Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms

Brain, Behavior, and Immunity

Volumn 70, Issue , 2018, Pages 354-368

  Rose, Destanie R ^a   Yang, Houa ^a   Serena, Gloria ^b,c   Sturgeon, Craig ^b,c   Ma, Bing ^c   Careaga, Milo ^a   Hughes, Heather K ^a   Angkustsiri, Kathy ^a   Rose, Melissa ^a   Hertz Picciotto, Irva ^a   Van de Water, Judy ^a   Hansen, Robin L ^a   Ravel, Jacques ^c   Fasano, Alessio ^b   Ashwood, Paul ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

ASD; Autism; Cytokines; Gastrointestinal; Immune; Microbiota; Mucosal Immunity; Zonulin

Indexed keywords

CYTOKINE; INTERLEUKIN 15; INTERLEUKIN 17; INTERLEUKIN 5; TOLL LIKE RECEPTOR 4; TRANSFORMING GROWTH FACTOR BETA1;

ARTICLE; AUTISM; CELL ISOLATION; CELL STIMULATION; CHILD; CHILD DEVELOPMENT; COMORBIDITY; CONTROLLED STUDY; CYTOKINE PRODUCTION; DEFECATION HABIT; FECES ANALYSIS; FEMALE; GASTROINTESTINAL SYMPTOM; GENE FUNCTION; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNOPATHOLOGY; INTESTINE MUCOSA PERMEABILITY; MAJOR CLINICAL STUDY; MALE; METAGENOME; MICROFLORA; MOLECULAR BIOLOGY; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRESCHOOL CHILD; PRIORITY JOURNAL; REGULATORY MECHANISM; SCHOOL CHILD; SPECIES COMPOSITION; GASTROINTESTINAL DISEASE; IMMUNOLOGY; INTESTINE FLORA; METABOLISM; MICROBIOLOGY; MONOCYTE; MONONUCLEAR CELL; PHYSIOLOGY;

AUTISM SPECTRUM DISORDER; CHILD; CHILD DEVELOPMENT; CHILD, PRESCHOOL; COMORBIDITY; CYTOKINES; FEMALE; GASTROINTESTINAL DISEASES; GASTROINTESTINAL MICROBIOME; HUMANS; LEUKOCYTES, MONONUCLEAR; MALE; MICROBIOTA; MONOCYTES;

EID: 85044507674     PISSN: 08891591     EISSN: 10902139     Source Type: Journal    
DOI: 10.1016/j.bbi.2018.03.025     Document Type: Article

References (129)

1. Abrahams, B.S., Geschwind, D.H., Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9:5 (2008), 341–355.
2. Ahmad, S.F., Zoheir, K.M., Ansari, M.A., Nadeem, A., Bakheet, S.A., Al-Ayadhi, L.Y., Alzahrani, M.Z., Al-Shabanah, O.A., Al-Harbi, M.M., Attia, S.M., Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. Mol. Neurobiol., 2016.
3. Ander, B.P., Barger, N., Stamova, B., Sharp, F.R., Schumann, C.M., Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders. Mol. Autism, 6, 2015, 37.
4. Arumugam, M., Raes, J., Pelletier, E., Le Paslier, D., Yamada, T., Mende, D.R., Fernandes, G.R., Tap, J., Bruls, T., Batto, J.-M., Bertalan, M., Borruel, N., Casellas, F., Fernandez, L., Gautier, L., Hansen, T., Hattori, M., Hayashi, T., Kleerebezem, M., Kurokawa, K., Leclerc, M., Levenez, F., Manichanh, C., Nielsen, H.B., Nielsen, T., Pons, N., Poulain, J., Qin, J., Sicheritz-Ponten, T., Tims, S., Torrents, D., Ugarte, E., Zoetendal, E.G., Wang, J., Guarner, F., Pedersen, O., de Vos, W.M., Brunak, S., Dore, J., Weissenbach, J., Ehrlich, S.D., Bork, P., Enterotypes of the human gut microbiome. Nature 473:7346 (2011), 174–180.
5. Ashwood, P., Anthony, A., Pellicer, A.A., Torrente, F., Walker-Smith, J.A., Wakefield, A.J., Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J. Clin. Immunol. 23:6 (2003), 504–517.
