Diet in treatment of autism spectrum disorders

Sabiha Alam, Cara J Westmark, Elizabeth A McCullagh, Sabiha Alam, Cara J Westmark, Elizabeth A McCullagh

Abstract

Altering the diet to treat disease dates to c. 400 BC when starvation was used to reduce seizures in persons with epilepsy. The current diversity of symptomology and mechanisms underlying autism spectrum disorders (ASDs) and a corresponding lack of disorder-specific effective treatments prompts an evaluation of diet as a therapeutic approach to improve symptoms of ASDs. In this review article, we summarize the main findings of nutritional studies in ASDs, with an emphasis on the most common monogenic cause of autism, Fragile X Syndrome (FXS), and the most studied dietary intervention, the ketogenic diet as well as other dietary interventions. We also discuss the gut microbiota in relation to pre- and probiotic therapies and provide insight into future directions that could aid in understanding the mechanism(s) underlying dietary efficacy.

Keywords: Fragile X Syndrome; autism spectrum disorders; diet; intervention; ketogenic; prebiotic; probiotic.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2023 Alam, Westmark and McCullagh.

References

    1. Aabed K., Bhat R. S., Al-Dbass A., Moubayed N., Algahtani N., Merghani N. M., et al. (2019). 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. 18:200. 10.1186/s12944-019-1150-0
    1. Abdellatif B., McVeigh C., Bendriss G., Chaari A. (2020). The promising role of probiotics in managing the altered gut in autism spectrum disorders. Int. J. Mol. Sci. 21:E4159. 10.3390/ijms21114159
    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 Gastroenterol. 11:22. 10.1186/1471-230X-11-22
    1. Ahn Y., Narous M., Tobias R., Rho J. M., Mychasiuk R. (2014). The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder. DNE 36 371–380. 10.1159/000362645
    1. Ahn Y., Sabouny R., Villa B. R., Yee N. C., Mychasiuk R., Uddin G. M., et al. (2020). Aberrant mitochondrial morphology and function in the BTBR mouse model of autism is improved by two weeks of ketogenic diet. Int. J. Mol. Sci. 21:3266. 10.3390/ijms21093266
    1. Altimiras F., Garcia J. A., Palacios-García I., Hurley M. J., Deacon R., González B., et al. (2021). Altered gut microbiota in a fragile X syndrome mouse model. Front. Neurosci. 15:653120. 10.3389/fnins.2021.653120
    1. Amiet C., Gourfinkel-An I., Bouzamondo A., Tordjman S., Baulac M., Lechat P., et al. (2008). Epilepsy in autism is associated with intellectual disability and gender: Evidence from a meta-analysis. Biol. Psychiatry 64 577–582. 10.1016/j.biopsych.2008.04.030
    1. Arqoub A. M. S., Flynn K. G., Martinez L. A. (2020). Gestational exposure to a ketogenic diet increases sociability in CD-1 mice. Behav. Neurosci. 134 358–368. 10.1037/bne0000368
    1. Augustin K., Khabbush A., Williams S., Eaton S., Orford M., Cross J. H., et al. (2018). Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol. 17 84–93. 10.1016/S1474-4422(17)30408-8
    1. Bagni C., Zukin R. S. (2019). A synaptic perspective of fragile x syndrome and autism spectrum disorders. Neuron 101 1070–1088. 10.1016/j.neuron.2019.02.041
    1. Balietti M., Casoli T., Di Stefano G., Giorgetti B., Aicardi G., Fattoretti P. (2010). Ketogenic diets: An historical antiepileptic therapy with promising potentialities for the aging brain. Ageing Res. Rev. 9 273–279. 10.1016/j.arr.2010.02.003
    1. Barnhill K., Devlin M., Moreno H. T., Potts A., Richardson W., Schutte C., et al. (2020). Brief report: Implementation of a specific carbohydrate diet for a child with autism spectrum disorder and fragile X Syndrome. J Autism Dev. Disord. 50 1800–1808. 10.1007/s10803-018-3704-9
    1. Bertuccioli A., Cardinali M., Di Pierro F., Zonzini G. B., Matera M. R. (2022). Ketogenic and low FODMAP diet in therapeutic management of a young autistic patient with epilepsy and dysmetabolism poorly responsive to therapies: Clinical response and effects of intestinal microbiota. Int. J. Mol. Sci. 23:8829. 10.3390/ijms23158829
    1. Billeci L., Callara A. L., Guiducci L., Prosperi M., Morales M. A., Calderoni S., et al. (2022). A randomized controlled trial into the effects of probiotics on electroencephalography in preschoolers with autism. Autism:13623613221082710. 10.1177/13623613221082710
    1. Bledsoe R., Smith B., Simpson R. L. (2003). Use of a social story intervention to improve mealtime skills of an adolescent with asperger syndrome. Autism 7 289–295. 10.1177/1362361303007003005
    1. Boison D. (2017). New insights into the mechanisms of the ketogenic diet. Curr. Opin. Neurol. 30 187–192. 10.1097/WCO.0000000000000432
