dawson VL,Snyder SH.A novel neuronal messenger molecule in brain:the free radical,nitric oxide.Ann Neurol 1992;32:297-311.
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[57]Gnanavel S,Robert RS.Diagnostic and statistical manual of mental disorders,fifth edition,and the impact of events scalerevised.Chest 2013;144:1974.
[58]Wong D,Cederbaum S,Crombez EA.Arginase deficiency.In:Adam MP,Ardinger HH,Pagon RA,et al.,editors.GeneReviews[Internet].Seattle(WA):University of Washington,Seattle;1993-2019,https://www.ncbi.nlm.nih.gov/books/NBK1159/.
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[2]Xu G,Strathearn L,Liu B,Bao W.Prevalence of autism spectrum disorder among US children and adolescents,2014-2016.JAMA2018;319:81-2.
[3]Wang F,Lu L,Wang SB,Zhang L,Ng CH,Ungvari GS,et al.The prevalence of autism spectrum disorders in China:a comprehensive meta-analysis.Int J Biol Sci 2018;14:717-25.
[4]Krishnan A,Zhang R,Yao V,Theesfeld CL,Wong AK,Tadych A,et al.Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder.Nat Neurosci2016;19:1454-62.
[5]D’Gama AM,Walsh CA.Somatic mosaicism and neurodevelopmental disease.Nat Neurosci 2018;21:1504-14.
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[7]Weiner DJ,Wigdor EM,Ripke S,Walters RK,Kosmicki JA,Grove J,et al.Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.Nat Genet 2017;49:978-85.
[8]Vorstman JAS,Parr JR,Moreno-De-Luca D,Anney RJL,Nurnberger Jr JI,Hallmayer JF.Autism genetics:opportunities and challenges for clinical translation.Nat Rev Genet2017;18:362-76.
[9]Hsiao EY,McBride SW,Hsien S,Sharon G,Hyde ER,McCue T,et al.Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.Cell2013;155:1451-63.
[10]Broek JA,Brombacher E,Stelzhammer V,Guest PC,Rahmoune H,Bahn S.The need for a comprehensive molecular characterization of autism spectrum disorders.Int J Neuropsychopharmacol2014;17:651-73.
[11]Yu L,Wu Y,Wu BL.Genetic architecture,epigenetic influence and environment exposure in the pathogenesis of Autism.Sci China Life Sci 2015;58:958-67.
[12]Quesnel-Vallieres M,Weatheritt RJ,Cordes SP,Blencowe BJ.Autism spectrum disorder:insights into convergent mechanisms from transcriptomics.Nat Rev Genet 2018;20:51-63.
[13]Patterson PH.Maternal infection and immune involvement in autism.Trends Mol Med 2011;17:389-94.
[14]Kim S,Kim H,Yim YS,Ha S,Atarashi K,Tan TG,et al.Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.Nature 2017;549:528-32.
[15]Shin Yim Y,Park A,Berrios J,Lafourcade M,Pascual LM,Soares N,et al.Reversing behavioural abnormalities in mice exposed to maternal inflammation.Nature 2017;549:482-7.
[16]Buffington SA,Di Prisco GV,Auchtung TA,Ajami NJ,Petrosino JF,Costa-Mattioli M.Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring.Cell2016;165:1762-75.
[17]Leckman JF.What are the transgenerational consequences of maternal childhood adversity and maternal stress during pregnancy?J Am Acad Child Adolesc Psychiatry 2017;56:914-5.
[18]Estes ML,McAllister AK.Maternal immune activation:implications for neuropsychiatric disorders.Science 2016;353:772-7.
[19]Osokine I,Erlebacher A.Inflammation and autism:from maternal gut to fetal brain.Trends Mol Med 2017;23:1070-1.
[20]Nardone S,Elliott E.The interaction between the immune system and epigenetics in the etiology of autism spectrum disorders.Front Neurosci 2016;10:329.
