Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Molecular Psychiatry Open Access 25 November 2022
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Scripts for data-visualization and statistical analysis of correlations, pathway enrichment, and microbiome analysis are available at: https://github.com/jboktor/NHP_MIA_Omics.
Doernberg E, Hollander E. Neurodevelopmental Disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11. CNS Spectr. 2016;21:295–9.
Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z, et al. Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018;67:1–23.
Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, et al. Most genetic risk for autism resides with common variation. Nat Genet. 2014;46:881–5.
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA 2014;311:1770–7.
Gardener H, Spiegelman D, Buka SL. Prenatal risk factors for autism: a comprehensive meta-analysis. Br J Psychiatry. 2009;195:7–14.
Bilbo SD, Block CL, Bolton JL, Hanamsagar R, Tran PK. Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Exp Neurol. 2018;299:241–51.
Bromley RL, Mawer GE, Briggs M, Cheyne C, Clayton-Smith J, García-Fiñana M, et al. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry. 2013;84:637–43.
Roullet FI, Wollaston L, Decatanzaro D, Foster JA. Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience 2010;170:514–22.
Coretti L, Cristiano C, Florio E, Scala G, Lama A, Keller S, et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. Sci Rep. 2017;7:srep45356.
Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451–63.
Lim JS, Lim MY, Choi Y, Ko G. Modeling environmental risk factors of autism in mice induces IBD-related gut microbial dysbiosis and hyperserotonemia. Mol Brain. 2017;10:14.
Liu F, Horton-Sparks K, Hull V, Li RW, Martínez-Cerdeño V. The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism. Mol Autism. 2018;9:61.
Tabouy L, Getselter D, Ziv O, Karpuj M, Tabouy T, Lukic I, et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav Immun. 2018;73:310–9.
Pulikkan J, Mazumder A, Grace T. Role of the gut microbiome in autism spectrum disorders. Adv Exp Med Biol. 2019;1118:253–69.
Sharon G, Cruz NJ, Kang D-W, Gandal MJ, Wang B, Kim Y-M, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 2019;177:1600–18.e17.
Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012;26:607–16.
Haida O, Al Sagheer T, Balbous A, Francheteau M, Matas E, Soria F, et al. Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism. Transl Psychiatry. 2019;9:1–12.
Amodeo DA, Lai C-Y, Hassan O, Mukamel EA, Behrens MM, Powell SB. Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex. Neurobiol Dis. 2019;125:211–8.
Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, Ashwood P. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Transl Psychiatry. 2013;3:e240.
Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27:10695–702.
Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 2016;351:933–9.
Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci. 2012;109:12776–81.
Lammert CR, Frost EL, Bolte AC, Paysour MJ, Shaw ME, Bellinger CE, et al. Cutting edge: critical roles for microbiota-mediated regulation of the immune system in a prenatal immune activation model of autism. J Immunol. 2018;201:845–50.
A Hypothesis-Based Approach: The Use of Animals in Mental Health Research. Natl Inst Ment Health NIMH. https://www.nimh.nih.gov/about/director/messages/2019/a-hypothesis-based-approach-the-use-of-animals-in-mental-health-research. Accessed 23 June 2022.
Lombardo MV, Moon HM, Su J, Palmer TD, Courchesne E, Pramparo T. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol Psychiatry. 2018;23:1001–13.
Shi L, Smith SEP, Malkova N, Tse D, Su Y, Patterson PH. Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav Immun. 2009;23:116–23.
Corradini I, Focchi E, Rasile M, Morini R, Desiato G, Tomasoni R, et al. Maternal immune activation delays excitatory-to-inhibitory gamma-aminobutyric acid switch in offspring. Biol Psychiatry. 2018;83:680–91.
Li Y, Missig G, Finger BC, Landino SM, Alexander AJ, Mokler EL, et al. Maternal and early postnatal immune activation produce dissociable effects on Neurotransmission in mPFC–amygdala circuits. J Neurosci. 2018;38:3358–72.