    1. Borre Y. E., O’Keeffe G. W., Clarke G., Stanton C., Dinan T. G., Cryan J. F. (2014). Microbiota and neurodevelopmental windows: Implications for brain disorders. Trends Mol. Med. 20 509–518. 10.1016/j.molmed.2014.05.002
    1. Bostock E., Kirkby K. C., Taylor B. V. (2017). The current status of the ketogenic diet in psychiatry. Front. Psychiatry 8:43. 10.3389/fpsyt.2017.00043
    1. Budimirovic D. B., Kaufmann W. E. (2011). What can we learn about autism from studying fragile X Syndrome? Dev. Neurosci. 33 379–394. 10.1159/000330213
    1. Castro K., Baronio D., Perry I. S., Riesgo R., dos S., Gottfried C. (2017). The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid. Nutr. Neurosci. 20 343–350. 10.1080/1028415X.2015.1133029
    1. Cekici H., Sanlier N. (2019). Current nutritional approaches in managing autism spectrum disorder: A review. Nutr. Neurosci. 22 145–155. 10.1080/1028415X.2017.1358481
    1. Cheng N., Rho J., Masino S. (2017). Metabolic dysfunction underlying autism spectrum disorder and potential treatment approaches. Front. Mol. Neurosci. 10:34. 10.3389/fnmol.2017.00034
    1. Ciaccio C., Fontana L., Milani D., Tabano S., Miozzo M., Esposito S. (2017). Fragile X syndrome: A review of clinical and molecular diagnoses. Ital. J. Pediatr. 43:39. 10.1186/s13052-017-0355-y
    1. Dai Y., Zhao Y., Tomi M., Shin B.-C., Thamotharan S., Mazarati A., et al. (2017). Sex-specific life course changes in the neuro-metabolic phenotype of Glut3 null heterozygous mice: Ketogenic diet ameliorates electroencephalographic seizures and improves sociability. Endocrinology 158 936–949. 10.1210/en.2016-1816
    1. Davani-Davari D., Negahdaripour M., Karimzadeh I., Seifan M., Mohkam M., Masoumi S. J., et al. (2019). Prebiotics: Definition, types, sources, mechanisms, and clinical applications. Foods 892. 10.3390/foods8030092
    1. de Diego-Otero Y., Romero-Zerbo Y., el Bekay R., Decara J., Sanchez L., Fonseca F. R., et al. (2009). α-Tocopherol protects against oxidative stress in the fragile X knockout mouse: An experimental therapeutic approach for the Fmr1 deficiency. Neuropsychopharmacol 34 1011–1026. 10.1038/npp.2008.152
    1. Dinan T. G., Stilling R. M., Stanton C., Cryan J. F. (2015). Collective unconscious: How gut microbes shape human behavior. J. Psychiatr. Res. 63 1–9. 10.1016/j.jpsychires.2015.02.021
    1. El-Ansary A., Bacha A. B., Bjørklund G., Al-Orf N., Bhat R. S., Moubayed N., et al. (2018). Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile hamsters induced by orally administered propionic acid and clindamycin. Metab. Brain Dis. 33 1155–1164. 10.1007/s11011-018-0212-8
    1. El-Rashidy O., El-Baz F., El-Gendy Y., Khalaf R., Reda D., Saad K. (2017). Ketogenic diet versus gluten free casein free diet in autistic children: A case-control study. Metab. Brain Dis. 32 1935–1941. 10.1007/s11011-017-0088-z
    1. Evangeliou A., Vlachonikolis I., Mihailidou H., Spilioti M., Skarpalezou A., Makaronas N., et al. (2003). Application of a ketogenic diet in children with autistic behavior: Pilot study. J. Child Neurol. 18 113–118. 10.1177/08830738030180020501
    1. Feng K., Zhao Y., Yu Q., Deng J., Wu J., Liu L. (2021). Can probiotic supplements improve the symptoms of autism spectrum disorder in children? Medicine (Baltimore) 100:e18621. 10.1097/MD.0000000000018621
    1. Freche D., Lee C.-Y., Rouach N., Holcman D. (2012). Synaptic transmission in neurological disorders dissected by a quantitative approach. Commun. Integr. Biol. 5 448–452. 10.4161/cib.20818
    1. Frye R. E., Cakir J., Rose S., Palmer R. F., Austin C., Curtin P., et al. (2021). Mitochondria may mediate prenatal environmental influences in autism spectrum disorder. J. Pers. Med. 11218. 10.3390/jpm11030218
    1. Frye R. E., Melnyk S., Fuchs G., Reid T., Jernigan S., Pavliv O., et al. (2013). Effectiveness of methylcobalamin and folinic acid treatment on adaptive behavior in children with autistic disorder is related to glutathione redox status. Autism Res. Treat. 2013:e609705. 10.1155/2013/609705
    1. Frye R. E., Sreenivasula S., Adams J. (2011). Traditional and non-traditional treatments for autism spectrum disorder with seizures: An on-line survey. BMC Pediatr. 11:37. 10.1186/1471-2431-11-37
    1. Garber K. B., Visootsak J., Warren S. T. (2008). Fragile X syndrome. Eur. J. Hum. Genet. 16 666–672. 10.1038/ejhg.2008.61
    1. Garcia-Gutierrez E., Narbad A., Rodríguez J. M. (2020). Autism spectrum disorder associated with gut microbiota at immune, metabolomic, and neuroactive level. Front. Neurosci. 14:578666. 10.3389/fnins.2020.578666
    1. Garcia-Penas J. J. (2016). Autism spectrum disorder and epilepsy: The role of ketogenic diet. Rev. Neurol. 62 Suppl 1 S73–S78.
