INTRODUCTION
Autism spectrum disorder (ASD) is a broad term which refers to complex developmental disorders including repetitive-restricted behavior, trouble socializing, atypical food patterns, emotional, and mental complexities with an onset of mild to severe symptoms.[1] Behavioral complexities such as anxiety, depression, aggression, hyperactivity, self-harm, and tantrums have been widely reported in people with ASD.[2] In the past people co-related autism with schizophrenia.[3] Leo Kanner back in 1943 at Johns Hopkins University defined autism as introversion, difficulty in social interactions, repetitive restrictive behavior, and peculiar food choices.[4]
Recent studies suggested that various genes are involved in ASD occurrence, each playing a specific role. The heritability percentage is 50% to 80%, leaving a major portion to non-heritable acquired risk factors.[5] Furthermore, the non-heritable acquired risk factors such as environmental factors play a dual role in ASD etiology.[6] Maternal and paternal age, perinatal obstructive complications, hypoxia, use of certain medications, vitamin D, zinc, iron, and copper deficiency, excessive smoking, alcohol abuse, and consumption of toxic substances (heavy metals, lead, mercury, and pesticides) might be some ASD causative factors.[7]
Malnutrition is common in children with ASD owing to gastrointestinal issues, abnormal sensory processing, unusual food choices, and consumption of food allergies.[8] Particular food choices and preferences are the primary causes of nutritional imbalance.[9] In particular, artificial food colors and food additives are linked with the development of hyperactivity and sleep disturbances in ASD.[10] Experiments in this area revealed that a short chain fatty acid known as propionic acid (PA) causes behavioral alterations and neuro-inflammatory conditions in rats that are similar to the symptoms of ASD.[11] Considering the above-mentioned facts, extensive research is required to elucidate the special needs and characteristics of children with autism, as well as possible treatments, to ensure that quality of life improves over time.[12]
The objective of the current review is to investigate the prevalence of ASD, its associated complexities, and role of gut brain axis in its etiology. Furthermore, dietary approaches in managing ASD related complications are also covered in this review.
CAUSES AND PREVALENCE OF AUTISM SPECTRUM DISORDER
Rapid increase in “Autistic Disorder diagnoses” between 50% and over 2000% have been charted, studied, and discussed over the past decade worldwide. Evidence-based best practices, teacher training techniques, special education instructors regarding personnel connect, cooperate, and work on daily basis with such individuals can be productive and beneficial. Also, inclusive educational environment along with frequent input from national education agencies and ministries on their obligations through providing autistic people’s rights and better environment is needed.[13]
Genetic variables are well recognized to play a significant role in autism etiology, in combination with environmental factors that may interfere with development. Environmental factors are also known to play an important role through complex gene–environment interactions. Early detection is considered to be vital for better interventions.[14] However, no specific causative element with substantial impact is recognized yet.[15]
A systematic review on epidemiology of ASD was conducted to investigate the influence of regional, cultural, and socioeconomic variables on ASD coinsurance and pervasive developmental disorders (PDDs). Results estimated a median value of 62/10,000 showing the higher risks of autism prevalence and complexities.[16] Studies around the world indicate that ASD prevalence is somewhat lower in regions outside North America and Europe. A study in the United States reported that Hispanic origin children have the lowest ASD prevalence while Whites tend to have the highest ASD prevalence.[17]
DIAGNOSIS AND SCREENING METHODS
Due to underlying disease characteristics, autistic children have been increasingly reported to have atypical eating patterns but unfortunately there is no biological test for diagnosis of ASD.[18] Usually, diagnosis is based on indications such as decreased social interaction and inability to relate to people. 87.3% of people aged 6 to 17 years show symptoms such as behavioral problems, attention deficit disorder, hyperactivity, and anxiety.[19]
Previous studies state that the methods for estimating energy and nutrient intake such as dietary reference intake (DRIs),[20] recommended dietary allowances (RDAs), estimated energy needs (EERs), appropriate intake (AI), tolerable upper intake limits (UL), and acceptable macronutrient distribution ranges (AMDR) are all prominent methods for determining nutrient requirements of ASD patients.[21] One of the current screening approaches for ASD include filling out a questionnaire about numerous autistic traits such as a child’s overall attitude at a pediatrics appointment. If the symptoms fall outside of a specified range, the patient is referred to a specialized clinician for additional diagnostic tests and procedures, which may include a standardized behavior assessment. From there, the need for additional therapies is determined based on severity of symptoms.[22] With few notable exceptions, health care professionals in low-income countries are untrained in early screening, diagnosis, and intervention. A recent survey conducted in Karachi, Pakistan revealed that the word “autism” has never been heard by more than half of general specialists.[23] Diagnosis before adverse disorder effects could significantly reduce the healthcare cost associated with ASD, though the current processes are time-consuming, ineffectual, and uneconomical.[24]
ROLE OF GUT BRAIN AXIS AND GUT MICROBIOTA
As scientific research on Autism has improved, it has become clear that the brain is not the only organ involved in autism. The gastrointestinal tract (GI) is equally important in the etiology and treatment of autism.[25] In this regard, gut brain axis is known as the mode of communication between the gut and brain.[26] The makeup of gut bacteria appears to have an impact on prenatal and neonatal brain development. Nutritional status of an individual can affect gut microbiota which can in turn affect immunological and neurological systems as well as brain development, leading to poor cognitive abilities.[27] However, mother feed can reduce the occurrence and severity of infections by promoting a healthy gut microflora.[28]
