Gut Microbiota and Autism: Key Concepts and Findings

Journal of Autism and Developmental Disorders

Volumn 47, Issue 2, 2017, Pages 480-489

  Ding, Helen T ^a,b   Taur, Ying ^a,c   Walkup, John T ^a,b  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

^b NEW YORK PRESBYTERIAN HOSPITAL   (United States)

^c MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Autism; Autism spectrum disorder (ASD); Gastrointestinal symptoms; Microbiome; Microbiota; Regressive autism

Indexed keywords

AMINO ACID; PHENOL DERIVATIVE; PROPIONIC ACID; SHORT CHAIN FATTY ACID;

AMINO ACID METABOLISM; AUTISM; BRAIN; CLOSTRIDIUM; DYSBIOSIS; GASTROINTESTINAL SYMPTOM; GRAM NEGATIVE BACTERIUM; HUMAN; INTESTINE; INTESTINE FLORA; METABOLOMICS; MICROBIOME; NONHUMAN; PREVALENCE; PRIORITY JOURNAL; REVIEW; SUTTERELLA; ANIMAL; AUTISM SPECTRUM DISORDER; AUTISTIC DISORDER; CHILD; CLOSTRIDIUM HISTOLYTICUM; GASTROINTESTINAL ABSORPTION; IMMUNOLOGY; ISOLATION AND PURIFICATION; MICROBIOLOGY;

ANIMALS; AUTISM SPECTRUM DISORDER; AUTISTIC DISORDER; CHILD; CLOSTRIDIUM HISTOLYTICUM; GASTROINTESTINAL ABSORPTION; GASTROINTESTINAL MICROBIOME; HUMANS;

EID: 84996969464     PISSN: 01623257     EISSN: 15733432     Source Type: Journal    
DOI: 10.1007/s10803-016-2960-9     Document Type: Review

References (70)

1. Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterology, 11, 22. doi:10.1186/1471-230X-11-22.
2. Arndt, T. L., Stodgell, C. J., & Rodier, P. M. (2005). The teratology of autism. International Journal of Developmental Neuroscience: The Official Journal of the International Society for Developmental Neuroscience, 23(2–3), 189–199. doi:10.1016/j.ijdevneu.2004.11.001.
3. Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I., & Van de Water, J. (2011). Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain, Behavior, and Immunity, 25(1), 40–45. doi:10.1016/j.bbi.2010.08.003.
4. Barger, B. D., Campbell, J. M., & McDonough, J. D. (2013). Prevalence and onset of regression within autism spectrum disorders: A meta-analytic review. Journal of Autism and Developmental Disorders, 43(4), 817–828. doi:10.1007/s10803-012-1621-x.
5. Bessis, A., Bechade, C., Bernard, D., & Roumier, A. (2007). Microglial control of neuronal death and synaptic properties. Glia, 55(3), 233–238. doi:10.1002/glia.20459.
6. Bolte, E. R. (1998). Autism and Clostridium tetani. Medical Hypotheses, 51(2), 133–144.
7. Buie, T., Campbell, D. B., Fuchs, G. J. 3rd, Furuta, G. T., Levy, J., Vandewater, J.,… Winter, H. (2010). Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: A consensus report. Pediatrics, 125(Suppl 1), S1–S18. doi:10.1542/peds.2009-1878C.
8. Centers for Disease Control and Prevention, Autism and Developmental Disabilities Monitoring Network Surveillance. (2014). Prevalence of autism spectrum disorder among children aged 8 years: Autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveillance Summaries, 63(2), 1–21.
9. De Angelis, M., Piccolo, M., Vannini, L., Siragusa, S., De Giacomo, A., Serrazzanetti, D. I.,… Francavilla, R. (2013). Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One, 8(10), e76993. doi:10.1371/journal.pone.0076993.
10. de Magistris, L., Familiari, V., Pascotto, A., Sapone, A., Frolli, A., Iardino, P.,… Bravaccio, C. (2010). Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. Journal of Pediatric Gastroenterology and Nutrition, 51(4), 418–424. doi:10.1097/MPG.0b013e3181dcc4a5.
11. DiCicco-Bloom, E., Lord, C., Zwaigenbaum, L., Courchesne, E., Dager, S. R., Schmitz, C.,… Young, L. J. (2006). The developmental neurobiology of autism spectrum disorder. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26(26), 6897–6906. doi:10.1523/JNEUROSCI.1712-06.2006.
12. Eckburg, P. B., Bik, E. M., Bernstein, C. N., Purdom, E., Dethlefsen, L., Sargent, M.,… Relman, D. A. (2005). Diversity of the human intestinal microbial flora. Science, 308(5728), 1635–1638. doi:10.1126/science.1110591.
13. Fasano, A. (2012). Leaky gut and autoimmune diseases. Clinical Reviews in Allergy & Immunology, 42(1), 71–78. doi:10.1007/s12016-011-8291-x.
14. Finegold, S. M., Dowd, S. E., Gontcharova, V., Liu, C., Henley, K. E., Wolcott, R. D.,… Green, J. A. 3rd (2010). Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe, 16(4), 444–453. doi:10.1016/j.anaerobe.2010.06.008.
15. Finegold, S. M., Molitoris, D., Song, Y., Liu, C., Vaisanen, M. L., Bolte, E.,… Kaul, A. (2002). Gastrointestinal microflora studies in late-onset autism. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 35(Suppl 1), S6–S16. doi:10.1086/341914.
16. Gabriele, S., Sacco, R., Cerullo, S., Neri, C., Urbani, A., Tripi, G.,… Persico, A. M. (2014). Urinary p-cresol is elevated in young French children with autism spectrum disorder: A replication study. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals, 19(6), 463–470. doi:10.3109/1354750X.2014.936911.
17. Goehler, L. E., Park, S. M., Opitz, N., Lyte, M., & Gaykema, R. P. (2008). Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: Possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain, Behavior, and Immunity, 22(3), 354–366. doi:10.1016/j.bbi.2007.08.009.
18. Hollander, D. (1999). Intestinal permeability, leaky gut, and intestinal disorders. Current Gastroenterology Reports, 1(5), 410–416.
19. Hooper, L. V., Littman, D. R., & Macpherson, A. J. (2012). Interactions between the microbiota and the immune system. Science, 336(6086), 1268–1273. doi:10.1126/science.1223490.
20. Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T.,… Mazmanian, S. K. (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155(7), 1451–1463. doi:10.1016/j.cell.2013.11.024.
21. Human Microbiome Project Consortium. (2012). Structure, function and diversity of the healthy human microbiome. Nature, 486(7402), 207–214. doi:10.1038/nature11234.
22. Kang, D. W., Park, J. G., Ilhan, Z. E., Wallstrom, G., Labaer, J., Adams, J. B., & Krajmalnik-Brown, R. (2013). Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One, 8(7), e68322. doi:10.1371/journal.pone.0068322.
23. Kohane, I. S., McMurry, A., Weber, G., MacFadden, D., Rappaport, L., Kunkel, L.,… Churchill, S. (2012). The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One, 7(4), e33224. doi:10.1371/journal.pone.0033224.
24. Li, X., Chauhan, A., Sheikh, A. M., Patil, S., Chauhan, V., Li, X. M.,… Malik, M. (2009). Elevated immune response in the brain of autistic patients. Journal of Neuroimmunology, 207(1–2), 111–116. doi:10.1016/j.jneuroim.2008.12.002.