[21]Kang DW,Adams JB,Gregory AC,Borody T,Chittick L,Fasano A,et al.Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms:an openlabel study.Microbiome 2017;5:10.
[22]Mayer EA,Padua D,Tillisch K.Altered brain-gut axis in autism:comorbidity or causative mechanisms?BioEssays 2014;36:933-9.
[23]Strati F,Cavalieri D,Albanese D,De Felice C,Donati C,Hayek J,et al.New evidences on the altered gut microbiota in autism spectrum disorders.Microbiome 2017;5:24.
[24]Kushak RI,Winter HS,Buie TM,Cox SB,Phillips CD,Ward NL.Analysis of the duodenal microbiome in autistic individuals:association with carbohydrate digestion.J Pediatr Gastroenterol Nutr 2017;64:e110-6.
[25]Tomova A,Husarova V,Lakatosova S,Bakos J,Vlkova B,Babinska K,et al.Gastrointestinal microbiota in children with autism in Slovakia.Physiol Behav 2015;138:179-87.
[26]Wang L,Christophersen CT,Sorich MJ,Gerber JP,Angley MT,Conlon MA.Increased abundance of Sutterella spp.and Ruminococcus torques in feces of children with autism spectrum disorder.Mol Autism 2013;4:42.
[27]Kang DW,Park JG,Ilhan ZE,Wallstrom G,Labaer J,Adams JB,et al.Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.PLoS One 2013;8:e68322.
[28]De Angelis M,Piccolo M,Vannini L,Siragusa S,De Giacomo A,Serrazzanetti DI,et al.Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified.PLoS One 2013;8:e76993.
[29]Williams BL,Hornig M,Parekh T,Lipkin WI.Application of novel PCR-based methods for detection,quantitation,and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances.MBio 2012;3:e00261-e311.
[30]Williams BL,Hornig M,Buie T,Bauman ML,Cho Paik M,Wick I,et al.Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances.PLoS One 2011;6:e24585.
[31]Adams JB,Johansen LJ,Powell LD,Quig D,Rubin RA.Gastrointestinal flora and gastrointestinal status in children with autism-comparisons to typical children and correlation with autism severity.BMC Gastroenterol 2011;11:22.
[32]Finegold SM,Dowd SE,Gontcharova V,Liu C,Henley KE,Wolcott RD,et al.Pyrosequencing study of fecal microflora of autistic and control children.Anaerobe 2010;16:444-53.
[33]Parracho HM,Bingham MO,Gibson GR,McCartney AL.Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.J Med Microbiol2005;54:987-91.
[34]Bolte ER.Autism and Clostridium tetani.Med Hypotheses1998;51:133-44.
[35]Cui J,Cui H,Yang M,Du S,Li J,Li Y,et al.Tongue coating microbiome as a potential biomarker for gastritis including precancerous cascade.Protein Cell 2018.https://doi.org/10.1007/s13238-018-0596-6.
[36]Kesli R,Gokcen C,Bulug U,Terzi Y.Investigation of the relation between anaerobic bacteria genus clostridium and late-onset autism etiology in children.J Immunoassay Immunochem2014;35:101-9.
[37]Finegold SM,Molitoris D,Song Y,Liu C,Vaisanen ML,Bolte E,et al.Gastrointestinal microflora studies in late-onset autism.Clin Infect Dis 2002;35:S6-16.
[38]Allard MJ,Bergeron JD,Baharnoori M,Srivastava LK,Fortier LC,Poyart C,et al.A sexually dichotomous,autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation.Autism Res 2017;10:233-45.
[39]Ding HT,Taur Y,Walkup JT.Gut microbiota and autism:key concepts and findings.J Autism Dev Disord 2017;47:480-9.
[40]Bloch KC,Nadarajah R,Jacobs R.Chryseobacterium meningosepticum:an emerging pathogen among immunocompromised adults.Report of 6 cases and literature review.Medicine1997;76:30-41.