Several studies have suggested that gut bacteria may affect brain chemistry and functioning of vagus nerve which plays an eminent role in distinguishing between harmful and beneficial bacteria. They also have the potential to change the chemistry and role of gut microbiota, impacting behavior in the long run.[29] The endocrine, neuro-immune, and autonomic nervous systems are all involved in the gut brain axis’ function. However, probiotics have demonstrated to be extremely effective in alleviating symptoms.[30] Studies suggest that greater toxin levels are linked to Candida albicans overgrowth in the intestine, which causes poor carbohydrate and mineral absorption, culminating in autism-related issues.[31]
A comprehensive analysis in children with ASD reported occurrence of at least one gastrointestinal symptom like constipation, bloating, diarrhea or irregular stools, and gastroesophageal reflux (GERD).[32] According to the findings from another study on ASD in children, 70% of autistic children had GI problems, compared to control group.[33] Another study found the difference in the composition of gastric microbiota between children with a late onset of autism condition compared to non-autistic control children.[19] Further research is needed to fully understand the link between gut brain axis and complexities of ASD to implement better preventive and treatment strategies.[34]
NUTRITIONAL APPROACHES IN MANAGING ASD
Recent studies reveal that nutrition plays an important role in the development of ASD. Moreover, nutritional deficiencies in the maternal diet have also been associated with the onset of ASD and other mental problems in off springs. Research on ASD has confirmed the benefits of dietary supplements in treating symptoms.[35] Adopting certain dietary measures can effectively reduce the severity of symptoms linked to ASD such as repetitive behavior, communication issues, self-harm, tantrums, and hostility.[36] In contrast, high levels of pro-inflammatory cytokines such as IL-1B, IL-6, IL-8, and IL-12p40 are generated, which have been linked to the development of neuropsychiatric diseases associated with autism spectrum disorder.[33]
Regarding dietary modifications, the gluten free casein-free (GFCF) diet is the most effective in alleviating ASD symptoms. However, the Academy of Nutrition & Dietetics suggested the need for robust studies to recommend the usefulness of dietary practices for ASD therapy.[3738] Elimination diet is another approach to determine the triggering effects of certain foods leading to aggravate the disease symptoms.[39] Considering the above-mentioned facts, dietary approaches in managing ASD are discussed in detail below.
Elimination diets and ASD
The primary focus of the diet is to eliminate gluten (present in wheat and barley) as well as rye and casein protein found in dairy products. Gluten and casein peptides are known to cause aberrant cytokine production, immune system abnormalities, and central nervous system damage contributing to the development of ASD complexities.[40] Also, antibodies to neuro specific antigen and gliadin have been discovered in individuals with ASD, adding the linked evidence between gluten and casein peptides and ASD symptoms.[41] A study of the effects of a modified ketogenic gluten-free diet with medium chain triglycerides (MCTs) found an improvement in autism features and other clinical outcomes.[4243]
Several studies suggest that gastrointestinal issues in ASD have been linked to carbohydrate metabolism and recommend to restricts the use of complex carbohydrates in ASD.[1933] Fermentable oligo-di-monosaccharides and polyols (FODMAPs) are a kind of short-chain carbohydrates that are included in fructose (fruits and high-fructose corn-syrup), lactose (milk and dairy products), fructans (grains, vegetables, and fruits), galactans (legumes and vegetables), and sugar alcohols (polyols, e.g., sorbitol, fruits, and vegetables).[44] In children with ASD, a restricted FODMAP diet has been found as a popular dietary intervention to reduce the adverse ASD outcomes including irritable bowel syndrome symptoms (IBS).[4546]
The Feingold diet, which excludes artificial food colorings, artificial sweeteners, preservatives, and chemicals such as aspartame, neotame, and alitame has shown the beneficial effects in the treatment of ASD.[4748] However, further research is needed to confirm the relationship. Excluding sugar and chocolate from the diets of children with ASD is another dietary approach showed to have some positive effects.[49] Furthermore, processed food produces excessive acids responsible to damage neurons and disrupt interbody communication circuit resulting in difficulties such as repeated behavior, movement challenges, and an inability to interact with others.[50]
C. albicans, the most common human fungal pathogen, can cause infections with a 40% mortality rate.[5152] In relation to spectrum of autism, C. albicans in GI tract generates an interaction between propionic acid and ammonia owing to produce beta-alanine and gamma-aminobutyric acid (GABA), which is a prohibitive neurotransmitter and might be a causative factor of autism.[53]
Effect of dietary supplements on ASD
The omega-3 and omega-6 families are the two most common classes of PUFA compounds.[54] For the treatment of ASD, long-chain omega-3 polyunsaturated fatty acids (n-3 LCPUFA) are commonly used and thought to be essential for brain development.[55] Studies have reported that taking vitamin D along with omega-3 polyunsaturated fatty acids supplements can help to reduce ASD symptoms. In a study, children with ASD (n = 73; 2.5–8.0 years old) in New Zealand who were given daily doses of 2000 IU vitamin D3 along with 722 mg docosahexaenoic acid, showed improvement in their ASD symptoms as compared to the placebo group.[56]
Autistic children are usually deficient in vitamin D, vitamin C, calcium, folate, magnesium, phosphorus, zinc, and iron.[57] Additionally, ASD children also have lower macronutrient (energy, carbohydrates, protein, and fiber) intakes followed by picky eating patterns.[58] The most commonly used supplements for ASD therapy include vitamin B6, vitamin C, vitamin D, vitamin B12, fatty acids (omega-3 fatty acids and cod liver oil), melatonin, folic acid, l-carnitine, iron, magnesium, zinc, and copper.[5960] Large prospective controlled trials are needed to investigate serum levels and folic acid consumption in autistic people.[61] Studies have found that vitamin B6 along with magnesium administration improves expressiveness, reduces aggressiveness, improves eye contact, increases intelligence quotient (IQ), and improves social interaction.[62] In a recent double-blind randomized controlled trial, involving oral vitamin D supplementation (300 IU vitamin D3/kg/day), it was found that children with ASD significantly reduced core ASD symptoms as compared to the control group.[6364]