6. Ashwood, P., Anthony, A., Torrente, F., Wakefield, A.J., Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J. Clin. Immunol. 24:6 (2004), 664–673.
7. Ashwood, P., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R.L., Croen, L.A., Ozonoff, S., Pessah, I.N., Van de Water, J., Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J. Neuroimmunol. 204:1–2 (2008), 149–153.
8. Asperger, H., Psychopathology of children with coeliac disease. Ann. Paediatr. 197 (1961), 346–351.
9. Ballard, J., Crane, D.R., Harper, J.M., Fawcett, D., Sandberg, J., Mental health service utilization in autism spectrum disorders. Res. Autism Spectrum Disorders 23 (2016), 84–93.
10. Bauman, M.L., Medical comorbidities in autism: challenges to diagnosis and treatment. Neurotherapeutics 7:3 (2010), 320–327.
11. Blum, S., Milman, U., Shapira, C., Levy, A.P., Pharmacogenomic application of the haptoglobin genotype in the prevention of diabetic cardiovascular disease. Pharmacogenomics 9:8 (2008), 989–991.
12. Buie, T., Campbell, D.B., Fuchs, G.J. 3rd, Furuta, G.T., Levy, J., Vandewater, J., Whitaker, A.H., Atkins, D., Bauman, M.L., Beaudet, A.L., Carr, E.G., Gershon, M.D., Hyman, S.L., Jirapinyo, P., Jyonouchi, H., Kooros, K., Kushak, R., Levitt, P., Levy, S.E., Lewis, J.D., Murray, K.F., Natowicz, M.R., Sabra, A., Wershil, B.K., Weston, S.C., Zeltzer, L., Winter, H., Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125:Suppl 1 (2010), S1–18.
13. Bushara, K.O., Neurologic presentation of celiac disease. Gastroenterology 128:4 Suppl 1 (2005), S92–97.
14. Caporaso, J.G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F.D., Costello, E.K., Fierer, N., Pena, A.G., Goodrich, J.K., Gordon, J.I., Huttley, G.A., Kelley, S.T., Knights, D., Koenig, J.E., Ley, R.E., Lozupone, C.A., McDonald, D., Muegge, B.D., Pirrung, M., Reeder, J., Sevinsky, J.R., Turnbaugh, P.J., Walters, W.A., Widmann, J., Yatsunenko, T., Zaneveld, J., Knight, R., QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7:5 (2010), 335–336.
15. Chaidez, V., Hansen, R.L., Hertz-Picciotto, I., Gastrointestinal problems in children with autism, developmental delays or typical development. J. Autism Dev. Disord. 44:5 (2014), 1117–1127.
16. Choi, G.B., Yim, Y.S., Wong, H., Kim, S., Kim, H., Kim, S.V., Hoeffer, C.A., Littman, D.R., Huh, J.R., The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 2016.
17. Cohen, A., On the graphical display of the significant components in a two-way contingency table. Commun. Stat. — Theory Methods A9 (1980), 1025–1041.
18. Coombes, J.L., Powrie, F., Dendritic cells in intestinal immune regulation. Nat. Rev. Immunol. 8:6 (2008), 435–446.
19. Coury, D.L., Ashwood, P., Fasano, A., Fuchs, G., Geraghty, M., Kaul, A., Mawe, G., Patterson, P., Jones, N.E., Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130:Suppl 2 (2012), S160–168.
20. D'Eufemia, P., Celli, M., Finocchiaro, R., Pacifico, L., Viozzi, L., Zaccagnini, M., Cardi, E., Giardini, O., Abnormal intestinal permeability in children with autism. Acta Paediatr. 85:9 (1996), 1076–1079.
21. de Magistris, L., Familiari, V., Pascotto, A., Sapone, A., Frolli, A., Iardino, P., Carteni, M., De Rosa, M., Francavilla, R., Riegler, G., Militerni, R., Bravaccio, C., Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J. Pediatr. Gastroenterol. Nutr. 51:4 (2010), 418–424.
22. Delanghe, J.R., Langlois, M.R., Boelaert, J.R., Van Acker, J., Van Wanzeele, F., van der Groen, G., Hemmer, R., Verhofstede, C., De Buyzere, M., De Bacquer, D., Arendt, V., Plum, J., Haptoglobin polymorphism, iron metabolism and mortality in HIV infection. AIDS 12:9 (1998), 1027–1032.