25. Macfabe, D. F. (2012). Short-chain fatty acid fermentation products of the gut microbiome: Implications in autism spectrum disorders. Microbial Ecology in Health and Disease, 23. doi:10.3402/mehd.v23i0.19260.
26. Ming, X., Stein, T. P., Barnes, V., Rhodes, N., & Guo, L. (2012). Metabolic perturbance in autism spectrum disorders: A metabolomics study. Journal of Proteome Research, 11(12), 5856–5862. doi:10.1021/pr300910n.
27. Morgan, J. T., Chana, G., Pardo, C. A., Achim, C., Semendeferi, K., Buckwalter, J.,… Everall, I. P. (2010). Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological Psychiatry, 68(4), 368–376. doi:10.1016/j.biopsych.2010.05.024.
28. Nicholson, J. K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., & Pettersson, S. (2012). Host-gut microbiota metabolic interactions. Science, 336(6086), 1262–1267. doi:10.1126/science.1223813.
29. Nikolov, R. N., Bearss, K. E., Lettinga, J., Erickson, C., Rodowski, M., Aman, M. G.,… Scahill, L. (2009). Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. Journal of Autism and Developmental Disorders, 39(3), 405–413. doi:10.1007/s10803-008-0637-8.
30. O’Mahony, S. M., Hyland, N. P., Dinan, T. G., & Cryan, J. F. (2011). Maternal separation as a model of brain–gut axis dysfunction. Psychopharmacology, 214(1), 71–88. doi:10.1007/s00213-010-2010-9.
31. O’Mahony, S. M., Marchesi, J. R., Scully, P., Codling, C., Ceolho, A. M., Quigley, E. M.,… Dinan, T. G. (2009). Early life stress alters behavior, immunity, and microbiota in rats: Implications for irritable bowel syndrome and psychiatric illnesses. Biological Psychiatry, 65(3), 263–267. doi:10.1016/j.biopsych.2008.06.026.
32. Onore, C., Careaga, M., & Ashwood, P. (2012). The role of immune dysfunction in the pathophysiology of autism. Brain, Behavior, and Immunity, 26(3), 383–392. doi:10.1016/j.bbi.2011.08.007.
33. Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P.,… Gross, C. T. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science, 333(6048), 1456–1458. doi:10.1126/science.1202529.
34. Pardo, C. A., Buckley, A., Thurm, A., Lee, L. C., Azhagiri, A., Neville, D. M., & Swedo, S. E. (2013). A pilot open-label trial of minocycline in patients with autism and regressive features. Journal of Neurodevelopmental Disorders, 5(1), 9. doi:10.1186/1866-1955-5-9.
35. Parracho, H. M., Bingham, M. O., Gibson, G. R., & McCartney, A. L. (2005). Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Journal of Medical Microbiology, 54(Pt 10), 987–991. doi:10.1099/jmm.0.46101-0.
36. Penders, J., Thijs, C., van den Brandt, P. A., Kummeling, I., Snijders, B., Stelma, F.,… Stobberingh, E. E. (2007). Gut microbiota composition and development of atopic manifestations in infancy: The KOALA Birth Cohort Study. Gut, 56(5), 661–667. doi:10.1136/gut.2006.100164.
37. Persico, A. M., & Napolioni, V. (2013). Urinary p-cresol in autism spectrum disorder. Neurotoxicology and Teratology, 36, 82–90. doi:10.1016/j.ntt.2012.09.002.
38. Pirbaglou, M., Katz, J., de Souza, R. J., Stearns, J. C., Motamed, M., & Ritvo, P. (2016). Probiotic supplementation can positively affect anxiety and depressive symptoms: A systematic review of randomized controlled trials. Nutrition Research, 36(9), 889–898. doi:10.1016/j.nutres.2016.06.009.
39. Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J. S.,… Crews, F. T. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55(5), 453–462. doi:10.1002/glia.20467.
40. Sandler, R. H., Finegold, S. M., Bolte, E. R., Buchanan, C. P., Maxwell, A. P., Vaisanen, M. L.,… Wexler, H. M. (2000). Short-term benefit from oral vancomycin treatment of regressive-onset autism. Journal of Child Neurology, 15(7), 429–435.
41. Santocchi, E., Guiducci, L., Fulceri, F., Billeci, L., Buzzigoli, E., Apicella, F.,… Muratori, F. (2016). Gut to brain interaction in autism spectrum disorders: A randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry, 16, 183. doi:10.1186/s12888-016-0887-5.
42. Sekirov, I., Russell, S. L., Antunes, L. C., & Finlay, B. B. (2010). Gut microbiota in health and disease. Physiological Reviews, 90(3), 859–904. doi:10.1152/physrev.00045.2009.
43. Selmer, T., & Andrei, P. I. (2001). p-Hydroxyphenylacetate decarboxylase from Clostridium difficile. A novel glycyl radical enzyme catalysing the formation of p-cresol. European Journal of Biochemistry, 268(5), 1363–1372.
44. Sheldon, A. L., & Robinson, M. B. (2007). The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochemistry International, 51(6–7), 333–355. doi:10.1016/j.neuint.2007.03.012.
45. Shimmura, C., Suda, S., Tsuchiya, K. J., Hashimoto, K., Ohno, K., Matsuzaki, H.,… Mori, N. (2011). Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One, 6(10), e25340. doi:10.1371/journal.pone.0025340.
46. Shultz, S. R., Macfabe, D. F., Martin, S., Jackson, J., Taylor, R., Boon, F.,… Cain, D. P. (2009). Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long-Evans rat: Further development of a rodent model of autism. Behavioural Brain Research, 200(1), 33–41. doi:10.1016/j.bbr.2008.12.023.