Bergdolt L, Dunaevsky A. Brain changes in a maternal immune activation model of neurodevelopmental brain disorders. Prog Neurobiol. 2019;175:1–19.
Careaga M, Murai T, Bauman MD. Maternal immune activation and autism spectrum disorder: From rodents to nonhuman and human primates. Biol Psychiatry. 2017;81:391–401.
Bauman MD, Iosif A-M, Smith SEP, Bregere C, Amaral DG, Patterson PH. Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring. Biol Psychiatry. 2014;75:332–41.
Machado CJ, Whitaker AM, Smith SEP, Patterson PH, Bauman MD. Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol Psychiatry. 2015;77:823–32.
Willette AA, Lubach GR, Knickmeyer RC, Short SJ, Styner M, Gilmore JH, et al. Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia. Behav Brain Res. 2011;219:108–15.
Rose DR, Careaga M, Van de Water J, McAllister K, Bauman MD, Ashwood P. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun. 2017;63:60–70.
Short SJ, Lubach GR, Karasin AI, Olsen CW, Styner M, Knickmeyer RC, et al. Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey. Biol Psychiatry. 2010;67:965–73.
Vlasova RM, Iosif A-M, Ryan AM, Funk LH, Murai T, Chen S, et al. Maternal immune activation during pregnancy alters postnatal brain growth and cognitive development in nonhuman primate offspring. J Neurosci. 2021;41:9971–87.
Bauman MD, Lesh TA, Rowland DJ, Schumann CM, Smucny J, Kukis DL, et al. Preliminary evidence of increased striatal dopamine in a nonhuman primate model of maternal immune activation. Transl Psychiatry. 2019;9:1–8.
Weir RK, Forghany R, Smith SEP, Patterson PH, McAllister AK, Schumann CM, et al. Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. Brain Behav Immun. 2015;48:139–46.
Garbett KA, Hsiao EY, Kálmán S, Patterson PH, Mirnics K. Effects of maternal immune activation on gene expression patterns in the fetal brain. Transl Psychiatry. 2012;2:e98.
Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav Immun. 2012;26:623–34.
Adams JB, Vargason T, Kang D-W, Krajmalnik-Brown R, Hahn J. Multivariate analysis of plasma metabolites in children with autism spectrum disorder and gastrointestinal symptoms before and after microbiota transfer therapy. Processes. 2019;7:806.
Bitar T, Mavel S, Emond P, Nadal-Desbarats L, Lefèvre A, Mattar H, et al. Identification of metabolic pathway disturbances using multimodal metabolomics in autistic disorders in a Middle Eastern population. J Pharm Biomed Anal. 2018;152:57–65.
Gevi F, Zolla L, Gabriele S, Persico AM. Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism. Mol Autism. 2016;7:47.
Kang D-W, Ilhan ZE, Isern NG, Hoyt DW, Howsmon DP, Shaffer M, et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe 2018;49:121–31.
Kuwabara H, Yamasue H, Koike S, Inoue H, Kawakubo Y, Kuroda M, et al. Altered metabolites in the plasma of autism spectrum disorder: a capillary electrophoresis time-of-flight mass spectroscopy study. PloS One. 2013;8:e73814.
Lussu M, Noto A, Masili A, Rinaldi AC, Dessì A, Angelis MD, et al. The urinary 1H-NMR metabolomics profile of an italian autistic children population and their unaffected siblings. Autism Res. 2017;10:1058–66.
Orozco JS, Hertz-Picciotto I, Abbeduto L, Slupsky CM. Metabolomics analysis of children with autism, idiopathic-developmental delays, and Down syndrome. Transl Psychiatry. 2019;9:243.
West PR, Amaral DG, Bais P, Smith AM, Egnash LA, Ross ME, et al. Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PLoS ONE. 2014;9:e112445.
Yap IKS, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010;9:2996–3004.