23. den Besten, G., van Eunen, K., Groen, A.K., Venema, K., Reijngoud, D.J., Bakker, B.M., The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54:9 (2013), 2325–2340.
24. DePaolo, R.W., Abadie, V., Tang, F., Fehlner-Peach, H., Hall, J.A., Wang, W., Marietta, E.V., Kasarda, D.D., Waldmann, T.A., Murray, J.A., Semrad, C., Kupfer, S.S., Belkaid, Y., Guandalini, S., Jabri, B., Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:7337 (2011), 220–224.
25. Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T.G., Cryan, J.F., Microbiota is essential for social development in the mouse. Mol. Psychiatry 19:2 (2014), 146–148.
26. Eckmann, L., Karin, M., NOD2 and Crohn's disease: loss or gain of function?. Immunity 22:6 (2005), 661–667.
27. Edgar, R.C., Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26:19 (2010), 2460–2461.
28. Edgar, R.C., Haas, B.J., Clemente, J.C., Quince, C., Knight, R., UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27:16 (2011), 2194–2200.
29. Elinav, E., Strowig, T., Kau, Andrew L., Henao-Mejia, J., Thaiss, Christoph A., Booth, Carmen J., Peaper, David R., Bertin, J., Eisenbarth, Stephanie C., Gordon, Jeffrey I., Flavell, Richard A., NLRP6 Inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:5 (2011), 745–757.
30. Emanuele, E., Orsi, P., Boso, M., Broglia, D., Brondino, N., Barale, F., di Nemi, S.U., Politi, P., Low-grade endotoxemia in patients with severe autism. Neurosci. Lett. 471:3 (2010), 162–165.
31. Enstrom, A.M., Onore, C.E., Van de Water, J.A., Ashwood, P., Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav. Immun. 24:1 (2010), 64–71.
32. Fadrosh, D., Ma, B., Gajer, P., Sengamalay, N., Ott, S., Brotman, R.M., Ravel, J., under review. An Improved Dual-Indexing Approach for Multiplexed 16S rRNA Gene Sequencing on the Illumina MiSeq Platform.
33. Fadrosh, D.W., Ma, B., Gajer, P., Sengamalay, N., Ott, S., Brotman, R.M., Ravel, J., An improved dual-indexing approach for multiplexed 16S rRNA gene sequencing on the Illumina MiSeq platform. Microbiome, 2(1), 2014, 6.
34. Fasano, A., Catassi, C., Coeliac disease in children. Best Pract. Res. Clin. Gastroenterol. 19:3 (2005), 467–478.
35. Finegold, S.M., Dowd, S.E., Gontcharova, V., Liu, C., Henley, K.E., Wolcott, R.D., Youn, E., Summanen, P.H., Granpeesheh, D., Dixon, D., Liu, M., Molitoris, D.R., Green, J.A. 3rd, Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe 16:4 (2010), 444–453.
36. Finegold, S.M., Molitoris, D., Song, Y., Liu, C., Vaisanen, M.L., Bolte, E., McTeague, M., Sandler, R., Wexler, H., Marlowe, E.M., Collins, M.D., Lawson, P.A., Summanen, P., Baysallar, M., Tomzynski, T.J., Read, E., Johnson, E., Rolfe, R., Nasir, P., Shah, H., Haake, D.A., Manning, P., Kaul, A., Gastrointestinal microflora studies in late-onset autism. Clin. Infect. Dis. 35:Suppl 1 (2002), S6–S16.
37. Friendly, M., Graphical methods for categorical data. SAS User Group Int. Conf. Proc. 17 (1992), 190–200.
38. Frye, R.E., Melnyk, S., MacFabe, D.F., Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl. Psychiatry, 3(1), 2013, e220.
39. Frye, R.E., Nankova, B., Bhattacharyya, S., Rose, S., Bennuri, S.C., MacFabe, D.F., Modulation of immunological pathways in autistic and neurotypical lymphoblastoid cell lines by the enteric microbiome metabolite propionic acid. Front. Immunol., 8(1670), 2017.
40. Frye, R.E., Rose, S., Chacko, J., Wynne, R., Bennuri, S.C., Slattery, J.C., Tippett, M., Delhey, L., Melnyk, S., Kahler, S.G., MacFabe, D.F., Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Transl. Psychiatry, 6(10), 2016, e927.
