Abstract
Autism spectrum disorder (ASD) is a severe neurodevelopmental or neuropsychiatric disorder with elusive etiology and obscure pathophysiology. Cognitive inabilities, impaired communication, repetitive behavior pattern, and restricted social interaction and communication lead to a debilitating situation in autism. The pattern of co-occurrence of medical comorbidities is most intriguing in autism, compared to any other neurodevelopmental disorders. They have an elevated comorbidity burden among which most frequently are seizures, psychiatric illness, and gastrointestinal disorders. The gut microbiota is believed to play a pivotal role in human health and disease through involvement in physiological homoeostasis, immunological development, glutathione metabolism, amino acid metabolism, etc., which in a reasonable way explain the role of gut-brain axis in autism. Branded as a neurodevelopmental disorder with psychiatric impairment and often misclassified as a mental disorder, many experts in the field think that a therapeutic solution to autism is unlikely to emerge. As the pathophysiology is still elusive, taking into account of the various symptoms that are concurrent in autism is important. Gastrointestinal problems that are seen associated with most of the autism cases suggest that it is not just a psychiatric disorder as many claim but have a physiological base, and alleviating the gastrointestinal problems could help alleviating the symptoms by bringing out the much needed overall improvement in the affected victims. A gut disorder akin to Crohn’s disease is, sometimes, reported in autistic children, an extremely painful gastrointestinal disease which is named as autistic enterocolitis. This disturbed situation hypothesized to be initiated by dysbiosis or microbial imbalance could in turn perturb the coordination of microbiota-gut-brain axis which is important in human mental health as goes the popular dictum: “fix your gut, fix your brain.”
Keywords
- Autism spectrum disorder (ASD)
- Gastrointestinal problems
- Microbial dysbiosis
- Gut-brain axis
This is a preview of subscription content, access via your institution.
Buying options


References
Lederberg J, McCray AT (2001) Ome SweetOmics--A Genealogical Treasury of Words. The Scientist 15(7):8–8
Turnbaugh PJ, Gordon JI (2009) The core gut microbiome, energy balance and obesity. J Physiol 587(17):4153–4158
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C et al (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464(7285):59–65
Glendinning L, Free A (2013) Supra-organismal interactions in the human intestine. Front Cell Infect Microbiol 4:47–47
Walker AW, Lawley TD (2013) Therapeutic modulation of intestinal dysbiosis. Pharmacol Res 9(1):75–86
Sommer F, Bäckhed F (2013) The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 11(4):227–238
Wang Y, Kasper LH (2014) The role of microbiome in central nervous system disorders. Brain Behav Immun 38:1–12
Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immun 9(5):313–323
Collins SM, Bercik P (2009) The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 136(6):2003–2014
Faust K, Sathirapongsasuti JF, Izard J, Segata N, Gevers D, Raes J et al (2012) Microbial co-occurrence relationships in the human microbiome. PLoS Comput Biol 8(7):e1002606. https://doi.org/10.1371/journal.pcbi.1002606
MacDonald TT, Monteleone G (2005) Immunity inflammation and allergy in the gut. Science 307(5717):1920–1925
Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E et al (2002) Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis 35(Supplement 1):S6–S16
Hume G, Radford-Smith GL (2002) The pathogenesis of Crohn's disease in the 21st century. Pathology-Abingdon 34(6):561–567
McGarr SE, Ridlon JM, Hylemon PB (2005) Diet anaerobic bacterial metabolism and colon cancer: a review of the literature. J Clin Gastroenterol 39(2):98–109
Hartstra AV, Bouter KE, Bäckhed F, Nieuwdorp M (2015) Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care 38(1):159–165
Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W et al (2012) Host-gut microbiota metabolic interactions. Science 336(6086):1262–1267
Carding S, Verbeke K, Vipond DT, Corfe BM, Owen L (2015) Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 26. https://doi.org/10.3402/mehd.v26.26191
Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain–gut–enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6(5):306–314
Sudo N (2014) Microbiome HPA axis and production of endocrine hormones in the gut. Adv Exp Med Biol 817:177–194
Lyte M (2004) Microbial endocrinology and infectious disease in the 21st century. Trends Microbiol 12(1):14–20
Hughes DT, Sperandio V (2008) Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol 6(2):111–120
Mayer EA, Tillisch K, Gupta A (2015) Gut/brain axis and the microbiota. J Clin Invest 125(3):926–938
Barbara G, Stanghellini V, Brandi G, Cremon C, Di Nardo G, De Giorgio R et al (2005) Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol 100(11):2560–2568
Clarke G, Grenham S, Scully P, Fitzgeral P, Moloney RD, Shanahan F et al (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18(6):666–673
Abrams GD, Bishop JE (1967) Effect of the normal microbial flora on gastrointestinal motility. Proc Soc Exp Biol Med 126(1):301–304
Iwai H, Ishihara Y, Yamanaka J, Ito T (1973) Effects of bacterial flora on cecal size and transit rate of intestinal contents in mice. Jpn J Exp Med 43(4):297–305
Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI (2001) Molecular analysis of commensal host-microbial relationships in the intestine. Science 291(5505):881–884
Carabotti M, Scirocco A, Maselli MA, Severi C (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28(2):203–209
Eisenhofer G, Kopin IJ, Goldstein DS (2004) Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 56(3):331–349
Asano Y, Hiramoto T, Nishino R, Aiba Y, Kimura T, Yoshihara K (2012) Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am J Physiol-Gastrointest Liver Physiol 303(11):G1288–G1295
Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S et al (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 108(19):8030–8035
Reigstad CS, Salmonson CE, Rainey JF, Szurszewski JH, Linden DR, Sonnenburg JL et al (2015) Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 29(4):1395–1403
Stefanko DP, Barrett RM, Ly AR, Reolon GK, Wood MA (2009) Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci U S A 106(23):9447–9452
Uribe A, Alam M, Johansson O, Midtvedt T, Theodorsson E (1994) Microflora modulates endocrine cells in the gastrointestinal mucosa of the rat. Gastroenterology 107(5):1259–1269
Galley JD, Nelson MC, Yu Z, Dowd SE, Walter J, Kumar PS et al (2014) Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. BMC Microbiol 14(1):189. https://doi.org/10.1186/1471-2180-14-189
Guthrie GD, Nicholson-Guthrie CS (1989) gamma-Aminobutyric acid uptake by a bacterial system with neurotransmitter binding characteristics. Proc Natl Acad Sci U S A 86(19):7378–7381
Macfarlane S, Dillon JF (2007) Microbial biofilms in the human gastrointestinal tract. J Appl Microbiol 102(5):1187–1196
Rubio CA, Huang CB (1991) Quantification of the sulphomucin-producing cell population of the colonic mucosa during protracted stress in rats. In Vivo 6(1):81–84
Gue M, Peeters T, Depoortere I, Vantrappen G, Bueno L (1989) Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone levels in dogs. Gastroenterology 97(5):1101–1107
Gue M, Junien JL, Bueno L (1991) Conditioned emotional response in rats enhances colonic motility through the central release of corticotropin-releasing factor. Gastroenterology 100(4):964–970
Schaedler RW, Dubos RJ (1962) The fecal flora of various strains of mice. Its bearing on their susceptibility to endotoxin. J Exp Med 115(6):1149–1160
Bailey MT, Coe CL (1999) Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol 35(2):146–155
Gaykema RP, Goehler LE, Lyte M (2004) Brain response to cecal infection with Campylobacter jejuni: analysis with Fos immunohistochemistry. Brain Behav Immun 18(3):238–245
Lyte M, Li W, Opitz N, Gaykema RP, Goehler LE (2006) Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol Behav 89(3):350–357
Bercik P, Verdu EF, Foster JA, Macri J, Potter M, Huang X et al (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139(6):2102–2112
Ohland CL, Kish L, Bell H, Thiesen A, Hotte N, Pankiv E et al (2013) Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology 38(9):1738–1747
Jepson B, Johnson J (2007) Changing the course of autism: A scientific approach for parents and physicians. 1st edn, Sentient Publications Boulder. ISBN-10: 1591810612
Williams BL, Hornig M, Parekh T, Lipkin WI (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). https://doi.org/10.1128/mBio.00261-11
Parracho HM, Bingham MO, Gibson GR, McCartney AL (2005) Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol 54(10):987–991
Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA (2011) Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11(1):22. https://doi.org/10.1186/1471-230X-11-22
Ming X, Brimacombe M, Chaaban J, Zimmerman-Bier B, Wagner GC (2008) Autism spectrum disorders: concurrent clinical disorders. J Child Neurol 23(1):6–13
Valicenti-McDermott M, McVicar K, Rapin I, Wershil BK, Cohen H, Shinnar S (2006) Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr 27(2):S128–S136
Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M et al (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 352(9123):234–235
Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O'leary JJ, Murch SH (2002) The concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther 16(4):663–674
d'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M et al (1996) Abnormal intestinal permeability in children with autism. Acta Paediatr 85(9):1076–1079
Horvath K, Perman JA (2002) Autistic disorder and gastrointestinal disease. Cur Opin Pediatr 14(5):583–587
Sharp WG, Jaquess DL, Lukens CT (2013) Multi-method assessment of feeding problems among children with autism spectrum disorders. Autism Spectr Disord 7(1):56–65
Field D, Garland M, Williams K (2003) Correlates of specific childhood feeding problems. J Paediatr Child Health 39(4):299–304
Shaw W (2010) Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci 13(3):135–143
Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaug J, Knight R et al (2011) Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A 108(Supplement 1):4578–4585
Song Y, Liu C, Finegold SM (2004) Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol 70(11):6459–6465
Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Väisänen ML et al (2000) Short-term benefit from oral vancomycin treatment of regressive-onset autism. JChild Neurol 15(7):429–435
Elsden SR, Hilton MG (1978) Volatile acid production from threonine, valine, leucine and isoleucine by clostridia. Arch Microbiol 117(2):165–172
Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R et al (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
Pulikkan J, Maji A, Dhakan DB, Saxena R, Mohan B, Anto MM et al (2018) Gut microbial dysbiosis in Indian children with autism spectrum disorders. Microb Ecol 76(4):1102–1114
Kang DW, Park JG, Ilhan ZE, Wallstrom G, LaBaer J, Adams JB et al (2013) Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS One 8(7):e68322. https://doi.org/10.1371/journal.pone.0068322
Dillon SM, Lee EJ, Kotter CV, Austin GL, Dong Z, Hecht DK et al (2014) An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 7(4):983–994
Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci 106(34):14728–14733
Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Patterson PH (2013) Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155(7):1451–1463
De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI et al (2013) Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One 8(10):e76993. https://doi.org/10.1371/journal.pone.0076993
Dickerson AS, Rahbar MH, Bakian AV, Bilder DA, Harrington RA, Pettygrove S et al (2016) Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic. Environ Monit Assess 188(7):407. https://doi.org/10.1007/s10661-016-5405-1
Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E et al (2013) Toxicological status of children with autism vs. neurotypical children and the association with autism severity. Biol Trace Elem Res 151(2):171–180
Breton J, Daniel C, Dewulf J, Pothion S, Froux N, Sauty M et al (2013) Gut microbiota limits heavy metals burden caused by chronic oral exposure. Toxicol Lett 222(2):132–138
Meyer J, Michalke K, Kouril T, Hensel R (2008) Volatilisation of metals and metalloids: an inherent feature of methanoarchaea? Syst Appl Microbiol 31(2):81–87
Dostal A, Fehlbaum S, Chassard C, Zimmermann MB, Lacroix C (2013) Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. FEMS Microbiol Ecol 83(1):161–175
Reed S, Neuman H, Moscovich S, Glahn RP, Koren O, Tako E (2015) Chronic zinc deficiency alters chick gut microbiota composition and function. Nutrients 7(12):9768–9784
Smith JC, McDaniel EG, McBean LD, Doft FS, Halsted JA (1972) Effect of microorganisms upon zinc metabolism using germfree and conventional rats. J Nutr 102(6):711–719
Pieper R, Vahjen W, Neumann K, Van Kessel AG, Zentek J (2012) Dose-dependent effects of dietary zinc oxide on bacterial communities and metabolic profiles in the ileum of weaned pigs. J Anim Physiol Anim Nutr 96(5):825–833
Vahjen W, Pieper R, Zentek J (2010) Bar-coded pyrosequencing of 16S rRNA gene amplicons reveals changes in ileal porcine bacterial communities due to high dietary zinc intake. Appl Environ Microbiol 76(19):6689–6691
Højberg O, Canibe N, Poulsen HD, Hedemann MS, Jensen B (2005) Influence of dietary zinc oxide and copper sulfate on the gastrointestinal ecosystem in newly weaned piglets. Appl Environ Microbiol 71(5):2267–2277
Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (2003) The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66(8):1499–1503
Mardinogl A, Shoaie S, Bergentall M, Ghaffari P, Zhang C, Larsson E et al (2015) The gut microbiota modulates host amino acid and glutathione metabolism in mice. Mol Syst Biol 11(10):834. https://doi.org/10.15252/msb.20156487
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Pulikkan, J., Mazumder, A., Grace, T. (2019). Role of the Gut Microbiome in Autism Spectrum Disorders. In: Guest, P. (eds) Reviews on Biomarker Studies in Psychiatric and Neurodegenerative Disorders. Advances in Experimental Medicine and Biology(), vol 1118. Springer, Cham. https://doi.org/10.1007/978-3-030-05542-4_13
Download citation
DOI: https://doi.org/10.1007/978-3-030-05542-4_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-05541-7
Online ISBN: 978-3-030-05542-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)