    1. Geraghty M. E., Bates-Wall J., Ratliff-Schaub K., Lane A. E. (2010). Nutritional interventions and therapies in autism: A spectrum of what we know: Part 2. ICAN Infant Child Adolesc. Nutr. 2 120–133. 10.1177/1941406410366848
    1. Gialloreti L., Mazzone L., Benvenuto A., Fasano A., Garcia Alcon A., Kraneveld A., et al. (2019). Risk and protective environmental factors associated with autism spectrum disorder: Evidence-based principles and recommendations. J. Clin. Med. 8:217. 10.3390/jcm8020217
    1. Gibson G. R., Roberfroid M. B. (1995). Dietary modulation of the human colonic microbiota: Introducing the concept of prebiotics. J. Nutr. 125 1401–1412. 10.1093/jn/125.6.1401
    1. Goo N., Bae H. J., Park K., Kim J., Jeong Y., Cai M., et al. (2020). The effect of fecal microbiota transplantation on autistic-like behaviors in Fmr1 KO mice. Life Sci. 262118497. 10.1016/j.lfs.2020.118497
    1. Gottschall E. (1994). Breaking the vicious cycle: Intestinal health through diet. Ontario: Kirkton Press.
    1. Gottschall E. (2004). Digestion-gut-autism connection: The specific carbohydrate diet. Med. Veritas 1. 2 261–271.
    1. Greener M. (2014). Food for thought: The ketogenic diet for epilepsy. Progress Neurol. Psychiatry 18 6–9. 10.1002/pnp.329
    1. Grimaldi R., Gibson G. R., Vulevic J., Giallourou N., Castro-Mejía J. L., Hansen L. H., et al. (2018). A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome 6:133. 10.1186/s40168-018-0523-3
    1. Grossi E., Melli S., Dunca D., Terruzzi V. (2016). Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics. SAGE Open Med. Case Rep. 4:2050313X16666231. 10.1177/2050313X16666231
    1. Hagerman R. J. (2013). Epilepsy drives autism in neurodevelopmental disorders. Dev. Med. Child Neurol. 55, 101–102. 10.1111/dmcn.12071
    1. Hagerman R. J., Hagerman P. J. (2002). Fragile X Syndrome: Diagnosis, treatment and research. Baltimore: Johns Hopkins University Press.