[41]Kang DW,Ilhan ZE,Isern NG,Hoyt DW,Howsmon DP,Shaffer M,et al.Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders.Anaerobe2018;49:121-31.
[42]Hung YM,Chang YT,Kao CH.Polymicrobial bacteremia involving comamonas testosteroni in a patient on dialysis with acute appendicitis.Ther Apher Dial 2017;21:637-8.
[43]Ba¨ckhed F,Roswall J,Peng Y,Feng Q,Jia H,Kovatchevadatchary P,et al.Dynamics and stabilization of the human gut microbiome during the first year of life.Cell Host Microbe2015;17:690.
[44]MacFabe DF,Cain DP,Rodriguez-Capote K,Franklin AE,Hoffman JE,Boon F,et al.Neurobiological effects of intraventricular propionic acid in rats:possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders.Behav Brain Res2007;176:149-69.
[45]Sandler RH,Finegold SM,Bolte ER,Buchanan CP,Maxwell AP,Vaisanen ML,et al.Short-term benefit from oral vancomycin treatment of regressive-onset autism.J Child Neurol2000;15:429-35.
[46]Madigan MT,Bender KS,Buckley DH,Sattley WM,Stahl DA.Brock biology of microorganisms.15th ed.New York:Pearson;2018.
[47]Carvalho FA,Koren O,Goodrich JK,Johansson ME,Nalbantoglu I,Aitken JD,et al.Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice.Cell Host Microbe 2012;12:139-52.
[48]Velden LBJVD,Jong ASD,Jong HD,Gier RPED.Rentenaar RJ.First report of a Wautersiella falsenii isolated from the urine of an infant with pyelonephritis.Diagn Microbiol Infect Dis2012;74:404-5.
[49]Jr DW,Tillman J,Murray JC.Recovery of a strain of Agrobacterium radiobacter with a mucoid phenotype from an immunocompromised child with bacteremia.J Clin Microbiol1993;31:2541-3.
[50]Bergogne-Be′re′zin E,Joly-Guillou ML,Vieu JF.Epidemiology of nosocomial infections due to Acinetobacter calcoaceticus.J Hosp Infect 1987;10:105-13.
[51]French GL,Casewell MW,Roncoroni AJ,Knight S,Phillips I.Ahospital outbreak of antibiotic-resistant Acinetobacter anitratus:epidemiology and control.J Hosp Infect 1980;1:125-31.
[52]Joly-Guillou ML,Bergogne-Be′re′zin E.In-vitro activity of sparfloxacin,pefloxacin,ciprofloxacin and temafloxacin against clinical isolates of Acinetobacter spp..J Antimicrob Chemother1992;29:466-8.
[53]Ng PC,Herrington RA,Beane CA,Ghoneim AT,Dear PR.An outbreak of acinetobacter septicaemia in a neonatal intensive care unit.J Hosp Infect 1989;14:363-8.
[54]Kang DW,Jin GP,Ilhan ZE,Wallstrom G,Labaer J,Adams JB,et al.Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.PLoS One 2013;8:e68322.
[55]Dawson TM,Dawson VL,Snyder SH.A novel neuronal messenger molecule in brain:the free radical,nitric oxide.Ann Neurol 1992;32:297-311.
[56]Peunova N,Enikolopov G.Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells.Nature1995;375:68-73.
[57]Gnanavel S,Robert RS.Diagnostic and statistical manual of mental disorders,fifth edition,and the impact of events scalerevised.Chest 2013;144:1974.
[58]Wong D,Cederbaum S,Crombez EA.Arginase deficiency.In:Adam MP,Ardinger HH,Pagon RA,et al.,editors.GeneReviews[Internet].Seattle(WA):University of Washington,Seattle;1993-2019,https://www.ncbi.nlm.nih.gov/books/NBK1159/.
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