Dysbiotic Gut Microbiota and Dysregulation of Cytokine Profile in Children and Teens With Autism Spectrum Disorder

Frontiers in Neuroscience - Tập 15
Xia Cao1, Kevin Liu2, Jun Liu2, Yen-Wenn Liu3, Xu Li1, Hua Wang4, Yunhui Zhu4, Pengfei Wang1, Zhiwei Li1, Jie Wen1, Chen‐Yang Shen1, Meng Li1, Zuqing Nie1, Xuejun Kong2,5
1Second Affiliated Hospital of Kunming Medical University, Kunming, China
2Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
3Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
4Hong-Ta District Maternal and Child Health Hospital, Yuxi, China
5Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, United States

Tóm tắt

Inflammation and the gut-brain axis have been implicated in the pathogenesis of autism spectrum disorders (ASDs). To further understand the relationship between aberrant immune responses and dysbiotic features of the gut microbiome in ASD, we enrolled 45 ASD individuals and 41 healthy control subjects with ages ranging from 2 to 19 years. We found that ASD group subjects have significantly higher plasma levels of IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, TNF-β, and IFN-γ when compared to healthy controls (FDR-adjusted p < 0.05). The plasma levels of pro-inflammatory cytokines IFN-γ and IL-6 are found to be further associated with several largely pathogenic gut microbiota uniquely detected in subjects with ASD. Furthermore, the ASD gut microbiome is characterized by reduced levels of several beneficial microbiota, including Bacteroides (FDR-adjusted p < 0.01) and Lachnospiraceae (FDR-adjusted p < 0.001). Analysis of Lachnospiraceae family and genus level taxa suggested that relative abundances of such taxa are negatively correlated with pro-inflammatory signaling cytokines IFN-γ and IL-6, particularly in subjects with severe ASD as defined by CARS (p < 0.05). Several largely pathogenic genera are determined to be associated with the pro-inflammatory cytokines IFN-γ and IL-6 (FDR-adjusted p < 0.1). Additionally, IL-4 is significantly negatively correlated with CARS total score (p < 0.05). Based on such results, we propose that the association between the disturbances of specific cytokines and alterations in gut microbiota abundance observed in children and adolescents with ASD provides additional evidence on the induction of aberrant pro-inflammatory mechanisms in ASD and its early diagnosis.

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Tài liệu tham khảo

Ahmad, 2020, Involvement of Cd45 cells in the development of autism spectrum disorder through dysregulation of granulocyte-macrophage colony-stimulating factor, key inflammatory cytokines, and transcription factors, Int. Immunopharmacol., 83, 10.1016/j.intimp.2020.106466

Ahmad, 2018, Dysregulation of the expression of HLA-DR, costimulatory molecule, and chemokine receptors on immune cells in children with autism, Int. Immunopharmacol., 65, 360, 10.1016/j.intimp.2018.10.027

Ahmad, , Dysregulation of T cell immunoglobulin and mucin domain 3 (TIM-3) signaling in peripheral immune cells is associated with immune dysfunction in autistic children, Mol. Immunol., 106, 77, 10.1016/j.molimm.2018.12.020

Ahmad, , Elevated IL-16 expression is associated with development of immune dysfunction in children with autism, Psychopharmacology, 236, 831, 10.1007/s00213-018-5120-4

Ansari, 2020, C-C motif chemokine receptor 6-mediated pro-inflammatory mediator expression is associated with immune dysfunction in children with autism, Res. Autism. Spect. Dis., 71, 10.1016/j.rasd.2019.101500

Argou-Cardozo, 2018, Clostridium bacteria and autism spectrum conditions: a systematic review and hypothetical contribution of environmental glyphosate levels, Med. Sci., 6, 10.3390/medsci6020029

Baio, 2018, Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 Sites, United States, 2014, Mmwr. Surveillance Summ., 67, 1, 10.15585/mmwr.ss6706a1

Ballak, 2015, IL-1 family members in the pathogenesis and treatment of metabolic disease: focus on adipose tissue inflammation and insulin resistance, Cytokine, 75, 280, 10.1016/j.cyto.2015.05.005

Canani, 2011, Potential beneficial effects of butyrate in intestinal and extraintestinal diseases, World J. Gastroentero., 17, 1519, 10.3748/wjg.v17.i12.1519