    1. Hagerman R., Au J., Hagerman P. (2011). FMR1 premutation and full mutation molecular mechanisms related to autism. J. Neurodev. Disord. 3 211–224. 10.1007/s11689-011-9084-5
    1. Hagmeyer S., Haderspeck J. C., Grabrucker A. M. (2015). Behavioral impairments in animal models for zinc deficiency. Front. Behav. Neurosci. 8:443. 10.3389/fnbeh.2014.00443
    1. Hartley-McAndrew M. E., Weinstock A. (2010). Autism spectrum disorder: Correlation between aberrant behaviors, EEG abnormalities and seizures. Neurol. Int. 2e10. 10.4081/ni.2010.e10
    1. Hemarajata P., Versalovic J. (2013). Effects of probiotics on gut microbiota: Mechanisms of intestinal immunomodulation and neuromodulation. Therap. Adv. Gastroenterol. 6 39–51. 10.1177/1756283X12459294
    1. Herbert M., Buckley J. (2013). Autism and dietary therapy: Case report and review of the literature. J. Child Neurol. 28 975–982. 10.1177/0883073813488668
    1. Hsiao E. Y., McBride S. W., Hsien S., Sharon G., Hyde E. R., McCue T., et al. (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155 1451–1463. 10.1016/j.cell.2013.11.024
    1. Iovene M. R., Bombace F., Maresca R., Sapone A., Iardino P., Picardi A., et al. (2017). Intestinal dysbiosis and yeast isolation in stool of subjects with autism spectrum disorders. Mycopathologia 182 349–363. 10.1007/s11046-016-0068-6
    1. Jóźwiak S., Kossoff E. H., Kotulska-Jóźwiak K. (2011). Dietary treatment of epilepsy: Rebirth of an ancient treatment. Neurologia Neurochirurgia Polska 45 370–378. 10.1016/S0028-3843(14)60108-0
    1. Kałużna-Czaplińska J., Błaszczyk S. (2012). The level of arabinitol in autistic children after probiotic therapy. Nutrition 28 124–126. 10.1016/j.nut.2011.08.002
    1. Kantarcioglu A. S., Kiraz N., Aydin A. (2016). Microbiota–gut–brain axis: Yeast species isolated from stool samples of children with suspected or diagnosed autism spectrum disorders and in vitro susceptibility against nystatin and fluconazole. Mycopathologia 181 1–7. 10.1007/s11046-015-9949-3
    1. Karimi P., Kamali E., Mousavi S. M., Karahmadi M. (2017). Environmental factors influencing the risk of autism. J. Res. Med. Sci. 22:27. 10.4103/1735-1995.200272
    1. Kasprowska-Liśkiewicz D., Liśkiewicz A. D., Nowacka-Chmielewska M. M., Nowicka J., Małecki A., Barski J. J. (2017). The ketogenic diet affects the social behavior of young male rats. Physiol. Behav. 179 168–177. 10.1016/j.physbeh.2017.06.007
    1. Kawicka A., Regulska-Ilow B. (2013). How nutritional status, diet and dietary supplements can affect autism. A review. Available online at: (accessed on August 24, 2022).
    1. Kong X.-J., Liu J., Liu K., Koh M., Sherman H., Liu S., et al. (2021). Probiotic and oxytocin combination therapy in patients with autism spectrum disorder: A randomized, double-blinded, placebo-controlled pilot trial. Nutrients 131552. 10.3390/nu13051552
    1. Kossoff E. H., Zupec-Kania B. A., Rho J. M. (2009). Ketogenic diets: An update for child neurologists. J. Child Neurol. 24 979–988. 10.1177/0883073809337162
    1. Leboucher A., Pisani D. F., Martinez-Gili L., Chilloux J., Bermudez-Martin P., Van Dijck A., et al. (2019). The translational regulator FMRP controls lipid and glucose metabolism in mice and humans. Mol. Metab. 21 22–35. 10.1016/j.molmet.2019.01.002
    1. Lee R. W. Y., Corley M. J., Pang A., Arakaki G., Abbott L., Nishimoto M., et al. (2018). A modified ketogenic gluten-free diet with MCT improves behavior in children with autism spectrum disorder. Physiol. Behav. 188 205–211. 10.1016/j.physbeh.2018.02.006
    1. Li B., Xu Y., Zhang X., Zhang L., Wu Y., Wang X., et al. (2022). The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: A systematic review and meta-analysis of randomized controlled trials. Nutr. Neurosci. 25 835–845. 10.1080/1028415X.2020.1815332
    1. Li Q., Liang J., Fu N., Han Y., Qin J. (2021). A ketogenic diet and the treatment of autism spectrum disorder. Front. Pediatr. 9:650624. 10.3389/fped.2021.650624