41. Frye, R.E., Rose, S., Slattery, J., MacFabe, D.F., Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome. Microb. Ecol. Health Dis., 26, 2015, 27458.
42. Furlano, R.I., Anthony, A., Day, R., Brown, A., McGarvey, L., Thomson, M.A., Davies, S.E., Berelowitz, M., Forbes, A., Wakefield, A.J., Walker-Smith, J.A., Murch, S.H., Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J. Pediatr. 138:3 (2001), 366–372.
43. Genuis, S.J., Bouchard, T.P., Celiac disease presenting as autism. J. Child Neurol. 25:1 (2010), 114–119.
44. Geschwind, D.H., Autism: many genes, common pathways?. Cell 135:3 (2008), 391–395.
45. Gillberg, C., Billstedt, E., Autism and Asperger syndrome: coexistence with other clinical disorders. Acta Psychiatr. Scand. 102:5 (2000), 321–330.
46. Goehler, L.E., Gaykema, R.P., Hansen, M.K., Anderson, K., Maier, S.F., Watkins, L.R., Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci. 85:1–3 (2000), 49–59.
47. Hadjivassiliou, M., Grunewald, R.A., Davies-Jones, G.A., Gluten sensitivity as a neurological illness. J. Neurol. Neurosurg. Psychiatry 72:5 (2002), 560–563.
48. Hale-Donze, H., Wahl, S.M., Jackson, R.J., McGhee, J.R., Measurement of TGF-β in Biological Fluids. Current Protocols in Immunology. 2001, John Wiley & Sons, Inc.
49. Hallert, C., Derefeldt, T., Psychic Disturbances in Adult Coeliac Disease. Scand. J. Gastroenterol. 17:1 (1982), 17–19.
50. Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., Miller, J., Fedele, A., Collins, J., Smith, K., Lotspeich, L., Croen, L.A., Ozonoff, S., Lajonchere, C., Grether, J.K., Risch, N., Genetic heritability and shared environmental factors among twin pairs with autism. Arch. Gen. Psychiatry 68:11 (2011), 1095–1102.
51. Harriman, G.R., Kunimoto, D.Y., Elliott, J.F., Paetkau, V., Strober, W., The role of IL-5 in IgA B cell differentiation. J. Immunol. 140:9 (1988), 3033–3039.
52. Harrison, O.J., Powrie, F.M., Regulatory T cells and immune tolerance in the intestine. Cold Spring Harb. Perspect. Biol., 5(7), 2013.
53. Hertz-Picciotto, I., Croen, L.A., Hansen, R., Jones, C.R., van de Water, J., Pessah, I.N., The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ. Health Perspect. 114:7 (2006), 1119–1125.
54. Hirata, I., Mohri, I., Kato-Nishimura, K., Tachibana, M., Kuwada, A., Kagitani-Shimono, K., Ohno, Y., Ozono, K., Taniike, M., Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder. Res. Dev. Disabil. 49–50 (2016), 86–99.
55. Hooper, L.V., Littman, D.R., Macpherson, A.J., Interactions between the microbiota and the immune system. Science 336:6086 (2012), 1268–1273.
56. Horvath, K., Perman, J.A., Autism and gastrointestinal symptoms. Curr. Gastroenterol. Rep. 4:3 (2002), 251–258.
57. Huang, F., Long, Z., Chen, Z., Li, J., Hu, Z., Qiu, R., Zhuang, W., Tang, B., Xia, K., Jiang, H., Investigation of gene regulatory networks associated with autism spectrum disorder based on MiRNA expression in China. PLoS One, 10(6), 2015, e0129052.
58. Huppler, A.R., Conti, H.R., Hernandez-Santos, N., Darville, T., Biswas, P.S., Gaffen, S.L., Role of neutrophils in IL-17-dependent immunity to mucosal candidiasis. J. Immunol. 192:4 (2014), 1745–1752.
59. Iwakura, Y., Ishigame, H., The IL-23/IL-17 axis in inflammation. J. Clin. Invest. 116:5 (2006), 1218–1222.
60. Jiang, W., Wang, X., Zeng, B., Liu, L., Tardivel, A., Wei, H., Han, J., MacDonald, H.R., Tschopp, J., Tian, Z., Zhou, R., Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med. 210:11 (2013), 2465–2476.