Carding, 2015, Dysbiosis of the gut microbiota in disease, Microb. Ecol. Health D, 26, 10.3402/mehd.v26.26191

Chen, 2013, Comorbidity of allergic and autoimmune diseases in patients with autism spectrum disorder: a nationwide population-based study, Res. Autism Spect. Dis., 7, 205, 10.1016/j.rasd.2012.08.008

Corrêa-Oliveira, 2016, Regulation of immune cell function by short-chain fatty acids, Clin. Transl. Immunol., 5, 10.1038/cti.2016.17

Dantzer, 2001, Cytokine-induced sickness behavior: where do we stand?, Brain Behav. Immun., 15, 7, 10.1006/brbi.2000.0613

Dantzer, 2009, Cytokine, sickness behavior, and depression, Immunol. Allergy Clin., 29, 247, 10.1016/j.iac.2009.02.002

Dantzer, 2008, From inflammation to sickness and depression: when the immune system subjugates the brain, Nat. Rev. Neurosci., 9, 46, 10.1038/nrn2297

Delgado-Aros, 2005, Visceral Hypersensitivity, J. Clin. Gastroenterol., 39, S194, 10.1097/01.mcg.0000156114.22598.1b

Emerson, 2017, Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age, Sci. Transl. Med., 9, 10.1126/scitranslmed.aag2882

Fattorusso, 2019, Autism spectrum disorders and the gut microbiota, Nutrients, 11, 10.3390/nu11030521

Finegold, 2010, Pyrosequencing study of fecal microflora of autistic and control children, Anaerobe, 16, 444, 10.1016/j.anaerobe.2010.06.008

Goines, 2010, The immune system’s role in the biology of autism, Curr. Opin. Neurol., 23, 111, 10.1097/wco.0b013e3283373514

Goines, 2013, Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment, Neurotoxicol. Teratol., 36, 67, 10.1016/j.ntt.2012.07.006

Grimaldi, 2016, In vitro fermentation of B-GOS: impact on faecal bacterial populations and metabolic activity in autistic and non-autistic children, Fems. Microbiol. Ecol., 93, 10.1093/femsec/fiw233

Herbrík, 2020, A human lung-associated streptomyces sp. TR1341 produces various secondary metabolites responsible for virulence, cytotoxicity and modulation of immune response, Front. Microbiol., 10, 10.3389/fmicb.2019.03028

Hsiao, 2013, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell, 155, 1451, 10.1016/j.cell.2013.11.024

Immerseel, 2010, Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease, J. Med. Microbiol., 59, 141, 10.1099/jmm.0.017541-0

Jones, 2017, Parent−delivered early intervention in infants at risk for ASD: effects on electrophysiological and habituation measures of social attention, Autism Res., 10, 961, 10.1002/aur.1754

Jussila, 2003, Systemic immunoresponses in mice after repeated exposure of lungs to spores of streptomyces californicus, Clin. Diagnostic. Laboratory Immunol., 10, 30, 10.1128/cdli.10.1.30-37.2003

Klampfer, 2003, Inhibition of interferon gamma signaling by the short chain fatty acid butyrate, Mol. Cancer Res. Mcr., 1, 855

Kong, 2019, New and preliminary evidence on altered oral and gut microbiota in individuals with autism spectrum disorder (ASD): implications for ASD diagnosis and subtyping based on microbial biomarkers, Nutrients, 11, 10.3390/nu11092128

Langille, 2013, Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences, Nat. Biotechnol., 31, 814, 10.1038/nbt.2676

Li, 2017, The gut microbiota and autism spectrum disorders, Front. Cell Neurosci., 11, 10.3389/fncel.2017.00120

Liu, 2018, Butyrate: a double-edged sword for health?, Adv. Nutr., 9, 21, 10.1093/advances/nmx009

Liu, 2019, Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder, Sci. Rep-uk, 9, 10.1038/s41598-018-36430-z

Ma, 2019, Altered gut microbiota in chinese children with autism spectrum disorders, Front. Cell Infect. Mi., 9, 10.3389/fcimb.2019.00040

Mallick, 2020, Multivariable association in population-scale meta-omics studies, bioRxiv, 10.1101/2021.01.20.427420

Mandell, 2005, Factors associated with age of diagnosis among children with autism spectrum disorders, Pediatrics, 116, 1480, 10.1542/peds.2005-0185