    1. Licznerski P., Park H.-A., Rolyan H., Chen R., Mnatsakanyan N., Miranda P., et al. (2020). ATP synthase c-subunit leak causes aberrant cellular metabolism in Fragile X syndrome. Cell 182 1170.e–1185.e. 10.1016/j.cell.2020.07.008
    1. Lin C.-H., Zeng, Lin J.-H., Xiao F., Li B.-M., Chen S.-Q., et al. (2020). Altered behaviour associated with autism in a mouse model of fragile X syndrome treated with bacteroides fragilis BF839. Res. Square [Preprint]. 10.21203/-76080/v1
    1. Liu X., Zou M., Sun C., Wu L., Chen W.-X. (2022). Prenatal folic acid supplements and offspring’s autism spectrum disorder: A meta-analysis and meta-regression. J. Autism Dev. Disord. 52 522–539. 10.1007/s10803-021-04951-8
    1. Liu Z.-H., Chuang D.-M., Smith C. B. (2011). Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome. Int. J. Neuropsychopharmacol. 14 618–630. 10.1017/S1461145710000520
    1. Loesch D. Z., Huggins R. M., Hagerman R. J. (2004). Phenotypic variation and FMRP levels in fragile X. Ment. Retard. Dev. Disabil. Res. Rev. 10 31–41. 10.1002/mrdd.20006
    1. Lozano R., Azarang A., Wilaisakditipakorn T., Hagerman R. J. (2016). Fragile X syndrome: A review of clinical management. Intract. Rare Dis. Res. 5 145–157. 10.5582/irdr.2016.01048
    1. Malhotra S., Subodh B. N., Parakh P., Lahariya S. (2013). Brief Report: Childhood disintegrative disorder as a likely manifestation of Vitamin B12 deficiency. J. Autism Dev. Disord. 43 2207–2210. 10.1007/s10803-013-1762-6
    1. Mangiola F., Ianiro G., Franceschi F., Fagiuoli S., Gasbarrini G., Gasbarrini A. (2016). Gut microbiota in autism and mood disorders. World J. Gastroenterol. 22 361–368. 10.3748/wjg.v22.i1.361
    1. Manor O., Dai C. L., Kornilov S. A., Smith B., Price N. D., Lovejoy J. C., et al. (2020). Health and disease markers correlate with gut microbiome composition across thousands of people. Nat. Commun. 11:5206. 10.1038/s41467-020-18871-1
    1. Mantis J. G., Fritz C. L., Marsh J., Heinrichs S. C., Seyfried T. N. (2009). Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets. Epilepsy Behav. 15 133–141. 10.1016/j.yebeh.2009.02.038
    1. Marlborough M., Welham A., Jones C., Reckless S., Moss J. (2021). Autism spectrum disorder in females with fragile X syndrome: A systematic review and meta-analysis of prevalence. J. Neurodev. Disord. 13:28. 10.1186/s11689-021-09362-5
    1. Martínez-González A. E., Andreo-Martínez P. (2019). The role of gut microbiota in gastrointestinal symptoms of children with ASD. Medicina 55:408. 10.3390/medicina55080408
    1. Masino S. A., Kawamura M., Jr., Wasser C. A., Pomeroy L. T., Ruskin D. N. (2009). Adenosine, ketogenic diet and epilepsy: The emerging therapeutic relationship between metabolism and brain activity. Curr. Neuropharmacol. 7 257–268. 10.2174/157015909789152164
    1. Matricon J., Meleine M., Gelot A., Piche T., Dapoigny M., Muller E., et al. (2012). Review article: Associations between immune activation, intestinal permeability and the irritable bowel syndrome. Aliment Pharmacol. Ther. 36 1009–1031. 10.1111/apt.12080
    1. Mazahery H., Conlon C. A., Beck K. L., Mugridge O., Kruger M. C., Stonehouse W., et al. (2019). A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with autism spectrum disorder. J. Steroid Biochem. Mol. Biol. 187 9–16. 10.1016/j.jsbmb.2018.10.017
    1. McLennan Y., Polussa J., Tassone F., Hagerman R. (2011). Fragile X Syndrome. Curr. Genom. 12 216–224. 10.2174/138920211795677886
    1. Mintál K., Tóth A., Hormay E., Kovács A., László K., Bufa A., et al. (2022). Novel probiotic treatment of autism spectrum disorder associated social behavioral symptoms in two rodent models. Sci. Rep. 12:5399. 10.1038/s41598-022-09350-2
    1. Mintz M., Hollenberg E. (2019). Revisiting Lithium: Utility for behavioral stabilization in adolescents and adults with autism spectrum disorder. Psychopharmacol. Bull. 49 28–40.