61. Jyonouchi, H., Geng, L., Davidow, A.L., Cytokine profiles by peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?. J. Neuroinflammation, 11, 2014, 187.
62. Jyonouchi, H., Geng, L., Streck, D.L., Toruner, G.A., Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes. J. Neuroimmunol. 238:1–2 (2011), 73–80.
63. Jyonouchi, H., Sun, S., Itokazu, N., Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology 46:2 (2002), 76–84.
64. Jyonouchi, H., Sun, S., Le, H., Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J. Neuroimmunol. 120:1–2 (2001), 170–179.
65. Kang, D.W., Park, J.G., Ilhan, Z.E., Wallstrom, G., Labaer, J., Adams, J.B., Krajmalnik-Brown, R., Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One, 8(7), 2013, e68322.
66. Kanner, L., Autistic disturbances of affective contact. Nerv. Child, 2, 1943, 33.
67. Kasvosve, I., Gomo, Z.A., Mvundura, E., Moyo, V.M., Saungweme, T., Khumalo, H., Gordeuk, V.R., Boelaert, J.R., Delanghe, J.R., De Bacquer, D., Gangaidzo, I.T., Haptoglobin polymorphism and mortality in patients with tuberculosis. Int. J. Tuberc. Lung Dis. 4:8 (2000), 771–775.
68. Komatsu, N., Mariotti-Ferrandiz, M.E., Wang, Y., Malissen, B., Waldmann, H., Hori, S., Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. USA 106:6 (2009), 1903–1908.
69. Korn, T., Bettelli, E., Oukka, M., Kuchroo, V.K., IL-17 and Th17 Cells. Annu. Rev. Immunol. 27 (2009), 485–517.
70. Krieglstein, K., Zheng, F., Unsicker, K., Alzheimer, C., More than being protective: functional roles for TGF-β/activin signaling pathways at central synapses. Trends Neurosci. 34:8 (2011), 421–429.
71. Lahdenpera, A.I., Holtta, V., Ruohtula, T., Salo, H.M., Orivuori, L., Westerholm-Ormio, M., Savilahti, E., Falth-Magnusson, K., Hogberg, L., Ludvigsson, J., Vaarala, O., Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes. Clin. Exp. Immunol. 167:2 (2012), 226–234.
72. Landrigan, P.J., What causes autism? Exploring the environmental contribution. Curr. Opin. Pediatr. 22:2 (2010), 219–225.
73. Langille, M.G., Zaneveld, J., Caporaso, J.G., McDonald, D., Knights, D., Reyes, J.A., Clemente, J.C., Burkepile, D.E., Vega Thurber, R.L., Knight, R., Beiko, R.G., Huttenhower, C., Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat. Biotechnol. 31:9 (2013), 814–821.
74. Lee, Y.K., Mazmanian, S.K., Has the microbiota played a critical role in the evolution of the adaptive immune system?. Science 330:6012 (2010), 1768–1773.
75. Lochner, M., Peduto, L., Cherrier, M., Sawa, S., Langa, F., Varona, R., Riethmacher, D., Si-Tahar, M., Di Santo, J.P., Eberl, G., In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J. Exp. Med. 205:6 (2008), 1381–1393.
76. MacFabe, D.F., Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microbial Ecol. Health Disease, 26, 2015, 10.3402/mehd.v3426.28177.
77. Magoc, T., Salzberg, S.L., FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics 27:21 (2011), 2957–2963.
78. Mannion, A., Leader, G., An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with autism spectrum disorder: A two year follow-up. Res. Autism Spectrum Disorders 22 (2016), 20–33.
79. Mannion, A., Leader, G., Healy, O., An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with Autism Spectrum Disorder. Res. Autism Spectrum Disorders 7:1 (2013), 35–42.
80. Mantis, N.J., Rol, N., Corthesy, B., Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal. Immunol. 4:6 (2011), 603–611.
81. McDonald, C., Inohara, N., Nunez, G., Peptidoglycan signaling in innate immunity and inflammatory disease. J. Biol. Chem. 280:21 (2005), 20177–20180.