Masi, 2017, The immune system, cytokines, and biomarkers in autism spectrum disorder, Neurosci. Bull., 33, 194, 10.1007/s12264-017-0103-8

Masi, 2015, Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis, Mol. Psychiatr., 20, 440, 10.1038/mp.2014.59

McIver, 2017, bioBakery: a meta’omic analysis environment, Bioinform. Oxf. Engl., 34, 1235, 10.1093/bioinformatics/btx754

Mortensen, 1996, Short-Chain fatty acids in the human colon: relation to gastrointestinal health and disease, Scand. J. Gastroentero., 31, 132, 10.3109/00365529609094568

Nadeem, , Differential regulation of Nrf2 is linked to elevated inflammation and nitrative stress in monocytes of children with autism, Psychoneuroendocrino, 113, 10.1016/j.psyneuen.2019.104554

Nadeem, , Dysregulation in IL-6 receptors is associated with upregulated IL-17A related signaling in CD4+ T cells of children with autism, Prog Neuro Psychopharmacol. Biol. Psychiatr., 97, 10.1016/j.pnpbp.2019.109783

Nagpal, 2020, MetagenoNets: comprehensive inference and meta-insights for microbial correlation networks, Nucleic Acids Res., 48, W572, 10.1093/nar/gkaa254

Niu, 2019, Characterization of intestinal microbiota and probiotics treatment in children with autism spectrum disorders in China, Front. Neurol., 10, 10.3389/fneur.2019.01084

Oliphant, 2011, Insights into the initiation of type 2 immune responses, Immunology, 134, 378, 10.1111/j.1365-2567.2011.03499.x

Parracho, 2005, Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children, J. Med. Microbiol., 54, 987, 10.1099/jmm.0.46101-0

Pierce, 2009, The power and promise of identifying autism early: insights from the search for clinical and biological markers, Ann. Clin. Psychiatry Official J. Am. Acad. Clin. Psychiatrists, 21, 132

Rodriguez, 2011, Evidence of microglial activation in autism and its possible role in brain underconnectivity, Neuron. Glia. Biol., 7, 205, 10.1017/s1740925x12000142

Rosenfeld, 2015, Microbiome disturbances and autism spectrum disorders, Drug Metabolism Dispos. Biol. Fate Chem., 43, 1557, 10.1124/dmd.115.063826

Sanctuary, 2019, Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms, PLoS One, 14, 10.1371/journal.pone.0210064

Sgritta, 2018, Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder, Neuron, 101, 246, 10.1016/j.neuron.2018.11.018

Silva, 2020, The role of short-chain fatty acids from gut microbiota in gut-brain communication, Front. Endocrinol., 11, 10.3389/fendo.2020.00025

Sochocka, 2017, Inflammatory response in the CNS: friend or foe?, Mol. Neurobiol., 54, 8071, 10.1007/s12035-016-0297-1

Topping, 2001, Short-Chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides, Physiol. Rev., 81, 1031, 10.1152/physrev.2001.81.3.1031

Treuren, 2017, Microbial contribution to the human metabolome: implications for health and disease, Annu. Rev. Pathol. Mech. Dis., 15, 345, 10.1146/annurev-pathol-020117-043559

Turner, , Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease, Biochim. Biophys. Acta Mol. Cell Res., 1843, 2563, 10.1016/j.bbamcr.2014.05.014

Turner, , Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease, Biochim. Biophys. Acta Mol. Cell Res., 1843, 2563, 10.1016/j.bbamcr.2014.05.014

Vacca, 2020, The controversial role of human gut lachnospiraceae, Microorg, 8, 10.3390/microorganisms8040573

Val-Laillet, 2018, Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs, Faseb J. Official Publ. Fed. Am. Soc. Exp. Biol., 32, 2160, 10.1096/fj.201700547rr

Wang, 2013, Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease, J. Clin. Microbiol., 52, 398, 10.1128/jcm.01500-13

Wasilewska, 2015, Gastrointestinal symptoms and autism spectrum disorder: links and risks – a possible new overlap syndrome, Pediatric Heal. Med. Ther., 6, 153, 10.2147/phmt.s85717

Zhang, 2019, Beneficial effect of butyrate−producing Lachnospiraceae on stress−induced visceral hypersensitivity in rats, J. Gastroen. Hepatol., 34, 1368, 10.1111/jgh.14536

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Frontiers in Neuroscience

Tập 15

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