    1. Mor-Shaked H., Eiges R. (2018). Reevaluation of FMR1 hypermethylation timing in fragile X syndrome. Front. Mol. Neurosci. 11:31. 10.3389/fnmol.2018.00031
    1. Mu C., Corley M. J., Lee R. W. Y., Wong M., Pang A., Arakaki G., et al. (2020). Metabolic framework for the improvement of autism spectrum disorders by a modified ketogenic diet: A pilot study. J. Proteome Res. 19 382–390. 10.1021/acs.jproteome.9b00581
    1. Murphy M. E., Westmark C. J. (2020). Folic acid fortification and neural tube defect risk: Analysis of the food fortification initiative dataset. Nutrients 12:247. 10.3390/nu12010247
    1. Mychasiuk R., Rho J. M. (2017). Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder. Autism Res. 10 456–471. 10.1002/aur.1682
    1. Napoli E., Dueñas N., Giulivi C. (2014). Potential therapeutic use of the ketogenic diet in autism spectrum disorders. Front. Pediatr. 2:69. 10.3389/fped.2014.00069
    1. Nettleton J. E., Klancic T., Schick A., Choo A. C., Cheng N., Shearer J., et al. (2021). Prebiotic, probiotic, and synbiotic consumption alter behavioral variables and intestinal permeability and microbiota in BTBR Mice. Microorganisms 9:1833. 10.3390/microorganisms9091833
    1. Newell C., Bomhof M. R., Reimer R. A., Hittel D. S., Rho J. M., Shearer J. (2016a). Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol. Autism 737. 10.1186/s13229-016-0099-3
    1. Newell C., Johnsen V. L., Yee N. C., Xu W. J., Klein M. S., Khan A., et al. (2017). Ketogenic diet leads to O-GlcNAc modification in the BTBRT+tf/j mouse model of autism. Biochim. Biophys. Acta Mol. Basis Dis. 1863 2274–2281. 10.1016/j.bbadis.2017.05.013
    1. Newell C., Shutt T. E., Ahn Y., Hittel D. S., Khan A., Rho J. M., et al. (2016b). Tissue specific impacts of a ketogenic diet on mitochondrial dynamics in the BTBRT+tf/j Mouse. Front. Physiol. 7:654. 10.3389/fphys.2016.00654
    1. Nolan S. O., Hodges S. L., Binder M. S., Smith G. D., Okoh J. T., Jefferson T. S., et al. (2022). Dietary rescue of adult behavioral deficits in the Fmr1 knockout mouse. PLoS One 17:e0262916. 10.1371/journal.pone.0262916
    1. Nolan S. O., Hodges S. L., Okoh J. T., Binder M. S., Lugo J. N. (2020). Prenatal high-fat diet rescues communication deficits in Fmr1 mutant mice in a sex-specific manner. DNE 42 94–104. 10.1159/000509797
    1. Nye C., Brice A. (2005). Combined vitamin B6-magnesium treatment in autism spectrum disorder. Cochrane Database Syst. Rev. 2005:CD003497. 10.1002/14651858.CD003497.pub2
    1. Obih C., Wahbeh G., Lee D., Braly K., Giefer M., Shaffer M. L., et al. (2016). Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic IBD center. Nutrition 32 418–425. 10.1016/j.nut.2015.08.025
    1. Ozdemir S. (2010). Social stories: An intervention technique for children with Autism. Proc. Soc. Behav. Sci. 5 1827–1830. 10.1016/j.sbspro.2010.07.372
    1. Parracho H. M. R. T., Gibson G. R., Knott F., Bosscher D., Kleerebezem M., McCartney A. L. (2010). A double-blind, placebo-controlled, crossover-designed probiotic feeding study in children diagnosed with autistic spectrum disorders. Int. J. Probiotics Prebiotics 5 69–74.
    1. Pärtty A., Kalliomäki M., Wacklin P., Salminen S., Isolauri E. (2015). A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: A randomized trial. Pediatr. Res. 77 823–828. 10.1038/pr.2015.51
    1. Pasquaretta C., Gómez-Moracho T., Heeb P., Lihoreau M. (2018). Exploring interactions between the gut microbiota and social behavior through nutrition. Genes (Basel) 9:E534. 10.3390/genes9110534
    1. Penn A. H., Carver L. J., Herbert C. A., Lai T. S., McIntire M. J., Howard J. T., et al. (2016). Breast milk protects against gastrointestinal symptoms in infants at high risk for autism during early development. J. Pediatr. Gastroenterol. Nutr. 62 317–327. 10.1097/MPG.0000000000000907
    1. Pietropaolo S., Goubran M. G., Joffre C., Aubert A., Lemaire-Mayo V., Crusio W. E., et al. (2014). Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice. Psychoneuroendocrinology 49 119–129. 10.1016/j.psyneuen.2014.07.002
    1. Plaza-Díaz J., Gómez-Fernández A., Chueca N., Torre-Aguilar M. J., Gil Á, Perez-Navero J. L., et al. (2019). Autism Spectrum Disorder (ASD) with and without mental regression is associated with changes in the fecal microbiota. Nutrients 11:337. 10.3390/nu11020337
    1. Qin L., Ma K., Yan Z. (2021). Rescue of histone hypoacetylation and social deficits by ketogenic diet in a Shank3 mouse model of autism. Neuropsychopharmacology 47 1271–1279. 10.1038/s41386-021-01212-1
    1. Ródenas-González F., Blanco-Gandía M. C., Miñarro J., Rodríguez-Arias M. (2022). Cognitive profile of male mice exposed to a Ketogenic Diet. Physiol. Behav. 254:113883. 10.1016/j.physbeh.2022.113883
    1. Ruskin D. N., Murphy M. I., Slade S. L., Masino S. A. (2017a). Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder. PLoS One 12:e0171643. 10.1371/journal.pone.0171643
    1. Ruskin D. N., Fortin J. A., Bisnauth S. N., Masino S. A. (2017b). Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse. Physiol. Behav. 168, 138–145. 10.1016/j.physbeh.2016.10.023
    1. Ruskin D. N., Svedova J., Cote J. L., Sandau U., Rho J. M., Kawamura M., Jr., et al. (2013). Ketogenic diet improves core symptoms of autism in BTBR Mice. PLoS One 8:e65021. 10.1371/journal.pone.0065021
    1. Saldarriaga W., Tassone F., González-Teshima L. Y., Forero-Forero J. V., Ayala-Zapata S., Hagerman R. (2014). Fragile X Syndrome. Colomb. Med (Cali) 45 190–198.