82. McDonald, D., Price, M.N., Goodrich, J., Nawrocki, E.P., DeSantis, T.Z., Probst, A., Andersen, G.L., Knight, R., Hugenholtz, P., An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea. ISME J. 6:3 (2012), 610–618.
83. McMurdie, P.J., Holmes, S., phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One, 8(4), 2013, e61217.
84. Melamed-Frank, M., Lache, O., Enav, B.I., Szafranek, T., Levy, N.S., Ricklis, R.M., Levy, A.P., Structure-function analysis of the antioxidant properties of haptoglobin. Blood 98:13 (2001), 3693–3698.
85. Mention, J.J., Ben Ahmed, M., Begue, B., Barbe, U., Verkarre, V., Asnafi, V., Colombel, J.F., Cugnenc, P.H., Ruemmele, F.M., McIntyre, E., Brousse, N., Cellier, C., Cerf-Bensussan, N., Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125:3 (2003), 730–745.
86. Molloy, C.A., Manning-Courtney, P., Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism 7:2 (2003), 165–171.
87. Mundalil Vasu, M., Anitha, A., Thanseem, I., Suzuki, K., Yamada, K., Takahashi, T., Wakuda, T., Iwata, K., Tsujii, M., Sugiyama, T., Mori, N., Serum microRNA profiles in children with autism. Mol Autism, 5, 2014, 40.
88. Napolioni, V., Gianni, P., Carpi, F.M., Concetti, F., Lucarini, N., Haptoglobin (HP) polymorphisms and human longevity: a cross-sectional association study in a Central Italy population. Clin. Chim. Acta 412:7–8 (2011), 574–577.
89. Netea, M.G., Kullberg, B.J., de Jong, D.J., Franke, B., Sprong, T., Naber, T.H., Drenth, J.P., Van der Meer, J.W., NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease. Eur. J. Immunol. 34:7 (2004), 2052–2059.
90. Niehus, R., Lord, C., Early medical history of children with autism spectrum disorders. J. Dev. Behav. Pediatr. 27:2 Suppl (2006), S120–127.
91. O'Connor, W. Jr., Zenewicz, L.A., Flavell, R.A., The dual nature of T(H)17 cells: shifting the focus to function. Nat. Immunol. 11:6 (2010), 471–476.
92. Okada, K., Hashimoto, K., Iwata, Y., Nakamura, K., Tsujii, M., Tsuchiya, K.J., Sekine, Y., Suda, S., Suzuki, K., Sugihara, G., Matsuzaki, H., Sugiyama, T., Kawai, M., Minabe, Y., Takei, N., Mori, N., Decreased serum levels of transforming growth factor-beta1 in patients with autism. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 31:1 (2007), 187–190.
93. Oliviero, S., Cortese, R., The human haptoglobin gene promoter: interleukin-6-responsive elements interact with a DNA-binding protein induced by interleukin-6. EMBO J. 8:4 (1989), 1145–1151.
94. Onore, C., Careaga, M., Ashwood, P., The role of immune dysfunction in the pathophysiology of autism. Brain Behav. Immun. 26:3 (2012), 383–392.
95. Ostaff, M.J., Stange, E.F., Wehkamp, J., Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol. Med. 5:10 (2013), 1465–1483.
96. Papp, M., Foldi, I., Nemes, E., Udvardy, M., Harsfalvi, J., Altorjay, I., Mate, I., Dinya, T., Varvolgyi, C., Barta, Z., Veres, G., Lakatos, P.L., Tumpek, J., Toth, L., Szathmari, E., Kapitany, A., Gyetvai, A., Korponay-Szabo, I.R., Haptoglobin polymorphism: a novel genetic risk factor for celiac disease development and its clinical manifestations. Clin. Chem. 54:4 (2008), 697–704.
97. Parracho, H.M., Bingham, M.O., Gibson, G.R., McCartney, A.L., Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J. Med. Microbiol. 54:Pt 10 (2005), 987–991.
98. Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., Vorstman, J.A., Thompson, A., Regan, R., Pilorge, M., Pellecchia, G., Pagnamenta, A.T., Oliveira, B., Marshall, C.R., Magalhaes, T.R., Lowe, J.K., Howe, J.L., Griswold, A.J., Gilbert, J., Duketis, E., Dombroski, B.A., De Jonge, M.V., Cuccaro, M., Crawford, E.L., Correia, C.T., Conroy, J., Conceicao, I.C., Chiocchetti, A.G., Casey, J.P., Cai, G., Cabrol, C., Bolshakova, N., Bacchelli, E., Anney, R., Gallinger, S., Cotterchio, M., Casey, G., Zwaigenbaum, L., Wittemeyer, K., Wing, K., Wallace, S., van Engeland, H., Tryfon, A., Thomson, S., Soorya, L., Roge, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McInnes, L.A., McGrew, S.G., Lord, C., Leboyer, M., Le Couteur, A.S., Kolevzon, A., Jimenez Gonzalez, P., Jacob, S., Holt, R., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B.A., Duque, F., Delorme, R., Dawson, G., Chaste, P., Cafe, C., Brennan, S., Bourgeron, T., Bolton, P.F., Bolte, S., Bernier, R., Baird, G., Bailey, A.J., Anagnostou, E., Almeida, J., Wijsman, E.M., Vieland, V.J., Vicente, A.M., Schellenberg, G.D., Pericak-Vance, M., Paterson, A.D., Parr, J.R., Oliveira, G., Nurnberger, J.I., Monaco, A.P., Maestrini, E., Klauck, S.M., Hakonarson, H., Haines, J.L., Geschwind, D.H., Freitag, C.M., Folstein, S.E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J.S., Hallmayer, J., Gill, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Gallagher, L., Betancur, C., Scherer, S.W., Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94:5 (2014), 677–694.
99. Polticelli, F., Bocedi, A., Minervini, G., Ascenzi, P., Human haptoglobin structure and function–a molecular modelling study. FEBS J. 275:22 (2008), 5648–5656.
100. Ringel, Y., Drossman, D.A., Psychosocial aspects of Crohn's disease. Surg. Clin. North Am. 81:1 (2001), 231–252.
101. Ringel, Y., Drossman, D.A., Irritable bowel syndrome: classification and conceptualization. J. Clin. Gastroenterol. 35:1 Suppl (2002), S7–10.
102. Rose, D.R., Ashwood, P., Immunology of Autism. 2015, The Molecular Basis of Autism. S. H. Fatemi, Springer, New York, 93–115.
103. Rose, S., Bennuri, S.C., Murray, K.F., Buie, T., Winter, H., Frye, R.E., Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study. PLoS One, 12(10), 2017, e0186377.
104. Rosenfeld, C.S., Microbiome disturbances and autism spectrum disorders. Drug Metab. Dispos. 43:10 (2015), 1557–1571.
105. Sadakata, T., Furuichi, T., Developmentally regulated Ca2+-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion and is associated with autism susceptibility. Cerebellum 8:3 (2009), 312–322.
106. Sefik, E., Geva-Zatorsky, N., Oh, S., Konnikova, L., Zemmour, D., McGuire, A.M., Burzyn, D., Ortiz-Lopez, A., Lobera, M., Yang, J., Ghosh, S., Earl, A., Snapper, S.B., Jupp, R., Kasper, D., Mathis, D., Benoist, C., Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349:6251 (2015), 993–997.
107. Son, J.S., Zheng, L.J., Rowehl, L.M., Tian, X., Zhang, Y., Zhu, W., Litcher-Kelly, L., Gadow, K.D., Gathungu, G., Robertson, C.E., Ir, D., Frank, D.N., Li, E., Comparison of fecal microbiota in children with Autism spectrum disorders and neurotypical siblings in the Simons simplex collection. PLoS One, 10(10), 2015, e0137725.
108. Song, Y., Liu, C., Finegold, S.M., Real-time PCR quantitation of clostridia in feces of autistic children. Appl. Environ. Microbiol. 70:11 (2004), 6459–6465.
109. Sorbara, M.T., Philpott, D.J., Peptidoglycan: a critical activator of the mammalian immune system during infection and homeostasis. Immunol. Rev. 243:1 (2011), 40–60.
110. Spees, A.M., Wangdi, T., Lopez, C.A., Kingsbury, D.D., Xavier, M.N., Winter, S.E., Tsolis, R.M., Baumler, A.J., Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. MBio, 4(4), 2013.
111. Stevceva, L., Moniuszko, M., Ferrari, M.G., Utilizing IL-12, IL-15 and IL-7 as Mucosal Vaccine Adjuvants. Lett. Drug Des. Discov. 3:8 (2006), 586–592.
