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. Behavioral complexities such as anxiety, depression, aggression, hyperactivity, self-harm, and tantrums have been widely reported in people with ASD. In the past people co-related autism with schizophrenia. Leo Kanner back in 1943 at Johns Hopkins University defined autism as introversion, difficulty in social interactions, repetitive restrictive behavior, and peculiar food choices.
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. Furthermore, the non-heritable acquired risk factors such as environmental factors play a dual role in ASD etiology. 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.
Malnutrition is common in children with ASD owing to gastrointestinal issues, abnormal sensory processing, unusual food choices, and consumption of food allergies. Particular food choices and preferences are the primary causes of nutritional imbalance. In particular, artificial food colors and food additives are linked with the development of hyperactivity and sleep disturbances in ASD. 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. 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.
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.
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. However, no specific causative element with substantial impact is recognized yet.
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. 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.
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. 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.
Previous studies state that the methods for estimating energy and nutrient intake such as dietary reference intake (DRIs), 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. 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. 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. Diagnosis before adverse disorder effects could significantly reduce the healthcare cost associated with ASD, though the current processes are time-consuming, ineffectual, and uneconomical.
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. In this regard, gut brain axis is known as the mode of communication between the gut and brain. 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. However, mother feed can reduce the occurrence and severity of infections by promoting a healthy gut microflora.
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. 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. 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.
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). According to the findings from another study on ASD in children, 70% of autistic children had GI problems, compared to control group. 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. Further research is needed to fully understand the link between gut brain axis and complexities of ASD to implement better preventive and treatment strategies.
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. 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. 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.
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. Elimination diet is another approach to determine the triggering effects of certain foods leading to aggravate the disease symptoms. 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. 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. 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.
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. 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). 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).
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. 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. 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.
C. albicans, the most common human fungal pathogen, can cause infections with a 40% mortality rate. 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.
Effect of dietary supplements on ASD
The omega-3 and omega-6 families are the two most common classes of PUFA compounds. 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. 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.
Autistic children are usually deficient in vitamin D, vitamin C, calcium, folate, magnesium, phosphorus, zinc, and iron. Additionally, ASD children also have lower macronutrient (energy, carbohydrates, protein, and fiber) intakes followed by picky eating patterns. 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. Large prospective controlled trials are needed to investigate serum levels and folic acid consumption in autistic people. 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. 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.
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. 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.
Recent research has shown that probiotics may help to improve bowel habits, behavior, and social functioning in autistic people. 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). Most commonly used probiotic species include Bifidobacterium (bifidum, breve) and Lactobacillus (acidophilus, casein).Lactobacillus reuteri has the capacity to restore gut microbiota and behavioral abnormalities caused by maternal high fat diet. Though well-designed, randomized, placebo-controlled clinical studies are necessary to establish the efficacy of probiotics in the treatment of ASD.
Evidence has shown that the pathophysiology of ASD is correlated to oxidative stress due to interruption of body’s antioxidant defense system. 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. In this regard, polyphenols, present in cocoa, have been reported to scavenge free radicals from the body. Also, a study on the intake of a nutraceuticals, high in antioxidative properties have got potential benefits in enhancing behavior in children with ASD. In concomitant, glutathione, which can be used to treat ASD, detoxifies the body, and protects it from oxidative damage. Nutritional supplementation to minimize oxidative stress, as well as factors to increase reduced glutathione, is validated and rationale approaches to treat ASD. 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. Additionally, sulforaphane supplementation improves autism symptoms particularly in social responsiveness autism symptoms. [Table 1].
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. There are many beneficial effects of nano-bodies in this milk on infectious agents and the immune system. 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.
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. 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. Other neuro-psychiatric disorders can also be treated through a ketogenic diet.
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. 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.
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. 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. 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. Similarly, another study determined the efficacy of coconut oil in oral health and showed improvements in children’s oral hygiene.
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. 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. [Table 2].
In a child’s early years, a healthy diet is a predictor of subsequent academic success. 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. 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. 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. 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.
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. 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.
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. 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. 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. Further research is required to determine the scope of autistic spectrum disorder-related concerns in low/middle income countries.
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
Conflicts of interest
There are no conflicts of interest.
The authors would like to acknowledge Dr. Sana Ikram for her constructive input and revision of manuscript for the improvement of language.
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