    1. Sanctuary M. R., Kain J. N., Chen S. Y., Kalanetra K., Lemay D. G., Rose D. R., et al. (2019). Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS One 14:e0210064. 10.1371/journal.pone.0210064
    1. Santocchi E., Guiducci L., Prosperi M., Calderoni S., Gaggini M., Apicella F., et al. (2020). Effects of probiotic supplementation on gastrointestinal, sensory and core symptoms in autism spectrum disorders: A randomized controlled trial. Front. Psychiatry 11:550593. 10.3389/fpsyt.2020.550593
    1. Schenkman L. (2020). Autism’s genetic drivers may differ by sex. Spectrum News. Available on at: (accessed January 9, 2020).
    1. Schiavi S., Carbone E., Melancia F., Buzzelli V., Manduca A., Campolongo P., et al. (2022). Perinatal supplementation with omega-3 fatty acids corrects the aberrant social and cognitive traits observed in a genetic model of autism based on FMR1 deletion in rats. Nutr. Neurosci. 25 898–911. 10.1080/1028415X.2020.1819107
    1. Shaaban S. Y., El Gendy Y. G., Mehanna N. S., El-Senousy W. M., El-Feki H. S. A., Saad K., et al. (2018). The role of probiotics in children with autism spectrum disorder: A prospective, open-label study. Nutr. Neurosci. 21 676–681. 10.1080/1028415X.2017.1347746
    1. Shamsedine L., Mailhac A., Badaoui A., El Hakim R., Kibbi R., Oueidat H., et al. (2020). Breastfeeding association with autism spectrum disorders: A case-control study from Lebanon. Res. Autism Spectr. Disorder. 78:101651. 10.1016/j.rasd.2020.101651
    1. Shen L., Feng C., Zhang K., Chen Y., Gao Y., Ke J., et al. (2019). Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in autistic children. Front. Cell. Neurosci. 13:105. 10.3389/fncel.2019.00105
    1. Sichel L., Timoshok N., Pidgorskyy V., Spivak N. (2013). Study of interferonogenous activity of the new probiotic formulation Del-Immune V®. J. Probiotics Health 1:1000107.
    1. Smith J., Rho J. M., Teskey G. C. (2016). Ketogenic diet restores aberrant cortical motor maps and excitation-to-inhibition imbalance in the BTBR mouse model of autism spectrum disorder. Behav. Brain Res. 304 67–70. 10.1016/j.bbr.2016.02.015
    1. Smith P. H., Joris P. X., Carney L. H., Yin T. C. T. (1991). Projections of physiologically characterized globular bushy cell axons from the cochlear nucleus of the cat. J. Comp. Neurol. 304 387–407. 10.1002/cne.903040305
    1. Spilioti M., Evangeliou A., Tramma D., Theodoridou Z., Metaxas S., Michailidi E., et al. (2013). Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front. Hum. Neurosci. 7:858. 10.3389/fnhum.2013.00858
    1. Stafstrom C., Rho J. (2012). The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front. Pharmacol. 3:59. 10.3389/fphar.2012.00059
    1. Strati F., Cavalieri D., Albanese D., De Felice C., Donati C., Hayek J., et al. (2017). New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5:24. 10.1186/s40168-017-0242-1
    1. Sun C., Zou M., Zhao D., Xia W., Wu L. (2016). Efficacy of folic acid supplementation in autistic children participating in structured teaching: An open-label trial. Nutrients 8:337. 10.3390/nu8060337
    1. Suskind D. L., Wahbeh G., Gregory N., Vendettuoli H., Christie D. (2014). Nutritional therapy in pediatric Crohn disease: The specific carbohydrate diet. J. Pediatr. Gastroenterol. Nutr. 58 87–91. 10.1097/MPG.0000000000000103
    1. Tabouy L., Getselter D., Ziv O., Karpuj M., Tabouy T., Lukic I., et al. (2018). Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav. Immun. 73 310–319. 10.1016/j.bbi.2018.05.015
    1. Tai K.-K., Nguyen N., Pham L., Truong D. D. (2008). Ketogenic diet prevents cardiac arrest-induced cerebral ischemic neurodegeneration. J. Neural. Transm. 115 1011–1017. 10.1007/s00702-008-0050-7
    1. Turner T. N., Wilfert A. B., Bakken T. E., Bernier R. A., Pepper M. R., Zhang Z., et al. (2019). Sex-based analysis of de novo variants in neurodevelopmental disorders. Am. J. Hum. Genet. 105, 1274–1285. 10.1016/j.ajhg.2019.11.003