Smith AM, King JJ, West PR, Ludwig MA, Donley ELR, Burrier RE, et al. Amino acid dysregulation metabotypes: potential biomarkers for diagnosis and individualized treatment for subtypes of autism spectrum disorder. Biol Psychiatry. 2019;85:345–54.
Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori F, et al. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomark Biochem Indic Expo Response Susceptibility Chem. 2011;16:252–60.
Emond P, Mavel S, Aïdoud N, Nadal-Desbarats L, Montigny F, Bonnet-Brilhault F, et al. GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal Bioanal Chem. 2013;405:5291–300.
Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, et al. Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study. Biomark Biochem Indic Expo Response Susceptibility Chem. 2014;19:463–70.
Lis AW, Mclaughlin I, Mpclaughlin RK, Lis EW, Stubbs EG. Profiles of ultraviolet-absorbing components of urine from autistic children, as obtained by high-resolution ion-exchange chromatography. Clin Chem. 1976;22:1528–32.
Nadal-Desbarats L, Aïdoud N, Emond P, Blasco H, Filipiak I, Sarda P, et al. Combined 1 H-NMR and 1 H– 13 C HSQC-NMR to improve urinary screening in autism spectrum disorders. Analyst 2014;139:3460–8.
El-Ansary A, Al-Ayadhi L. Lipid mediators in plasma of autism spectrum disorders. Lipids Health Dis. 2012;11:160.
El-Ansary AK, Bacha AGB, Al-Ayahdi LY. Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia. Lipids Health Dis. 2011;10:63.
James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80:1611–7.
Lv Q-Q, You C, Zou X-B, Deng H-Z. Acyl-carnitine, C5DC, and C26 as potential biomarkers for diagnosis of autism spectrum disorder in children. Psychiatry Res. 2018;267:277–80.
Mostafa GA, AL-Ayadhi LY. Reduced levels of plasma polyunsaturated fatty acids and serum carnitine in autistic children: relation to gastrointestinal manifestations. Behav Brain Funct BBF. 2015;11:4.
Pastural E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, et al. Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism. Prostaglandins Leukot Ess Fat Acids. 2009;81:253–64.
Wang H, Liang S, Wang M, Gao J, Sun C, Wang J, et al. Potential serum biomarkers from a metabolomics study of autism. J Psychiatry Neurosci. 2016;41:27–37.
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.
Cheng N, Rho JM, Masino SA. Metabolic dysfunction underlying autism spectrum disorder and potential treatment approaches. Front Mol Neurosci. 2017;10:34.
Azhari A, Azizan F, Esposito G. A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder. Dev Psychobiol. 2018. https://doi.org/10.1002/dev.21803.
Cozzolino R, De Magistris L, Saggese P, Stocchero M, Martignetti A, Di Stasio M, et al. Use of solid-phase microextraction coupled to gas chromatography–mass spectrometry for determination of urinary volatile organic compounds in autistic children compared with healthy controls. Anal Bioanal Chem. 2014;406:4649–62.
Ming X, Stein TP, Barnes V, Rhodes N, Guo L. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. 2012;11:5856–62.
Noto A, Fanos V, Barberini L, Grapov D, Fattuoni C, Zaffanello M, et al. The urinary metabolomics profile of an Italian autistic children population and their unaffected siblings. J Matern-Fetal Neonatal Med J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2014;27 Suppl 2:46–52.
Shaw W, Kassen E, Chaves E. Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clin Chem. 1995;41:1094–104.
Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB, et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Transl Psychiatry. 2014;4:e400–e400.
Krijthe J, van der Maaten L, Krijthe MJ Package ‘Rtsne’. GitHub; 2018.
Xia J, Mandal R, Sinelnikov IV, Broadhurst D, Wishart DS. MetaboAnalyst 2.0—a comprehensive server for metabolomic data analysis. Nucleic Acids Res. 2012;40:W127–33.
Dixon P. VEGAN, a package of R functions for community ecology. J Veg Sci. 2003;14:927–30.
McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLOS ONE. 2013;8:e61217.