Digestive enzymes and probiotics
Digestive enzymes aid food absorption by breaking down large molecules of food into smaller molecules, allowing for easier absorption, digestion, and elimination of harmful chemicals from the stomach.[65] Low enzyme activity (glycoside hydrolase and polysaccharide lyase) and poor carbohydrate digestion/absorption in children with ASD can initiate the accumulation of saccharides in the intestinal lumen, resulting into osmotic diarrhea, bloating, and flatulence.[66]
Recent research has shown that probiotics may help to improve bowel habits, behavior, and social functioning in autistic people.[67] Disruption of the normal commensal microbial community in humans has been associated with a growing number of disorders like inflammatory intestinal disease and irritable bowel syndrome (IBS).[6869] Most commonly used probiotic species include Bifidobacterium (bifidum, breve) and Lactobacillus (acidophilus, casein).[70]Lactobacillus reuteri has the capacity to restore gut microbiota and behavioral abnormalities caused by maternal high fat diet.[71] Though well-designed, randomized, placebo-controlled clinical studies are necessary to establish the efficacy of probiotics in the treatment of ASD.[72]
Antioxidants
Evidence has shown that the pathophysiology of ASD is correlated to oxidative stress due to interruption of body’s antioxidant defense system.[7374] Changes in antioxidant protein levels, such as ceruloplasmin (copper-binding protein) and transferrin (iron-binding protein) may directly or indirectly increase oxidative stress, delaying the acquisition of linguistic abilities in autistic children.[75] In this regard, polyphenols, present in cocoa, have been reported to scavenge free radicals from the body.[76] Also, a study on the intake of a nutraceuticals, high in antioxidative properties have got potential benefits in enhancing behavior in children with ASD.[77] In concomitant, glutathione, which can be used to treat ASD, detoxifies the body, and protects it from oxidative damage.[78] Nutritional supplementation to minimize oxidative stress, as well as factors to increase reduced glutathione, is validated and rationale approaches to treat ASD.[79] Curcumin tends to help in autism treatment by increasing intracellular GSH (glutathione) levels, lowering inflammatory chemicals, counterbalancing the damage caused by heavy metals and improving the detoxification process of liver.[8081] Additionally, sulforaphane supplementation improves autism symptoms particularly in social responsiveness autism symptoms.[82] [Table 1].
;)
Table 1: Antioxidants sources and health benefits
Camel’s milk
Camel milk differs from other ruminants’ milk in composition. In comparison to cow’s milk, this includes more minerals (calcium, iron, magnesium, copper, zinc, and potassium), more vitamins (A, B2, E, and C), less fat, cholesterol, and lactose. As a result, beta-lactoglobulin and beta-casein are active components of cow’s milk allergy that are not found in camel’s milk.[90] There are many beneficial effects of nano-bodies in this milk on infectious agents and the immune system.[91] Owing to its special structure, camel milk is known to help treat autism in children by boosting superoxide dismutase (SOD), myeloperoxidase (MPO), and lowering oxidative stress, which is part of the autism etiology.[92]
Ketogenic diet
This diet, formulated for patients with seizures about eight decades ago, is based on the notion that autistic symptoms arise from defects in the metabolism of cellular carbohydrates and that ketogenic diet can compensate for this mitochondrial dysfunction.[93] The ketogenic diet is a high-fat, low-carbohydrate diet designed to induce metabolic ketosis in the body. Ketosis is the process through which ketones (molecules generated from fatty acids), replace carbohydrates as the body’s principal source of fuel during metabolic processes.[94] Other neuro-psychiatric disorders can also be treated through a ketogenic diet.[95]
Mediterranean diet (MD)
The Mediterranean diet comprises a high number of fruits, vegetables, legumes, nuts, grains, and olive oil as well as a reduced intake of saturated fats, sweets, and red and processed meat.[96] Moreover, Mediterranean diet enables adequate consumption of B vitamins and omega-3 fatty acids, both of which have a protective role in the treatment of mental disorders such as ASD and depression.[97]
Medium chain triglycerides (MCTs)
Medium chain triglycerides are plant derived fats, mainly coconut and palm oil. Medium chain triglyceride (MCT) oil helps in treating cardiovascular diseases, digestive problems, Alzheimer’s disease, epilepsy, and autism.[98] Virgin coconut oil (VOC) derived from fresh coconut kernel is a food supplement that is fortified with fatty acid and polyphenolic antioxidants. Many health benefits are identified including reduction in lipids and anti-inflammatory properties.[99] A study was carried out to investigate the effect of daily ingestion of virgin coconut oil in patients with ASD showed that adding 5 mL of VCO to normal gluten-free casein-free diet improved bowel movements.[100] Similarly, another study determined the efficacy of coconut oil in oral health and showed improvements in children’s oral hygiene.[101102]
Herbs
Herbal medications and integrative treatment are also recognized to have a positive effect in the treatment of autistic children when used in conjunction with traditional therapy. Nevertheless, it is impossible to draw firm conclusions because of the poor methodological consistency of the included research due to limited sample size and the variety of herbal medicines. More well-designed, large-scale RCTs with minimal bias risk are required to corroborate such findings.[103] Many natural compound-based plant products such as flavonoids, cannabinoids, curcuminoids, resveratrol, and bacosides, have been studied with remarkable success in murine autism models and clinical trials. Use of alternative plant-based medicines is safer because many psychiatric disorders and neurodegenerative pathologies do not often react well to drugs commonly administered and have significant side effects.[104] [Table 2].