112. Takei, N., Nawa, H., mTOR signaling and its roles in normal and abnormal brain development. Front. Mol. Neurosci., 7, 2014, 28.
113. Tomova, A., Husarova, V., Lakatosova, S., Bakos, J., Vlkova, B., Babinska, K., Ostatnikova, D., Gastrointestinal microbiota in children with autism in Slovakia. Physiol. Behav. 138 (2015), 179–187.
114. Torrente, F., Anthony, A., Heuschkel, R.B., Thomson, M.A., Ashwood, P., Murch, S.H., Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis. Am. J. Gastroenterol. 99:4 (2004), 598–605.
115. Torrente, F., Ashwood, P., Day, R., Machado, N., Furlano, R.I., Anthony, A., Davies, S.E., Wakefield, A.J., Thomson, M.A., Walker-Smith, J.A., Murch, S.H., Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry 7:4 (2002), 375–382 334.
116. Tripathi, A., Lammers, K.M., Goldblum, S., Shea-Donohue, T., Netzel-Arnett, S., Buzza, M.S., Antalis, T.M., Vogel, S.N., Zhao, A., Yang, S., Arrietta, M.C., Meddings, J.B., Fasano, A., Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc. Natl. Acad. Sci. USA 106:39 (2009), 16799–16804.
117. Valicenti-McDermott, M., McVicar, K., Rapin, I., Wershil, B.K., Cohen, H., Shinnar, S., Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J. Dev. Behav. Pediatr. 27:2 Suppl (2006), S128–136.
118. Vijay-Kumar, M., Aitken, J.D., Carvalho, F.A., Cullender, T.C., Mwangi, S., Srinivasan, S., Sitaraman, S.V., Knight, R., Ley, R.E., Gewirtz, A.T., Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5. Science 328:5975 (2010), 228–231.
119. Vinolo, M.A.R., Rodrigues, H.G., Nachbar, R.T., Curi, R., Regulation of inflammation by short chain fatty acids. Nutrients, 3(10), 2011, 858.
120. Walker-Smith, J., Andrews, J., Alpha-1-antitrypsin, autism, and coeliac disease. Lancet 2:7782 (1972), 883–884.
121. Walker LS, C.-D.A., Rasquin-Weber, A., 2006. Questionnaire on pediatric gastrointestinal symptoms, Rome III version (QPGS-RIII). Rome III: The Functional Gastrointestinal Disorders. McLean, Virginia, Degnon Associates, Inc.
122. Wang, L., Christophersen, C.T., Sorich, M.J., Gerber, J.P., Angley, M.T., Conlon, M.A., Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Mol Autism, 4(1), 2013, 42.
123. Wang, L., Conlon, M.A., Christophersen, C.T., Sorich, M.J., Angley, M.T., Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomark Med. 8:3 (2014), 331–344.
124. Wang, Q., Garrity, G.M., Tiedje, J.M., Cole, J.R., Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73:16 (2007), 5261–5267.
125. Williams, B.L., Hornig, M., Buie, T., Bauman, M.L., Cho Paik, M., Wick, I., Bennett, A., Jabado, O., Hirschberg, D.L., Lipkin, W.I., Impaired carbohydrate digestion and transport and mucosal Dysbiosis in the intestines of children with Autism and gastrointestinal disturbances. PLoS One, 6(9), 2011, e24585.
126. Wingate, M.S., Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill. Summ. 63:2 (2014), 1–21.
127. Winter, S.E., Winter, M.G., Xavier, M.N., Thiennimitr, P., Poon, V., Keestra, A.M., Laughlin, R.C., Gomez, G., Wu, J., Lawhon, S.D., Popova, I.E., Parikh, S.J., Adams, L.G., Tsolis, R.M., Stewart, V.J., Bäumler, A.J., Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339:6120 (2013), 708–711.
128. Xue, M., Brimacombe, M., Chaaban, J., Zimmerman-Bier, B., Wagner, G.C., Autism spectrum disorders: concurrent clinical disorders. J. Child Neurol. 23:1 (2008), 6–13.
129. Zhou, X., Bailey-Bucktrout, S.L., Jeker, L.T., Penaranda, C., Martinez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W., Bluestone, J.A., Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10:9 (2009), 1000–1007.