47. Shultz, S. R., MacFabe, D. F., Ossenkopp, K. P., Scratch, S., Whelan, J., Taylor, R., & Cain, D. P. (2008). Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism. Neuropharmacology, 54(6), 901–911. doi:10.1016/j.neuropharm.2008.01.013.
48. Song, Y., Liu, C., & Finegold, S. M. (2004). Real-time PCR quantitation of clostridia in feces of autistic children. Applied and Environmental Microbiology, 70(11), 6459–6465. doi:10.1128/AEM.70.11.6459-6465.2004.
49. Song, Y., Liu, C., Molitoris, D. R., Tomzynski, T. J., Lawson, P. A., Collins, M. D., & Finegold, S. M. (2003). Clostridium bolteae sp. nov., isolated from human sources. Systematic and Applied Microbiology, 26(1), 84–89. doi:10.1078/072320203322337353.
50. Stefanatos, G. A. (2008). Regression in autistic spectrum disorders. Neuropsychology Review, 18(4), 305–319. doi:10.1007/s11065-008-9073-y.
51. Taur, Y., Xavier, J. B., Lipuma, L., Ubeda, C., Goldberg, J., Gobourne, A.,… Pamer, E. G. (2012). Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 55(7), 905–914. doi:10.1093/cid/cis580.
52. The University of Texas Health Science Center Houston,and National Institutes of Health. (2016). Road to discovery for combination probiotic BB-12 with LGG in treating autism spectrum disorder. https://ClinicalTrials.gov/show/NCT02674984.
53. Thomas, R. H., Meeking, M. M., Mepham, J. R., Tichenoff, L., Possmayer, F., Liu, S., & MacFabe, D. F. (2012). The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: Further development of a rodent model of autism spectrum disorders. Journal of Neuroinflammation, 9, 153. doi:10.1186/1742-2094-9-153.
54. University Arizona State, University, Northern Arizona, Arizona, University of Clinical, University of Minnesota, and Institute, Translational Science. (2014). Beneficial bacteria treatment. https://ClinicalTrials.gov/show/NCT02504554.
55. University of California, Davis. (2014). Effect of milk oligosaccharides and bifidobacteria on the intestinal microflora of children with autism. https://ClinicalTrials.gov/show/NCT02086110.
56. van Duynhoven, J., Vaughan, E. E., Jacobs, D. M., Kemperman, R. A., van Velzen, E. J., Gross, G.,… Van de Wiele, T. (2011). Metabolic fate of polyphenols in the human superorganism. Proceedings of the National Academy of Sciences of the USA, 108(Suppl 1), 4531–4538. doi:10.1073/pnas.1000098107.
57. Vanholder, R., De Smet, R., & Lesaffer, G. (1999). p-cresol: A toxin revealing many neglected but relevant aspects of uraemic toxicity. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association-European Renal Association, 14(12), 2813–2815.
58. Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W., & Pardo, C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology, 57(1), 67–81. doi:10.1002/ana.20315.
59. Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2011). Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Applied and Environmental Microbiology, 77(18), 6718–6721. doi:10.1128/AEM.05212-11.
60. Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2012). Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Digestive Diseases and Sciences, 57(8), 2096–2102. doi:10.1007/s10620-012-2167-7.
61. Wang, L., Christophersen, C. T., Sorich, M. J., Gerber, J. P., Angley, M. T., & Conlon, M. A. (2013). Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder. Molecular Autism, 4(1), 42. doi:10.1186/2040-2392-4-42.
62. Wang, Y., & Kasper, L. H. (2014). The role of microbiome in central nervous system disorders. Brain, Behavior, and Immunity, 38C, 1–12. doi:10.1016/j.bbi.2013.12.015.
63. West, P. R., Amaral, D. G., Bais, P., Smith, A. M., Egnash, L. A., Ross, M. E.,… Burrier, R. E. (2014). Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PLoS One, 9(11), e112445. doi:10.1371/journal.pone.0112445.
64. Wetterstrand, K. A. (2013). DNA sequencing costs: Data from the NHGRI genome sequencing program (GSP). Retrieved from http://www.genome.gov/sequencingcosts. Accessed 20 Nov 2013.
65. Williams, B. L., Hornig, M., Buie, T., Bauman, M. L., Cho Paik, M., Wick, I.,… Lipkin, W. I. (2011). Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One, 6(9), e24585. doi:10.1371/journal.pone.0024585.
66. Williams, B. L., Hornig, M., Parekh, T., & Lipkin, W. I. (2012). 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, 3(1). doi:10.1128/mBio.00261-11.
67. Wong, J. M., de Souza, R., Kendall, C. W., Emam, A., & Jenkins, D. J. (2006). Colonic health: Fermentation and short chain fatty acids. Journal of Clinical Gastroenterology, 40(3), 235–243.
68. Yap, I. K., Angley, M., Veselkov, K. A., Holmes, E., Lindon, J. C., & Nicholson, J. K. (2010). Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. Journal of Proteome Research, 9(6), 2996–3004. doi:10.1021/pr901188e.
69. Yokoyama, M. T., & Carlson, J. R. (1981). Production of Skatole and para-Cresol by a Rumen Lactobacillus sp. Applied and Environmental Microbiology, 41(1), 71–76.
70. Zhan, Y., Paolicelli, R. C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F.,… Gross, C. T. (2014). Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature Neuroscience, 17(3), 400–406. doi:10.1038/nn.3641.