Mallick H, Rahnavard A, McIver LJ, Ma S, Zhang Y, Nguyen LH, et al. Multivariable association discovery in population-scale meta-omics studies. PLOS Computational. Biol. 2021;17:e1009442.
Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp Neurol. 2015;273:57–68.
Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015;16:445–57.
Wishart DS, Lewis MJ, Morrissey JA, Flegel MD, Jeroncic K, Xiong Y, et al. The human cerebrospinal fluid metabolome. J Chromatogr B Anal Technol Biomed Life Sci. 2008;871:164–73.
Perry TL, Jones RT. The amino acid content of human cerebrospinal fluid in normal individuals and in mental defectives. J Clin Invest. 1961;40:1363–72.
Mason S, Reinecke CJ, Solomons R. Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis. Front Neurosci. 2017;11:534.
Billard J-M. D-Amino acids in brain neurotransmission and synaptic plasticity. Amino Acids. 2012;43:1851–60.
Sonnenburg JL, Bäckhed F. Diet–microbiota interactions as moderators of human metabolism. Nature 2016;535:56–64.
Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 2017;549:528–32.
Strati F, Cavalieri D, Albanese D, De Felice C, Donati C, Hayek J, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017;5:24.
De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PloS One. 2013;8:e76993.
Luna RA, Oezguen N, Balderas M, Venkatachalam A, Runge JK, Versalovic J, et al. Distinct microbiome-neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell Mol Gastroenterol Hepatol. 2017;3:218–30.
Iglesias-Vázquez L, Van Ginkel Riba G, Arija V, Canals J. Composition of gut microbiota in children with autism spectrum disorder: a systematic review and meta-analysis. Nutrients 2020;12:792.
Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, et al. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res. 2013;57:523–35.
Koppel N, Rekdal VM, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science 2017;356:eaag2770.
Obrenovich M, Flückiger R, Sykes L, Donskey C. The co-metabolism within the gut-brain metabolic interaction: potential targets for drug treatment and design. CNS Neurol Disord Drug Targets. 2016;15:127–34.
Karasov WH. Integrative physiology of transcellular and paracellular intestinal absorption. J Exp Biol. 2017;220:2495–501.
Naviaux RK, Zolkipli Z, Wang L, Nakayama T, Naviaux JC, Le TP, et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PloS One. 2013;8:e57380.
Fumagalli M, Lecca D, Abbracchio MP, Ceruti S. Pathophysiological role of purines and pyrimidines in neurodevelopment: unveiling new pharmacological approaches to congenital brain diseases. Front Pharmacol. 2017;8:941.
Page T, Coleman M. Purine metabolism abnormalities in a hyperuricosuric subclass of autism. Biochim Biophys Acta. 2000;1500:291–6.
Guimarães-Souza EM, Joselevitch C, Britto LRG, Chiavegatto S. Retinal alterations in a pre-clinical model of an autism spectrum disorder. Mol Autism. 2019;10:19.
Pavăl D, Rad F, Rusu R, Niculae A-Ş, Colosi HA, Dobrescu I, et al. Low retinal dehydrogenase 1 (RALDH1) level in prepubertal boys with autism spectrum disorder: a possible link to dopamine dysfunction? Clin Psychopharmacol Neurosci. 2017;15:229–36.
Zhang X, Piano I, Messina A, D’Antongiovanni V, Crò F, Provenzano G, et al. Retinal defects in mice lacking the autism-associated gene Engrailed-2. Neuroscience 2019;408:177–90.
Wang YH, Wang DW, Wu N, Wang Y, Yin ZQ. Alpha-crystallin promotes rat retinal neurite growth on myelin substrates in vitro. Ophthalmic Res. 2011;45:164–8.
Hoffmann GF, Meier-Augenstein W, Stöckler S, Surtees R, Rating D, Nyhan WL. Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis. 1993;16:648–69.
Oztan O, Garner JP, Constantino JN, Parker KJ. Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder. Proc Natl Acad Sci. 2020;117:10609–13.
Stoessel D, Schulte C, Teixeira dos Santos MC, Scheller D, Rebollo-Mesa I, Deuschle C, et al. Promising metabolite profiles in the plasma and CSF of early clinical Parkinson’s disease. Front Aging Neurosci. 2018;10:51.
Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Cerebrospinal fluid biochemical studies in patients with Parkinson’s disease: toward a potential search for biomarkers for this disease. Front Cell Neurosci. 2014;8:369.
Czech C, Berndt P, Busch K, Schmitz O, Wiemer J, Most V, et al. Metabolite profiling of alzheimer’s disease cerebrospinal fluid. PLOS ONE. 2012;7:e31501.
Loomes R, Hull L, Mandy WPL. What is the male-to-female ratio in autism spectrum disorder? a systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56:466–74.
Castro K, Baronio D, Perry IS, Riesgo R, dos S, Gottfried C. The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid. Nutr Neurosci. 2017;20:343–50.
IJff DM, Postulart D, Lambrechts DAJE, Majoie MHJM, de Kinderen RJA, Hendriksen JGM, et al. Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial. Epilepsy Behav. 2016;60:153–7.
Ruskin DN, Murphy MI, Slade SL, Masino SA. Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder. PLOS ONE. 2017;12:e0171643.
Spilioti M, Evangeliou A, Tramma D, Theodoridou Z, Metaxas S, Michailidi E, et al. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci. 2013;7:858.
Cermak SA, Curtin C, Bandini LG. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J Am Diet Assoc. 2010;110:238–46.
Jaglin M, Rhimi M, Philippe C, Pons N, Bruneau A, Goustard B, et al. Indole, a signaling molecule produced by the gut microbiota, negatively impacts emotional behaviors in rats. Front Neurosci. 2018;12:216.
O’Connor JC, Lawson MA, André C, Moreau M, Lestage J, Castanon N, et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 2009;14:511–22.
Tian P, Wang G, Zhao J, Zhang H, Chen W. Bifidobacterium with the role of 5-hydroxytryptophan synthesis regulation alleviates the symptom of depression and related microbiota dysbiosis. J Nutr Biochem. 2019;66:43–51.
Wang D, Ho L, Faith J, Ono K, Janle EM, Lachcik PJ, et al. Role of intestinal microbiota in the generation of polyphenol-derived phenolic acid mediated attenuation of Alzheimer’s disease β-amyloid oligomerization. Mol Nutr Food Res. 2015;59:1025–40.
Reay WR, Cairns MJ. The role of the retinoids in schizophrenia: genomic and clinical perspectives. Mol Psychiatry. 2020;25:706–18.
Baranova J, Dragunas G, Botellho MCS, Ayub ALP, Bueno-Alves R, Alencar RR, et al. Autism spectrum disorder: signaling pathways and prospective therapeutic targets. Cell Mol Neurobiol. 2020. https://doi.org/10.1007/s10571-020-00882-7.
Lai X, Wu X, Hou N, Liu S, Li Q, Yang T, et al. Vitamin A deficiency induces autistic-like behaviors in rats by regulating the RARβ-CD38-oxytocin axis in the hypothalamus. Mol Nutr Food Res. 2018;62:5.
Bent S, Lawton B, Warren T, Widjaja F, Dang K, Fahey JW, et al. Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Mol Autism. 2018;9:35.
Diémé B, Mavel S, Blasco H, Tripi G, Bonnet-Brilhault F, Malvy J, et al. Metabolomics Study of Urine in Autism Spectrum Disorders Using a Multiplatform Analytical Methodology. J Proteome Res. 2015;14:5273–82.
Kałużna-Czaplińska J, Żurawicz E, Struck W, Markuszewski M. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2014;966:70–6.
Johannsen WJ, Friedman SH, Feldman EI, Negrete A. A re-examination of the hippuric acid—anxiety relationship. Psychosom Med. 1962;24:569.
Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, et al. Plasma and fecal metabolite profiles in autism spectrum disorder. Biol Psychiatry. 2020. https://doi.org/10.1016/j.biopsych.2020.09.025.
Frye RE, Melnyk S, MacFabe DF. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry. 2013;3:e220.
Naviaux RK, Curtis B, Li K, Naviaux JC, Bright AT, Reiner GE, et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Ann Clin Transl Neurol. 2017;4:491–505.
Li Q, Zhang C. A metabolome study on 90 autism spectrum disorder patients by mass spectrometry. Med Mass Spectrom. 2017;1:14–9.
Aydın Hİ, Sönmez FM. A novel mutation in two cousins with guanidinoacetate methyltransferase (GAMT) deficiency presented with autism. Turk J Pediatr. 2019;61:92–6.
Cameron JM, Levandovskiy V, Roberts W, Anagnostou E, Scherer S, Loh A, et al. Variability of creatine metabolism genes in children with autism spectrum disorder. Int J Mol Sci. 2017;18:1665.
Schulze A, Bauman M, Tsai AC-H, Reynolds A, Roberts W, Anagnostou E, et al. Prevalence of creatine deficiency syndromes in children with nonsyndromic autism. Pediatrics. 2016;137:1.
Rose S, Niyazov DM, Rossignol DA, Goldenthal M, Kahler SG, Frye RE. Clinical and molecular characteristics of mitochondrial dysfunction in autism spectrum disorder. Mol Diagn Ther. 2018;22:571–93.
Sotnikova TD, Beaulieu J-M, Espinoza S, Masri B, Zhang X, Salahpour A, et al. The dopamine metabolite 3-methoxytyramine is a neuromodulator. PloS One. 2010;5:e13452.
Nakazato T. The medial prefrontal cortex mediates 3-methoxytyramine-induced behavioural changes in rat. Eur J Pharm. 2002;442:73–9.
Frye RE. Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. Epilepsy Behav EB. 2015;47:147–57.
Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, et al. Plasma and fecal metabolite profiles in autism spectrum disorder. BioRxiv. 2020:2020.05.17.098806.
Jin Y, Yan E, Li X, Fan Y, Zhao Y, Liu Z, et al. Neuroprotective effect of sodium ferulate and signal transduction mechanisms in the aged rat hippocampus. Acta Pharm Sin. 2008;29:1399–408.
Aabed K, Bhat RS, Al-Dbass A, Moubayed N, Algahtani N, Merghani NM, et al. Bee pollen and propolis improve neuroinflammation and dysbiosis induced by propionic acid, a short chain fatty acid in a rodent model of autism. Lipids Health Dis. 2019;18:200.
We thank the veterinary and animal services staff of the CNPRC for care of the animals. Poly ICLC was kindly provided by Dr. Andres Salazar, MD, Oncovir, Washington D.C.
This work was supported by grants from Autism Speaks (Grant #7567 to PA, and SKM); the Johnson Foundation (to PA); the Brain Foundation (to PA and to SKM); NARSAD Foundation (to PA); Axial Biotherapeutics (to SKM); and the National Institutes of Health (HD090214 to PA) and (MH100556 to SKM). Development of the animal model was supported by a grant from the Simons Foundation to the late Dr. Paul Patterson (SFARI 9900060), with additional support provided by the base grant (RR00169) of the California National Primate Research Center (CNPRC), a gift from Ted and Ginger Jenkins and a UC Davis RISE Award (to PA and MB).
SKM has financial interest in Axial Biotherapeutics. JCB, MDA, DRR, CMS, KDM, MDB, MC, PA, and BDN report no financial conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Boktor, J.C., Adame, M.D., Rose, D.R. et al. Global metabolic profiles in a non-human primate model of maternal immune activation: implications for neurodevelopmental disorders. Mol Psychiatry 27, 4959–4973 (2022). https://doi.org/10.1038/s41380-022-01752-y
This article is cited by
Molecular Psychiatry (2023)