Table 2: Nutritional approaches and management of autism spectrum disorder (ASD)
Food labels
In a child’s early years, a healthy diet is a predictor of subsequent academic success.[123] However, the free market economy in the United States often allows households to unknowingly purchase unhealthy foods that can adversely affect learning and academic achievement of students. In 2010, the European Union (EU) voted to allow its food producers to put a warning label on products containing any ingredient found to increase children’s hyperactivity and inattention in autistic children.[124] Requirement for the warning label in the UK permits parents to avoid buying food products with artificial food colors and allowable heavy metals that may result in zinc losses when consumed. The shopping habits and patterns of parents in the UK is considered to be a key factor for the lower prevalence of autism and ADHD in the UK as compared to the USA, where there is no such provision for labeling products.[125] Under the Food Allergen Labeling and Consumer Protection Act (FALCPA), a “major food allergen” is defined as an ingredient that has one of the eight foods or food groups listed below, or an ingredient that contains even trace amounts of protein from one of the following products: milk, eggs, fish, tree nuts, wheat, peanuts, or soybeans. More than 160 foods have been identified as causing food allergies in sensitive individuals, with the “major food allergens” accounting for 90% of all food allergies.[126] When considering medical nutrition therapy for ASD, it is critical to assess the individual’s pathophysiology, dietary intake, food allergies, intolerance, and dietary habits to supplement food energy and nutrient deficits, ensure an adequate and balanced diet and also adhere to a therapeutic dietary strategy to alleviate symptoms.[47]
AUTISM SPECTRUM DISORDER IN ASIA
The diagnosis and incidence of autism spectrum condition have increased during the last decade. South Asia accounts for around 23% world’s population, with estimates ranging from 150 to 200 million individuals suffering from mental diseases. Specifically, eight South Asian countries namely, Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka have a high prevalence of mental disorders. Early therapies are employed to treat children in high-income nations, while there is no comprehensive treatment in poor and middle-income countries to address the mental health issues.[127] Prior to 1980, the average prevalence of ASD was roughly 1.9/10,000, but it has risen to 14.8/10,000 in recent years. Similarly, the data from 2000 to 2010, the median prevalence of ASD among children in China aged 2 to 6 years was 10.3/10,000.[128]
Most of these incidents go unreported, resulting in a population-wide burden of mental diseases. This is due to a variety of factors, the most significant of which is a lack of understanding and stigma around such disorders.[129] A study reviewed the data between January 1962 and July 2016 and found the high prevalence of ASD in eight South Asian nations. ASD prevalence in Dhaka (Bangladesh) was reported to be 3%, India 0.09%, and Sri Lanka 1.07%. Though no study has been conducted on a national level which reports ASD prevalence in Pakistan, Nepal, Bhutan, Maldives, or Afghanistan.[130] In countries such as Pakistan and India, where ASD is considered to be a taboo, there is a strong need to highlight the significance of family and community support in addressing this issue.[131] Further research is required to determine the scope of autistic spectrum disorder-related concerns in low/middle income countries.[132133]
CONCLUSION
Autism spectrum disorder is one of the rapidly evolving neuropsychiatric disorders. Changes in the balance of intestinal microbiota can cause a variety of symptoms indicating a strong relationship between the gut and the body. Active dietary treatments including the use of dietary supplements and elimination of certain products such as gluten, casein, processed foods, and artificial food colors might help to reduce the severe outcomes. Reading food labels is also one of the significant interventions to avoid and reduce the symptoms associated with ASD. However, further research is required to confirm these findings.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
The authors would like to acknowledge Dr. Sana Ikram for her constructive input and revision of manuscript for the improvement of language.
REFERENCES
1. Lord C, Brugha TS, Charman T, et al
Autism spectrum disorder Nat Rev Dis Primers. 2020;6:5
2. Nazeer A, Ghaziuddin M. Autism spectrum disorders: clinical features and diagnosis Pediatr Clin. 2012;59:19–25
3. Eltokhi A, Santuy A, Merchan-Perez A, Sprengel R. Glutamatergic dysfunction and synaptic ultrastructural alterations in schizophrenia and
autism spectrum disorder: evidence from human and rodent studies Int J Mol Sci. 2020;22:E59
4. Geoffray MM, Falissard B, Green J, et al
Autism spectrum disorder symptom profile across the RASopathies Front Psychiatry. 2021;11:585700
5. Akbaraly T. Nutritional epidemiology research in the field of autism spectrum disorders-a review Neuropsychiatry (London). 2019;9:2372–2378
6. Emberti Gialloreti L, Mazzone L, Benvenuto A, et al Risk and protective environmental factors associated with
autism spectrum disorder: evidence-based principles and recommendations J Clin Med. 2019;8:217
7. Bölte S, Girdler S, Marschik PB. The contribution of environmental exposure to the etiology of
autism spectrum disorder Cell Mol Life Sci. 2019;76:1275–1297
8. Sanctuary MR, Kain JN, Angkustsiri K, German JB. Dietary considerations in autism spectrum disorders: the potential role of protein digestion and microbial putrefaction in the gut-brain axis Front Nutr. 2018;5:40
9. Tas AA. Dietary strategies in
autism spectrum disorder (ASD) Prog Nutr. 2018;20:554–562
10. Bakthavachalu P, Kannan SM, Qoronfleh MW. Food color and autism: a meta-analysis Adv Neurobiol. 2020;24:481–504
11. El-Ansary AK, Bacha AB, Kotb M. Etiology of autistic features: the persisting neurotoxic effects of propionic acid J Neuroinflammation. 2012;9:74
12. Lord C, Charman T, Cusack J, et al
Autism spectrum disorder (primer) Nat Rev Dis Primer. 2020;6:5
13. Zeidan J, Fombonne E, Scorah J, et al Global prevalence of autism: a systematic review update Autism Res. 2022;15:778–790
14. Lai MC, Lombardo MV, Baron-Cohen S. Autism Lancet. 2014;383:896–910
15. Gómez-Vallejo S, Leoni M, Ronald A, Colvert E, Happé F, Bolton P.
Autism spectrum disorder and obstetric optimality: a twin study and meta-analysis of sibling studies J Child Psychol Psychiatry. 2021;62:1353–1362
16. Elsabbagh M, Divan G, Koh YJ, et al Global prevalence of autism and other pervasive developmental disorders Autism Res. 2012;5:160–179
17. Steinbrenner JR, McIntyre N, Rentschler LF, et al Patterns in reporting and participant inclusion related to race and ethnicity in autism intervention literature: data from a large-scale systematic review of evidence-based practices Autism. 2022 13623613211072592
18. Qureshi F, Hahn J. Towards the development of a diagnostic test for
autism spectrum disorder: big data meets metabolomics Can J Chem Eng. 2022
19. Piergies AMH, Hirota T, Monden R, Zheng S. Subgrouping school-aged children on the autism spectrum based on co-occurring psychiatric symptoms Res Autism Spectr Disord. 2022;95:101983
20. Zulkifli MN, Kadar M, Fenech M, Hamzaid NH. Interrelation of food selectivity, oral sensory sensitivity, and nutrient intake in children with
autism spectrum disorder: a scoping review Res Autism Spectr Disord. 2022;93:101928
21. Hyman SL, Stewart PA, Schmidt B, et al Nutrient intake from food in children with autism Pediatrics. 2012;130(Suppl):S145–S153
22. Dawson G, Sapiro G. Potential for digital behavioral measurement tools to transform the detection and diagnosis of
autism spectrum disorder JAMA Pediatr. 2019;173:305–306
23. Rahbar MH, Ibrahim K, Assassi P. Knowledge and attitude of general practitioners regarding autism in Karachi Pakistan J Autism Dev Disord. 2011;41:465–474
24. Thabtah F. An accessible and efficient autism screening method for behavioral data and predictive analyses Health Informatics J. 2019;25:1739–1755
25. Whiteley P. Food and the gut: relevance to some of the autisms Proc Nutr Soc. 2017;76:478–483
26. Bienenstock J, Kunze W, Forsythe P. Microbiota and the gut-brain axis Nutr Rev. 2015;73(suppl):28–31
27. Appleton J. The gut-brain axis: influence of microbiota on mood and mental health Integr Med Clin J. 2018;17:28–32
28. El-Ansary A, Shaker GH, Rizk MZ. Role of gut-brain axis in the aetiology of neurodevelopmental disorders with reference to autism J Clin Toxicol S. 2013;6:2161–2495
29. McVey Neufeld KA, Bienenstock J, Bharwani A, et al Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling Sci Rep. 2019;9:1–11
30. Li Q, Zhou JM. The microbiota-gut-brain axis and its potential therapeutic role in
autism spectrum disorder Neuroscience. 2016;324:131–139
31. Kantarcioglu AS, Kiraz N, Aydin A. 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. 2016;181:1–7
32. Lefter R, Ciobica A, Timofte D, Stanciu C, Trifan A. A descriptive review on the prevalence of gastrointestinal disturbances and their multiple associations in
autism spectrum disorder Medicina (Mex). 2019;56:11
33. Ristori MV, Quagliariello A, Reddel S, et al Autism, gastrointestinal symptoms and modulation of gut microbiota by nutritional interventions Nutrients. 2019;11:2812
34. Cerdó T, Diéguez E, Campoy C. Impact of gut microbiota on neurogenesis and neurological diseases during infancy Curr Opin Pharmacol. 2020;50:33–37
35. Onaolapo O, Onaolapo A. Nutrition in autism spectrum disorders: a review of evidence for an emerging central role in aetiology, expression, and management AIMS Med Sci. 2018:5
36. van der Wurff I, Oenema A, de Ruijter D, et al A scoping literature review of the relation between nutrition and asd symptoms in children Nutrients. 2022;14:1389
37. Abraham DA, Udayakumar N, Rajendran L, Rajendran R, Rajanandh MG. Herbal medicine as a first-line choice of complementary medicine for South Indian parents/caregivers in the management of ASD children J Herbal Med. 2022;34:100583
38. Trudeau MS, Madden RF, Parnell JA, Gibbard WB, Shearer J. Dietary and supplement-based complementary and alternative medicine use in pediatric
autism spectrum disorder Nutrients. 2019;11:1783
39. Ly V, Bottelier M, Hoekstra PJ, Vasquez AA, Buitelaar JK, Rommelse NN. Elimination diets’ efficacy and mechanisms in attention deficit hyperactivity disorder and
autism spectrum disorder Eur Child Adolesc Psychiatry. 2017;26:1067–1079
40. Quan L, Xu X, Cui Y, et al A systematic review and meta-analysis of the benefits of a gluten-free diet and/or casein-free diet for children with
autism spectrum disorder Nutr Rev. 2022;80:1237–1246
https://doi.org/10.1093/nutrit/nuab073
41. Cekici H, Sanlier N. Current nutritional approaches in managing
autism spectrum disorder: a review Nutr Neurosci. 2019;22:145–155
42. Lee RWY, Corley MJ, Pang A, et al A modified ketogenic gluten-free diet with MCT improves behavior in children with
autism spectrum disorder Physiol Behav. 2018;188:205–211
43. Hediger ML, England LJ, Molloy CA, Kai FY, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or
autism spectrum disorder J Autism Dev Disord. 2008;38:848–856
44. Kawicka A, Regulska-Ilow B. How nutritional status, diet and dietary supplements can affect autism. A review Rocz Państw Zakl Hig. 2013;64:1–12
45. Nanayakkara WS, Skidmore PM, O’Brien L, Wilkinson TJ, Gearry RB. Efficacy of the low FODMAP diet for treating irritable bowel syndrome: the evidence to date Clin Exp Gastroenterol. 2016;9:131
46. Mansueto P, Seidita A, D’Alcamo A, Carroccio A. Role of FODMAPs in patients with irritable bowel syndrome Nutr Clin Pract. 2015;30:665–682
47. Staudacher HM, Whelan K. The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS Gut. 2017;66:1517–1527
48. Hangül Z, Tufan AE. Use of complementary and alternative therapies in
autism spectrum disorder Psikiyatride Guncel Yaklasimlar. 2022;14:165–173
49. Bricklin P, Bricklin B, Ames LB. Why Your Child is Hyperactive. Ben F. Feingold. New York: Random House, 1975, 211 pp., $7.95 J Learn Disabil. 1975;8:537–538
50. Currais A, Farrokhi C, Dargusch R, Goujon-Svrzic M, Maher P. Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with
autism spectrum disorder Mol Psychiatry. 2016;21:426
51. Abdelli LS, Samsam A, Naser SA. Propionic acid induces gliosis and neuro-inflammation through modulation of PTEN/AKT pathway in
autism spectrum disorder Sci Rep. 2019;9:8824
52. Ashwood P, Hughes HK. Brief report: anti-Candida albicans IgG antibodies in children with autism spectrum disorders Front Psychiatry. 2018;9:627
53. Gunsalus KT, Tornberg-Belanger SN, Matthan NR, Lichtenstein AH, Kumamoto CA. Manipulation of host diet to reduce gastrointestinal colonization by the opportunistic pathogen Candida albicans MSphere. 2016;1:e00020–15
54. Burrus CJ. A biochemical rationale for the interaction between gastrointestinal yeast and autism Med Hypotheses. 2012;79:784–785
55. Bozzatello P, Rocca P, Mantelli E, Bellino S. Polyunsaturated fatty acids: what is their role in treatment of psychiatric disorders? Int J Mol Sci. 2019;20:5257
56. Mazahery H, Stonehouse W, Delshad M, et al Relationship between long chain n-3 polyunsaturated fatty acids and
autism spectrum disorder: systematic review and meta-analysis of case-control and randomised controlled trials Nutrients. 2017;9:155
57. Mazahery H, Conlon CA, Beck KL, et al A randomised-controlled trial of Vitamin D and Omega-3 long chain polyunsaturated fatty acids in the treatment of core symptoms of
autism spectrum disorder in children J Autism Dev Disorder. 2019;49:1778–1794
58. Meguid N, Anwar M, Zaki S, Kandeel W, Ahmed N, Tewfik I. Dietary patterns of children with
autism spectrum disorder: a study based in Egypt Open Access Maced J Med Sci. 2015;3:262
59. Siafis S, Çıray O, Wu H, et al Pharmacological and dietary-supplement treatments for
autism spectrum disorder: a systematic review and network meta-analysis Mol Autism. 2022;13:1–17
60. Marti L F. Dietary interventions in children with autism spectrum disorders-an updated review of the research evidence Curr Clin Pharmacol. 2014;9:335–349
61. Hoxha B, Hoxha M, Domi E, et al Folic acid and autism: a systematic review of the current state of knowledge Cells. 2021;10:1976
62. Castro K, Klein L, da S, Baronio D, Gottfried C, Riesgo R, Perry IS. Folic acid and autism: What do we know? Nutr Neuroscience. 2016;19:310–317
63. Levy SE, Hyman SL. Complementary and alternative medicine treatments for children with autism spectrum disorders Child Adolesc Psychiatr Clin N Am. 2008;17:803–820
64. Saad K, Eltayeb AA, Mohamad IL, et al A randomized, placebo-controlled trial of digestive enzymes in children with autism spectrum disorders Clin Psychopharmacol Neurosci. 2015;13:188–193
65. Adams JB, Audhya T, McDonough-Means S, et al Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity Nutr Metab. 2011;8:1–32
66. Dembowska A, Dubaj M, Bigosiński K. Small intestinal bacterial overgrowth - small intestine, big struggle J Educ Health Sport. 2022;12:210–222
67. Williams BL, Hornig M, Buie T, et al Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances PloS One. 2011;6:e24585
68. Navarro F, Liu Y, Rhoads JM. Can
probiotics benefit children with autism spectrum disorders? World J Gastroenterol. 2016;22:10093
69. Barbara G, Cremon C, Azpiroz F.
Probiotics in irritable bowel syndrome: where are we? Neurogastroenterol Motil. 2018;30:e13513
70. Vindigni SM, Zisman TL, Suskind DL, Damman CJ. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions Ther Adv Gastroenterol. 2016;9:606–625
71. Umbrello G, Esposito S. Microbiota and neurologic diseases: potential effects of
probiotics J Transl Med. 2016;14:298
72. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring Cell. 2016;165:1762–1775
73. Fattorusso A, Di Genova L, Dell’Isola GB, Mencaroni E, Esposito S. Autism spectrum disorders and the gut microbiota Nutrients. 2019:11
74. Chauhan A, Chauhan V. Oxidative stress in autism Pathophysiology. 2006;13:171–181
75. Manivasagam T, Arunadevi S, Essa MM, et al Role of oxidative stress and
antioxidants in autism Pers Food Interv Ther
Autism Spectrum Disorder Manag. 2020:193–206
76. Essa MM, Guillemin GJ, Waly MI, et al Reduced levels of antioxidant proteins in children with autism in Oman Int J Nutr Pharmacol Neurol Dis. 2012;2:53
77. Oracz J, Żyżelewicz D.
Antioxidants in cocoa
Antioxidants. 2020;9:1230
78. Sadek A. Effect of High Antioxidant Cacao Consumption on Behaviors in Children with
Autism Spectrum Disorder [PhD Thesis] 2018 Loma Linda University:10827914
https://scholarsrepository.llu.edu/etd/522
79. James SJ, Rose S, Melnyk S, et al Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism FASEB J. 2009;23:2374–2383
80. Rossignol DA, Bradstreet JJ. Evidence of mitochondrial dysfunction in autism and implications for treatment Am J Biochem Biotechnol. 2008;4:208–217
81. Blaylock RL, Strunecka A. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders Curr Med Chem. 2009;16:157–170
82. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring Cell. 2016;165:1762–1775
83. Lynch R, Diggins EL, Connors SL, et al Sulforaphane from broccoli reduces symptoms of autism: a follow-up case series from a randomized double-blind study Glob Adv Health Med. 2017:6 2164957X17735826
84. Khoo HE, Azlan A, Tang ST, Lim SM. Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits Food Nutr Res. 2017;61:1361779
85. Przybylska S. Lycopene-a bioactive carotenoid offering multiple health benefits: a review Int J Food Sci Technol. 2020;55:11–32
86. Janabi AHW, Kamboh AA, Saeed M, et al Flavonoid-rich foods (FRF): a promising nutraceutical approach against lifespan-shortening diseases Iran J Basic Med Sci. 2020;23:140
87. Bo S, Ciccone G, Castiglione A, et al Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial Curr Med Chem. 2013;20:1323–1331
88. Meng CC, Jalil AMM, Ismail A. Phenolic and theobromine contents of commercial dark, milk and white chocolates on the Malaysian market Molecules. 2009;14:200–209
89. Aruna G, Mamatha BS, Baskaran V. Lutein content of selected Indian vegetables and vegetable oils determined by HPLC J Food Compos Anal. 2009;22:632–636
90. Tsao R, Wang M, Deng Z. Lutein: separation, antioxidant activity, and potential health benefits ACS Symp Ser. 2007;956:352–372
91. Al-Ayadhi LY, Elamin NE. Camel milk as a potential therapy as an antioxidant in
autism spectrum disorder (ASD) Evid Based Complement Alternat Med. 2013:2013
92. Zafra O, Fraile S, Gutiérrez C, et al Monitoring biodegradative enzymes with nanobodies raised in Camelus dromedarius with mixtures of catabolic proteins Environ Microbiol. 2011;13:960–974
93. Varesio C, Grumi S, Zanaboni MP, et al Ketogenic dietary therapies in patients with
autism spectrum disorder: facts or fads? A scoping review and a proposal for a shared protocol Nutrients. 2021;13:2057
94. Evangeliou A, Vlachonikolis I, Mihailidou H, et al Application of a ketogenic diet in children with autistic behavior: pilot study J Child Neurol. 2003;18:113–118
95. Napoli E, Dueñas N, Giulivi C. Potential therapeutic use of the ketogenic diet in autism spectrum disorders Front Pediatr. 2014;2:69
96. Rho JM, Stafstrom CE. The ketogenic diet as a treatment paradigm for diverse neurological disorders Front Pharmacol. 2012;3:59
97. Štefan L, Prosoli R, Juranko D, et al The reliability of the mediterranean diet quality index (KIDMED) questionnaire Nutrients. 2017;9:419
98. Sanchez-Villegas A, Henriquez P, Bes-Rastrollo M, Doreste J. Mediterranean diet and depression Public Health Nutr. 2006;9:1104–1109
99. . MCT Oil for Ketosis, Your Brain and Health [Internet] Mental Strength. 2021 [cited 2022 Jun 22]. Available at:
https://mentalstrength.com/2021/07/10/mct-oil-for-ketosis-your-brain-and-health/ Accessed on 3rd June 2022
100. Illam SP, Narayanankutty A, Raghavamenon AC. Polyphenols of virgin coconut oil prevent pro-oxidant mediated cell death Toxicol Mech Methods. 2017;27:442–450
101. El-Meidany WM, Tayel DI, Waly MI. Can virgin coconut oil be the neutraceutical for chronic constipation among autistic children: a case study Can J Clin Nutr. 2019;7:26–33
102. Al-Rawi BAO. Coconut oil for improving oral health of autistic children J Res Med Dent Sci. 2018;6:75–80 Available at:
www.jrmds.in eNo.2347-2367: pNo.2347-2545
103. Olsen I, Hicks SD. Oral microbiota and
autism spectrum disorder (ASD) J Oral Microbiol. 2020;12:1702806
104. Bang M, Lee SH, Cho SH, et al Herbal medicine treatment for children with
autism spectrum disorder: a systematic review Evid Based Complement Alternat Med. 2017;2017:1–12
105. Urdaneta KE, Castillo MA, Montiel N, Semprún-Hernández N, Antonucci N, Siniscalco D. Autism spectrum disorders: potential neuro-psychopharmacotherapeutic plant-based drugs Assay Drug Dev Technol. 2018;16:433–444
106. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR. A clinical trial of glutathione supplementation in autism spectrum disorders Med Sci Monit. 2011;17:CR677–CR682
107. Johnson CR, Handen BL, Zimmer M, Sacco K, Turner K. Effects of gluten free/casein free diet in young children with autism: a pilot study J Dev Phys Disabil. 2011;23:213–225
108. Xia RR. Effectiveness of nutritional supplements for reducing symptoms in autism-spectrum disorder: a case report J Altern Complement Med. 2011;17:271–274
109. Pennesi CM, Klein LC. Effectiveness of the gluten-free, casein-free diet for children diagnosed with
autism spectrum disorder: based on parental report Nutr Neurosci. 2012;15:85–91
110. Graf-Myles J, Farmer C, Thurm A, et al Dietary adequacy of children with autism compared to controls and the impact of restricted diet J Dev Behav Pediatr. 2013;34:449–459
111. AL-Ayadhi LY, Elamin NE. Camel milk as a potential therapy as an antioxidant in
autism spectrum disorder (ASD) Evid Based Complement Alternat Med. 2013;2013:1–8
112. Singh K, Connors SL, Macklin EA, et al Sulforaphane treatment of
autism spectrum disorder (ASD) Proc Natl Acad Sci. 2014;111:15550–15555
113. Al-Ayadhi LY, Halepoto DM, AL-Dress AM, Mitwali Y, Zainah R. Behavioral benefits of camel milk in subjects with
autism spectrum disorder J Coll Physicians Surg Pak. 2015;25:819–823
114. Hyman SL, Stewart PA, Foley J, et al The gluten-free/casein-free diet: a double-blind challenge trial in children with autism J Autism Dev Disord. 2016;46:205–220
115. Ghalichi F, Ghaemmaghami J, Malek A, Ostadrahimi A. Effect of gluten free diet on gastrointestinal and behavioral indices for children with autism spectrum disorders: a randomized clinical trial World J Pediatr. 2016;12:436–442
116. El-Rashidy O, El-Baz F, El-Gendy Y, Khalaf R, Reda D, Saad K. Ketogenic diet versus gluten free casein free diet in autistic children: a case-control study Metab Brain Dis. 2017;32:1935–1941
117. Al-Askar M, Bhat RS, Selim M, Al-Ayadhi L, El-Ansary A. Postnatal treatment using curcumin supplements to amend the damage in VPA-induced rodent models of autism BMC Complement Altern Med. 2017;17:259
118. Sadek A, Berk LS, Mainess K, Daher NS. A pilot study: parent perceptions of behavior change in their child with
autism spectrum disorder following high antioxidant cacao consumption Integr Med Clin J. 2018;17:31–38
119. Mazahery H, Conlon CA, Beck KL, et al A randomised-controlled trial of vitamin d and omega-3 long chain polyunsaturated fatty acids in the treatment of core symptoms of
autism spectrum disorder in children J Autism Dev Disord. 2019;49:1778–1794
120. Arnold LE, Luna RA, Williams K, et al
Probiotics for gastrointestinal symptoms and quality of life in autism: a placebo-controlled pilot trial. J Child Adolesc Psychopharmacol. 2019;29:659–669
121. González-Domenech PJ, Díaz Atienza F, García Pablos C, Fernández Soto ML, Martínez-Ortega JM, Gutiérrez-Rojas L. Influence of a combined gluten-free and casein-free diet on behavior disorders in children and adolescents diagnosed with
autism spectrum disorder: a 12-month follow-up clinical trial J Autism Dev Disord. 2020;50:935–948
122. Nogay NH, Walton J, Roberts KM, Nahikian-Nelms M, Witwer AN. The effect of the low FODMAP diet on gastrointestinal symptoms, behavioral problems and nutrient intake in children with
autism spectrum disorder: a randomized controlled pilot trial J Autism Dev Disord. 2021;51:2800–2811
123. El-Meidany WMR, Tayel DI, Abd El-Maksoud MS, Fetoh EM, El-Sahn FAF. Inhibition of the intestinal candida overgrowth among autistic children after the virgin coconut oil intake Can J Clin Nutr. 2022;10:29–37
124. Nyaradi A, Li J, Foster JK, et al Good-quality diet in the early years may have a positive effect on academic achievement Acta Paediatr. 2016;105:e209–e218
125. Lofstedt R. Risk communication and the FSA: the food colourings case J Risk Res. 2009;12:537–557
126. Dufault RJ. Food labeling requirements may explain lower autism and ADHD prevalence in the United Kingdom Integr Food Nutr Metab. 2018;5:1–2
127. . Nutrition C for FS and A. Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) FDA [Internet]. 2022 [cited 2022 Sep 13]. Available at:
https://www.fda.gov/food/food-allergensgluten-free-guidance-documents-regulatory-information/food-allergen-labeling-and-consumer-protection-act-2004-falcpa Accessed on 8th June 2022
128. Rahman A, Divan G, Hamdani SU, et al Effectiveness of the parent-mediated intervention for children with
autism spectrum disorder in south Asia in India and Pakistan (PASS): a randomised controlled trial Lancet Psychiatry. 2016;3:128–136
129. Sun X, Allison C. A review of the prevalence of
Autism Spectrum Disorder in Asia Res Autism Spectr Disord. 2010;4:156–167
130. Didar Hossain M, Ahmed H, Uddin MMJ, et al Autism spectrum disorders (ASD) in South Asia: a systematic review BMC Psychiatry. 2017;17:281
131. Hossain MD, Ahmed HU, Jalal Uddin MM, et al Autism Spectrum disorders (ASD) in South Asia: a systematic review BMC Psychiatry. 2017;17:281
132. Minhas A, Vajaratkar V, Divan G, et al Parents’ perspectives on care of children with autistic spectrum disorder in South Asia - views from Pakistan and India Int Rev Psychiatry. 2015;27:247–256
133. Farooq A, Ahmed S. Sociocultural barriers to early diagnosis of
autism spectrum disorder Life Sci. 2020;1:6
