Key Autism Peer Reviewed Publications

This collection of peer reviewed articles is intended to provide an overview of some of the best research on autism pathophysiology and treatment, with an emphasis on biological approaches. Included are gene-environment interactions on neurdevelopment/neuroplasticity, metabolism, immune function, gut physiology, environmental toxins/infectious processes and their impact on systems biology. Primarily intended for students and professionals of basic and clinical sciences, there is a link to each publication for web access. As the production of papers are rapidly accelerating, we will attempt to keep this list up to date. This site and these references document that there is growing evidence that autism spectrum disorders are biologically based whole body conditions that are largely environmentally modulated and have many preventable and treatable forms.

Behavioral and Brain Ultrastructural Changes Following Systemic Administration of Propionic Acid in Adolescent Male Rats. Further Development of a Rodent Model of Autism. Lobzhanidze G, Japaridze N, Lordkipandize T, Rzayev F, MacFabe D, Zhvania M. Int J Dev Neurosci. 2020 Jan 30. doi: 10.1002/jdn.10011.

Enteric Short-Chain Fatty Acids Promote Proliferation of Human Neural Progenitor Cells. Yang LL, Millischer V, Rodin S, MacFabe DF, Villaescusa JC, Lavebratt C. J Neurochem. 2019 Nov 29:e14928. doi: 10.1111/jnc.14928.

Propionic acid induced behavioural effects of relevance to autism spectrum disorder evaluated in the hole board test with rats. Meeking MM, MacFabe DF, Mepham JR, Foley KA, Tichenoff LJ, Boon FH, Kavaliers M, Ossenkopp KP. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Oct 19:109794. doi: 10.1016/j.pnpbp.2019.109794.

Effect of propionic acid on the morphology of the amygdala in adolescent male rats and their behavior Giorgi Lobzhanidzea, Tamar Lordkipanidze, Mzia Zhvania, Nadezhda Japaridze, Derrick Fraser MacFabe, Nino Pochkidze, Eldar Gasimov, Fuad Rzaev. 2019 Oct. doi: 10.1016/j.micron.2019.10273

Impaired Spatial Cognition in Adult Rats Treated with Multiple Intracerebroventricular (ICV) Infusions of the Enteric Bacterial Metabolite, Propionic Acid, and Return to Baseline After 1 Week of No Treatment: Contribution to a Rodent Model of ASD. Mepham JR, Boon FH, Foley KA, Cain DP, MacFabe DF, Ossenkopp KP. Neurotox Res. 2019 Mar 8. doi: 10.1007/s12640-019-0002-z

Systemic treatment with the enteric bacterial metabolic product propionic acid results in reduction of social behavior in juvenile rats: Contribution to a rodent model of autism spectrum disorder. Foley KA, Kavaliers M, MacFabe DF, Ossenkopp KP. Dev Psychobiol. 2019 Jan 28. doi: 10.1002/dev.21825.

Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism. Rose S, Bennuri SC, Davis JE, Wynne R, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, MacFabe DF, Frye RE. Transl Psychiatry. 2018 Feb 2;8(1):42. doi: 10.1038/s41398-017-0089-z. PMID: 29391397

Modulation of Immunological Pathways in Autistic and Neurotypical Lymphoblastoid Cell Lines by the Enteric Microbiome Metabolite Propionic Acid. Richard E. Frye, Bistra Nankova, Sudeepa Bhattacharyya, Shannon Rose, Sirish C. Bennuri, Derrick F. MacFabe.Front. Immunol., 22 December 2017

Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Frye RE, Rose S, Chacko J, Wynne R, Bennuri SC, Slattery JC, Tippett M, Delhey L, Melnyk S, Kahler SG, MacFabe DF. Transl Psychiatry. 2016 Oct 25;6(10):e927. doi: 10.1038/tp.2016.189.

The Significance of the Enteric Microbiome on the Development of Childhood Disease: A Review of Prebiotic and Probiotic Therapies in Disorders of Childhood. Slattery J, MacFabe DF, Frye RE. Clin Med Insights Pediatr. 2016 Oct 9;10:91-107. Review.

Enteric Ecosystem Disruption in Autism Spectrum Disorder: Can the Microbiota and Macrobiota be Restored? Slattery J, MacFabe DF, Kahler SG, Frye RE. Curr Pharm Des. 2016 Sep 5.

MACFABE, Derrick F.. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders.Microbial Ecology in Health and Disease, [S.l.], v. 26, may. 2015. ISSN 1651-2235.

Richard E. Frye, John Slattery, Derrick F. MacFabe, Emma Allen-Vercoe, William Parker, John Rodakis, James B. Adams, Rosa Krajmalnik-Brown, Ellen Bolte, Stephen Kahler, Jana Jennings, Jill James, Carl E. Cerniglia, Tore Midtvedt, Approaches to studying and manipulating the enteric microbiome to improve autism symptoms (Published: 7 May 2015)

Richard E. Frye, Shannon Rose, John Slattery, Derrick F. MacFabe, Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome (Published: 7 May 2015)

Kelly A. Foley, Derrick F. MacFabe, Martin Kavaliers, Klaus-Peter Ossenkopp, Sexually dimorphic effects of prenatal exposure to lipopolysaccharide, and prenatal and postnatal exposure to propionic acid, on acoustic startle response and prepulse inhibition in adolescent rats: Relevance to autism spectrum disorders, behavioral Brain Research

Kelly A. Foley, Derrick F. MacFabe, Alisha Vaz, Klaus-Peter Ossenkopp, Martin Kavaliers, Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: Implications for autism spectrum disorders, International Journal of Developmental Neuroscience, Volume 39, December 2014, Pages 68-78

Nankova BB, Agarwal R, MacFabe DF, La Gamma EF. Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders. 2014 Aug 29;9(8):e103740. doi: 0.1371/journal.pone.0103740. eCollection 2014.

Foley KA, Macfabe DF, Vaz A, Ossenkopp KP, Kavaliers M. Sexually dimorphic effects of prenatal exposure to propionic acid and lipopolysaccharide on social behavior in neonatal, adolescent, and adult rats: Implications for autism spectrum disorders. Int J Dev Neurosci. 2014 Apr 18. pii: S0736-5748(14)00055-0. doi: 10.1016/j.ijdevneu.2014.04.001

MacFabe, D.F. Autism: Metabolism, Mitochondria, and the Microbiome Global Adv Health Med. 2013;2(6):52-66. DOI:10.7453/gahmj.2013.089

Frye RE, Rossignol D, Casanova MF, Brown GL, Martin V, Edelson S, Coben R, Lewine J, Slattery JC, Lau C, Hardy P, Fatemi SH, Folsom TD, MacFabe D and Adams JB (2013) A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front. Public Health 1:31. doi: 10.3389/fpubh.2013.00031

Frye RE, Melnyk S, MacFabe DF. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Translational Psychiatry 2013, 3: e220. doi: 10.1038/tp.2012.143

de Theije CG, Wu J, da Silva SL, Kamphuis PJ, Garssen J, Korte SM, Kraneveld AD (2011) Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol.

Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L (2009) Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem 42:1032-1040.

Al-Mosalem OA, El-Ansary A, Attas O, Al-Ayadhi L (2009) Metabolic biomarkers related to energy metabolism in Saudi autistic children. Clin Biochem 42:949-957.

Aneja A, Tierney E (2008) Autism: the role of cholesterol in treatment. Int Rev Psychiatry 20:165-170.

Ashwood P, Van de Water J (2004) Is autism an autoimmune disease? Autoimmun Rev 3:557-562.

Atladottir HO, Thorsen P, Schendel DE, Ostergaard L, Lemcke S, Parner ET (2010) Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study. Arch Pediatr Adolesc Med 164:470-477.

Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de WJ (2008) Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 29:226-231.

Buie T, et al. (2010a) Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125 Suppl 1:S1-18.

Buie T, Fuchs GJ, III, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H (2010b) Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics 125 Suppl 1:S19-S29.

Campbell DB, Buie TM, Winter H, Bauman M, Sutcliffe JS, Perrin JM, Levitt P (2009) Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions. Pediatrics 123:1018-1024.

Careaga M, Van de WJ, Ashwood P (2010) Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics 7:283-292.

Chauhan A, Audhya T, Chauhan V. Brain region-specific glutathione redox imbalance in autism. Neurochem Res 2012; 37: 1681–9.

Chauhan A, Chauhan V (2006) Oxidative stress in autism. Pathophysiology 13:171-181.

El-Ansary A, Al-Daihan S, Al-Dbass A, Al-Ayadhi L (2009) Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children. Clin Biochem.

El-Ansary AK, Ben Bacha AG, Al-Ayadhi LY (2011a) Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia. Lipids Health Dis 10:63.

El-Ansary AK, Ben Bacha AG, Al-Ayadhi LY (2011b) Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia. Lipids Health Dis 10:62.

Fahmy, S.F., El-hamamsy, M.H., Zaki, O.K., Badary, O.A. l-Carnitine supplementation improves the behavioral symptoms in autistic children. Research in Autism Spectrum Disorders; 2013: 7:159–166

Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, Smee DF, Pearce DA, Winter C, Sohr R, Juckel G (2008) Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders. Schizophr Res 99:56-70.

Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ (2004) Relative carnitine deficiency in autism. J Autism Dev Disord 34:615-623.

Finegold SM (2007) Therapy and epidemiology of autism-clostridial spores as key elements. Med Hypotheses.

Finegold SM, et al. (2002) Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis 35:S6-S16.

Finegold SM (2011a) Desulfovibrio species are potentially important in regressive autism. Med Hypotheses 77:270-274.

Finegold SM (2011b) State of the art; microbiology in health and disease. Intestinal bacterial flora in autism. Anaerobe.

Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, Youn E, Summanen PH, Granpeesheh D, Dixon D, Liu M, Molitoris DR, Green JA, III (2010) Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe.

Frye RE (2010) Central tetrahydrobiopterin concentration in neurodevelopmental disorders. Front Neurosci 4:52.

Frye RE, Butler I, Strickland D, Castillo E, Papanicolaou A (2010a) Electroencephalogram discharges in atypical cognitive development. J Child Neurol 25:556-566.

Frye RE, Huffman LC, Elliott GR (2010b) Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics 7:241-249.

Frye RE, Rossignol DA (2011) Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res.

Gargus JJ (2009) Genetic calcium signaling abnormalities in the central nervous system: seizures, migraine, and autism. Ann N Y Acad Sci 1151:133-156. Herbert MR (2005) Large brains in autism: the challenge of pervasive abnormality. Neuroscientist 11:417-440.

Herbert MR (2010) Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 23:103-110.

Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG, Cremer L, Hatchwell E (2006) Autism and environmental genomics. Neurotoxicology 27:671-684.

Hu VW, Nguyen A, Kim KS, Steinberg ME, Sarachana T, Scully MA, Soldin SJ, Luu T, Lee NH (2009) Gene expression profiling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal development and steroid biosynthesis. PLoS ONE 4:e5775.

Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 207–14.

James SJ, Melnyk S, Fuchs G, Reid T, Jernigan S, Pavliv O, Hubanks A, Gaylor DW (2009) Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr 89:425-430.

James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P, Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW (2006) Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet 141:947-956.

Jones LL, McDonald DA, Borum PR (2010) Acylcarnitines: role in brain. Prog Lipid Res 49:61-75.

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 2002; 46: 76–84

Jyonouchi H, Geng L, Streck DL, Toruner GA (2011) 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.

Kayser MA (2008) Inherited metabolic diseases in neurodevelopmental and neurobehavioral disorders. Semin Pediatr Neurol 15:127-131.

Kossoff EH, Zupec-Kania BA, Rho JM (2009) Ketogenic Diets: An Update for Child Neurologists. J Child Neurol.

Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111-116.

Li Z, Dong T, Proschel C, Noble M (2007) Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 5:e35.

MacFabe, D.F. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microbial Ecology in Health & Disease 2012, 23: 19260 MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP (2010) Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: Relevance to autism spectrum disorder. Behav Brain Res.

MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F, Taylor AR, Kavaliers M, Ossenkopp KP (2007) 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 Res 176:149-169.

MacFabe DF, Rodriguez-Capote K, Hoffman JE, Franklin AE, Mohammad-Asef Y, Taylor A, Boon F, Cain D.P., Kavaliers M, Possmayer F, Ossenkopp KP (2008) A novel rodent model of autism: Intraventricular infusions of propionic acid increase locomotor activity and induce neuroinflammation and oxidative stress in discrete regions of adult rat brain. Am J Biochem & Biotech 4:146-166. Manson JE (2008) Prenatal exposure to sex steroid hormones and behavioral/cognitive outcomes. Metabolism 57 Suppl 2:S16-S21.

Meguid NA, Atta HM, Gouda AS, Khalil RO (2008) Role of polyunsaturated fatty acids in the management of Egyptian children with autism. Clin Biochem 41:1044-1048.

Meidenbauer JJ, Mantis JG, Seyfried TN (2011) The EL mouse: a natural model of autism and epilepsy. Epilepsia 52:347-357.

Melnyk S, Fuchs GJ, Schulz E, Lopez M, Kahler SG, Fussell JJ, Bellando J, Pavliv O, Rose S, Seidel L, Gaylor DW, Jill JS (2011) Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism. J Autism Dev Disord.

Nguyen A, Rauch TA, Pfeifer GP, Hu VW (2010) Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J 24:3036-3051.

Ossenkopp K. P., Foley K. A., Gibson J., Fudge M. A., Kavaliers M., Cain D. P. and Macfabe D. F. (2011) Systemic treatment with the enteric bacterial fermentation product, propionic acid, produces both conditioned taste avoidance and conditioned place avoidance in rats. Behav. Brain Res. 227, 134-141.

Palmieri L, Persico AM (2010) Mitochondrial dysfunction in autism spectrum disorders: Cause or effect? Biochim Biophys Acta 1797:1130-1137.

Patterson PH (2011) Maternal infection and immune involvement in autism. Trends Mol Med.

Pessah IN, Seegal RF, Lein PJ, LaSalle J, Yee BK, Van de WJ, Berman RF (2008) Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology 29:532-545.

Rossignol DA, Frye RE (2011) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry.

Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM (2000) Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol 15:429-435.

Sarachana T, Zhou R, Chen G, Manji HK, Hu VW (2010) Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines. Genome Med 2:23.

Shoffner J, Hyams L, Langley GN, Cossette S, Mylacraine L, Dale J, Ollis L, Kuoch S, Bennett K, Aliberti A, Hyland K (2010) Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol 25:429-434.

Shultz SR, Macfabe DF, Martin S, Jackson J, Taylor R, Boon F, Ossenkopp KP, Cain DP (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. Behav Brain Res 200:33-41.

Shultz SR, Macfabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R, Cain DP (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 54:901-911.

Smith RA, Farnworth H, Wright B, Allgar V (2009) Are there more bowel symptoms in children with autism compared to normal children and children with other developmental and neurological disorders?: A case control study. Autism 13:343-355.

Suren P, Bakken IJ, Aase H, Chin R, Gunnes N, Lie KK, et al. Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in norwegian children. Pediatrics 2012; 130: e152–8.

Tamiji J, Crawford DA (2010) The neurobiology of lipid metabolism in autism spectrum disorders. Neurosignals 18:98-112.

Theoharides TC, Doyle R, Francis K, Conti P, Kalogeromitros D (2008) Novel therapeutic targets for autism. Trends Pharmacol Sci 29:375-382.

Thomas, R.H, Meeking, M. M., Mepham, J.R., Tichenoff, L.J., Possmayer, F. Suya Liu and MacFabe, D.F. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J. of Neuroinflammation –accepted May 2012 Thomas RH, Foley KA, Mepham JR, Tichenoff LJ, Possmayer F, Macfabe DF (2010) Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders. J Neurochem 113:515-529.

Tuchman R, Moshe SL, Rapin I (2008) Convulsing toward the pathophysiology of autism. Brain Dev.

Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57:67-81.

Waldman M, Nicholson S, Adilov N, Williams J (2008) Autism prevalence and precipitation rates in California, Oregon, and Washington counties. Arch Pediatr Adolesc Med 162:1026-1034.

Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci 2012; 57: 2096–102.

Wang LW, Tancredi DJ, Thomas DW (2011) The Prevalence of Gastrointestinal Problems in Children Across the United States with Autism Spectrum Disorders from Families with Multiple Affected Members. J Dev Behav Pediatr.

Wei H, Zou H, Sheikh A, Malik M, Dobkin C, Brown T, Li X (2011) IL-6 is increased in the cerebellum of the autistic brain and alters neural cell adhesion, migration and synapse formation. J Neuroinflammation 8:52.

Welch MG, Welch-Horan TB, Anwar M, Anwar N, Ludwig RJ, Ruggiero DA (2005) Brain effects of chronic IBD in areas abnormal in autism and treatment by single neuropeptides secretin and oxytocin. J Mol Neurosci 25:259-274.

Williams B. L., Hornig M., Buie T., Bauman M. L., Cho P. M., Wick I., Bennett A., Jabado O., Hirschberg D. L. and 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, e24585.

Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK (2010) Urinary Metabolic Phenotyping Differentiates Children with Autism from Their Unaffected Siblings and Age-Matched Controls. J Proteome Res.