    1. van Eeghen A. M., Pulsifer M. B., Merker V. L., Neumeyer A. M., van Eeghen E. E., Thibert R. L., et al. (2013). Understanding relationships between autism, intelligence, and epilepsy: A cross-disorder approach. Dev. Med. Child Neurol. 55 146–153. 10.1111/dmcn.12044
    1. Varesio C., Grumi S., Zanaboni M. P., Mensi M. M., Chiappedi M., Pasca L., et al. (2021). Ketogenic dietary therapies in patients with autism spectrum disorder: Facts or Fads? A scoping review and a proposal for a shared protocol. Nutrients 13:2057. 10.3390/nu13062057
    1. Verpeut J. L., DiCicco-Bloom E., Bello N. T. (2016). Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice. Physiol. Behav. 161 90–98. 10.1016/j.physbeh.2016.04.001
    1. Verrotti A., Iapadre G., Pisano S., Coppola G. (2017). Ketogenic diet and childhood neurological disorders other than epilepsy: An overview. Exp. Rev. Neurotherapeutics 17 461–473. 10.1080/14737175.2017.1260004
    1. Wallace D. C., Fan W., Procaccio V. (2010). Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5 297–348. 10.1146/annurev.pathol.4.110807.092314
    1. Westmark C. J. (2013). Soy infant formula may be associated with autistic behaviors. Autism Open Access. 3:20727. 10.4172/2165-7890.1000120
    1. Westmark C. J. (2014a). Soy infant formula and seizures in children with autism: A retrospective study. PLoS One 9:e80488. 10.1371/journal.pone.0080488
    1. Westmark C. J. (2014b). A hypothesis regarding the molecular mechanism underlying dietary soy-induced effects on seizure propensity. Front. Neurol. 5:169. 10.3389/fneur.2014.00169
    1. Westmark C. J. (2017). Soy-based therapeutic baby formulas: Testable hypotheses regarding the pros and cons. Front. Nutr. 3:59. 10.3389/fnut.2016.00059
    1. Westmark C. J. (2021a). Parental reports on early autism behaviors in their children with fragile X syndrome as a function of infant feeding. Nutrients 13:2888. 10.3390/nu13082888
    1. Westmark C. J. (2021b). Consumption of breast milk is associated with decreased prevalence of autism in fragile X syndrome. Nutrients 13:1785. 10.3390/nu13061785
    1. Westmark C. J. (2022). Increased incidence of epilepsy in response to soy-based infant formula in a National Korean Cohort Study. J. Nutr. 152 1378–1379. 10.1093/jn/nxac040
    1. Westmark C. J., Filon M. J., Maina P., Steinberg L. I., Ikonomidou C., Westmark P. R. (2022). Effects of soy-based infant formula on weight gain and neurodevelopment in an autism mouse model. Cells 11:1350. 10.3390/cells11081350
    1. Westmark C. J., Kniss C., Sampene E., Wang A., Milunovich A., Elver K., et al. (2020a). Based Infant Formula is Associated with an increased prevalence of comorbidities in Fragile X syndrome. Nutrients 123136. 10.3390/nu12103136
    1. Westmark P. R., Gutierrez A., Gholston A. K., Wilmer T. M., Westmark C. J. (2020b). Preclinical testing of the ketogenic diet in fragile X mice. Neurochem. Int. 134:104687. 10.1016/j.neuint.2020.104687
    1. Westmark C. J., Westmark P. R., Malter J. S. (2013). Soy-based diet exacerbates seizures in mouse models of neurological disease. J. Alzheimers Dis. 33 797–805. 10.3233/JAD-2012-121426
    1. Yu Y., Huang J., Chen X., Fu J., Wang X., Pu L., et al. (2022). Efficacy and safety of diet therapies in children with autism spectrum disorder: A systematic literature review and meta-analysis. Front. Neurol. 13:844117. 10.3389/fneur.2022.844117
    1. Żarnowska I., Chrapko B., Gwizda G., Nocuń A., Mitosek-Szewczyk K., Gasior M. (2018). Therapeutic use of carbohydrate-restricted diets in an autistic child; a case report of clinical and 18FDG PET findings. Metab. Brain Dis. 33 1187–1192. 10.1007/s11011-018-0219-1
    1. Zheng Y., Verhoeff T. A., Perez Pardo P., Garssen J., Kraneveld A. D. (2021). The gut-brain axis in autism spectrum disorder: A focus on the metalloproteases ADAM10 and ADAM17. Int. J. Mol. Sci. 22:118. 10.3390/ijms22010118

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe