Review Article

Brain-gut-brain axis, nutrition, and autism spectrum disorders: a

review
Najlaa Hamed Almohmadi^

Clinical Nutrition Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
Correspondence to: Najlaa Hamed Almohmadi, PhD. Clinical Nutrition Department, Faculty of Applied Medical Sciences, Umm Al-Qura University,
P.O Box 715, Makkah 21955, Saudi Arabia. Email: [email protected].

Abstract: Autism is a neurological disorder that affects social skills and behavior. A significant number of
children with autism spectrum disorders (ASDs) may not display noticeable symptoms until they reach the
age of three or older. Several factors, including genetic and environmental issues, could affect the progression
of ASD in children. Dietary behavior or administration may have a crucial role in the development of autism.
Epidemiological investigations have demonstrated that environmental influences play a significant role in
how changes in diet can affect behavior and physiology. However, exclusion diets have not been thoroughly
studied in relation to this effect. Atypical food behaviors, altered nutritional profiles, and being overweight,
obese, or underweight are all associated with autism in children. Overweight or underweight was common
in children with autism, but it was not necessarily uncommon in children with normal growth. Moreover,
deficiencies in certain vitamins (B12, B9, and D), minerals (calcium and iron), fatty acids (omega-3 and -6),
energy, and protein have been documented in children with ASD. The deficiency of these nutrients may
lead to gastrointestinal (GI) symptoms and change the microbiota in children with ASD. Some nutritional
interventions could help individuals with ASD to improve their mental health. Recognizing dietary habits
and nutrient requirements can help in planning the best overall treatment for autism. This review discusses
GI symptoms and disorders related to nutrition and nutrient-dense diets for ASD.

Keywords: Children; autism; nutrition deficiency; metabolism

Submitted May 12, 2024. Accepted for publication Jul 16, 2024. Published online Sep 20, 2024.
doi: 10.21037/tp-24-182
View this article at: https://dx.doi.org/10.21037/tp-24-182

Introduction percentage of cases are attributed to external variables like

teratogens, toxic environments, prenatal infections like
A neurologically based developmental illness that first
cytomegalovirus (CMV) and rubella, and perinatal traumas
appears in childhood is known as autism spectrum disorder
(3,4). People with ASD can also have gut syndrome, a
(ASD). It involves restricted or repetitive patterns of
behavior, interests, and activities, as well as challenges in condition characterized by abnormal colonies of bacteria
developing social relationships and interactions (1,2). and gastrointestinal (GI) irritation that impairs bowel
Over the past 20 years, there has been an enormous rise motility. There may be a basic connection between
in both the occurrence and the prevalence of autism. With nutrition, ASD, and the gut microbiome. The wide range
a male-to-female sex proportion between 2:1 and 3:1, it of GI symptoms present in ASD patients indicates the need
is more common in males. The cause of autism is mainly to incorporate nutritional support into standard treatment.
determined by genetics along with early environmental A healthy diet can help alleviate digestive, metabolic, and
factors. According to epidemiologic research, only a small mental health symptoms. Unfortunately, very few medical

^ ORCID: 0000-0002-1188-7036.

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Translational Pediatrics, Vol 13, No 9 September 2024 1653

professionals and dietitians monitor the dietary habits and to enhance their quality of life and prevent the worsening
food intake of patients with ASD (5). Approximately 25% of their condition. Different dietary strategies have been
of children diagnosed with ASD have at least one persistent explored to alleviate ASD symptoms, especially in addressing
digestive tract syndrome. digestive problems that individuals with ASD common
Moreover, GI problems may interfere with the experience. The relationship between microbiota, gut health,
absorption of vitamins and minerals. GI problems like and brain functions has been taken into consideration in the
diarrhea, constipation, discomfort in the abdomen, and development of various dietary interventions.
gastric acid can be relieved by following a healthy diet. Abdelhaliem et al. (16) indicated that children with ASD
Scientific studies suggested that the pathophysiology of often exhibit irregular feeding patterns and are at a higher
autism may start early in fetal development (2,4). One of risk of malnutrition compared to children without the
the responsibilities of a dietitian is to assess a mother’s condition. Consequently, it is essential to assess the dietary
dietary status accurately before and during pregnancy. needs of kids with ASD to prevent nutrient deficiencies
This assessment allows for dietary adjustments to be through dietary modifications or supplementation with the
made as necessary to improve metabolic indicators (6). appropriate minerals and vitamins. Additionally, Caetano
Eating habits may be impacted by some ASD traits, such and Gurgel (17) found that children with ASD have higher
as behavioral rigidity, a demand for uniformity, schedules, rates of obesity and overweight, along with inadequate
and routines (7). According to Nadon et al. (8), children intake of essential vitamins and minerals. Also, Moiniafshari
with ASD likewise have a distinct perceptual profile that et al. (18) concluded that combining nutrition and exercise
is susceptible to stringent food selection based on form, programs can have a more significant positive impact on
appearance, flavor, or warmth (9). These children may individuals with ASD when implemented together.
also exhibit low blood sugar or hyperactivity in response Individuals with ASD commonly experience behavioral
to tactile, smell, and visual cues. As a result, kids begin issues and GI problems due to disruptions in the gut-brain-
avoiding food and consume only a small amount of the microbiota axis. Research has explored the relationship between
items they eat regularly. In certain instances, kids may also diet and gut-related issues, with this review aiming to investigate
exhibit digestive problems, physiological reactions to food, diet therapies for ASD patients and explore novel dietary
or difficulties with movement related to eating and chewing interventions considering the microbiota-intestinal-brain axis.
food (10-12). Specific diets are restricted due to these
related disorders; for instance, acidic foods are frequently
Nutrition problems
avoided, while sweet foods with high energy levels are
encouraged (9,12). Diet and nutrition have crucial roles in According to Yang (19), feeding issues are conditions
maintaining a healthy body and mind. Consuming nutrient- that have detrimental effects on dietary habits, growth,
rich foods can help prevent obesity (13). socialization, and psychology because of an individual’s
Early-onset obesity can impact individuals across all age incapacity or unwillingness to orally consume the necessary
groups, including adults, adolescents, and children, as well amounts of nutrients, fluids, or calories to thrive. Several
as those with ASD and related illnesses. Eating disorders feeding problems were listed by Rastam (20) in the
can lead to the accumulation of oxidative radicals, leading DSM-5. The GI disorders pica/rumination disease (20) and
to a decline in both mental and physical health. Despite avoidant/restrictive food consumption disorders are the
awareness of these issues, parents often find it challenging most frequently observed in individuals with ASD. These
to regulate their children’s eating habits. Collaboration feeding disorders include food rejection, a limited variety
among doctors, parents, nutritionists, and dieticians is of foods, disrupted meal behaviors, food selectivity, and
essential to enhance their quality of life. restricted intake (21).
According to the study of Esparham et al. (14), individuals Co-occurring conditions that often accompany ASD
with ASD suggest that there may be biological, metabolic, include symptoms related to the digestive tract, sleep
and dietary connections to the disorder in affected youngsters. problems, seizures, behavioral issues, attention-deficit/
Additionally, Rodop et al. (15) stated that everyone is hyperactivity disorder, anxiety, and toileting difficulties
required to eat well because it is one of our fundamental (22-25). Another common issue associated with ASD is
biological necessities. It is important for individuals with feeding problems (26). The incidence of feeding issues in
systemic symptoms like ASD to pay attention to their diet children and adolescents with ASD varies greatly among

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1654 Almohmadi. Nutrients metabolism in autistic children

studies. Previously, a study by Schreck et al. (27) found significant dietary preferences. The research indicated that
that 13–80% of individuals experience feeding difficulties. some children experienced stomach symptoms on a weekly
Nadon et al. (8) also supported this finding, reporting that basis, and feeding issues were associated with bowel
80% of children with ASD struggle with eating. Children problems (38). To explore potential factors contributing
with ASD tend to have more digestive issues and a narrower to GI problems in children with development delays,
range of foods in their diet compared to children without Field et al. (37) examined nutritional issues in children.
ASD (28). Given the increasing recognition of feeding They identified gastroesophageal reflux disease (GERD)
issues in recent years, it is likely that a significant proportion as the most common condition in the group, closely
of individuals with ASD experience challenges related to linked to food aversion. Food aversion is a complex eating
food. Research indicates that concurrent eating issues could problem often observed in individuals with ASD. A study
put a person with ASD at risk for health issues. Chronic by Field et al. (37) reported that 14 out of 20 ASD children
alimentary problems can have a negative effect on health with selective eating also experienced constipation or
and development, leading to stunting, malnourishment, diarrhea. Chronic digestive problems affect vitamin and
social impairments, and subpar academic performance (21). mineral intake in 25% of children diagnosed with ASD. A
Major difficulties with food preparation are also related to healthy diet can help alleviate these symptoms. Dietitians
deficiencies in skills, including oral-motor impairments that evaluate mothers’ diets before and throughout pregnancy
impact the child’s ability to chew, swallow, and suck (29). and make necessary adjustments to improve metabolic
According to Schreck et al. (27), children with both ASD markers (6). Leaky gut syndrome is a potential side effect
and feeding issues are more experienced with medical of individuals with ASD because of bacterial proliferation
problems related to nutrition, such as osteoporosis or poor and inflammation. There is a proposed connection between
bone development (3). Children with ASD who struggle food, gut microbiota, and ASD. Nutritional therapy is
with eating can become malnourished and require invasive essential for relieving GI, metabolic, and psychological
medical procedures like the insertion of tubes for nutrition, symptoms, but few doctors and nutritionists can provide
as noted in (30). Deficiencies in vitamins and minerals, such close monitoring for patients with ASD (5). Additionally,
as reduced calcium intake (21), lowered levels of iron (31), eating disorders have been associated with an accumulation
and reduced vitamin C intake (32) are commonly observed of reactive radicals, which can negatively impact both
in children with ASD who have eating difficulties (1). physical and mental well-being (13).
Research by Egan et al. (33) suggests that children with Effective therapies to enhance metabolic conditions and
ASD tend to prefer foods high in fats or sweets, which overall health in individuals with ASD have been the subject
aligns with the growing body of evidence indicating a of current studies. Low levels of exercise, poor eating
higher risk of obesity in this population. habits and quality, problems with behavior, and poor social
relationships can all contribute to poor health. Dietary
and exercise treatments have garnered considerable
Nutrition disorder and symptoms of the GI
interest among the dozens of medical techniques. Owing
There are limited studies on the connection between to elevated inflammation levels, elevated interleukin-6
digestive tract symptoms and feeding issues (26,34). (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-
According to Mannion et al. (35), GI symptoms had alpha (TNF-α), and decreased cell adhesion molecules
occurred in 79.3% of individuals with ASD. As pointed (CAMs), nutrition and exercise will become increasingly
out by the last authors (35), 51.7% and 49.4% of those crucial for individuals with ASD (39). It has recently
surveyed with ASD experienced abdominal discomfort and been suggested that individuals with ASD may have a
diarrhea as the most frequent GI symptoms. Additionally, high frequency of nutritional deficits, potentially due to
research by Wang et al. (36) found that GI problems their food choices, eating habits, and restricted diets. By
were significantly higher in children with ASD compared analyzing food logs and using the Healthy Eating Index
to typically developing children. Field et al. (37) noted (HEI) in comparison to the Dietary Reference Intake (DRI),
that most participants had underlying health issues that nutritional assessment can help identify dietary patterns and
contributed to their feeding difficulties. In research by Özen nutritional status (40). Furthermore, nutritional quality and
et al. (38) on GI symptoms and dietary habits in children intake, as well as their impact on physiological markers such
with ASD, it was found that over 60% of the children had as IL-6, homocysteine, digestion, and other physiological

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Translational Pediatrics, Vol 13, No 9 September 2024 1655

markers, can be assessed using tools like dietary records and must address sensory sensitivity, such as color, taste, and
the Food Frequency Questionnaire (FFQ) (41). texture. As noted by Twachtman-Reilly et al. (47), sensory
regulation is the process that enables a person to misprocess
the vast amount of sensory data that continuously nourishes
Nutrition issues and challenging behavior
the neural network properly. Leekam et al. (48) found that
ASD is known for its repetitive and restricted habits, sensory processing problems affect 78–90% of children
including regulated meals and rigid feeding schedules (34). with ASD. A study by Laud et al. (49) revealed that there is
It has been claimed that problematic eating habits and eating a common observation in research that sensory impairment
issues may be linked to behavioral routines and mental or defensive behavior is the cause of the elevated incidences
obsessions associated with ASD. Social expectations of of feeding difficulties in ASD.
feeding circumstances can impact interpersonal abilities and Cermak et al. (50) found that the sense of smell can
interactions when mealtime behavior is problematic (21). play a significant role in clarifying food choice and that
Socialization challenges may affect the enjoyment of eating there is a connection between feeding problems and
with others (8), potentially leading to problematic habits. sensory defensive behavior. In their study, Nadon et al. (10)
Despite the recognition of the commonality of food issues investigated the connection between the frequency of
and challenging behavior, there is a lack of understanding in eating issues in kids with ASD and their sensory processing
research addressing the reasons underlying these actions (42). issues. They found a substantial correlation between the
In their research, Curtin et al. (43) explained the importance number of dietary disorders in kids diagnosed with ASD
of children eating healthily and embracing family rituals such as and their visual and aural sensitivity. The same authors
dining at the table without electronics or television, engaging identified phenotypes for additional co-occurring disorders,
in family conversations, and learning to eat independently. like sleep issues. Goldman et al. (51) supported a case study
Adjusting to new foods and eating routines can be particularly of the sleep phenotype associated with ASD. Żarnowska
challenging for children with autism and ASD (44). et al. (52) performed an investigation on the therapeutic
Additionally, children with ASD may exhibit a specific eating use of a ketogenic diet (KD) in children with autism.
pattern, given the connections between food issues and The research showed notable clinical benefits, including
other concurrent disorders. Some children with ASD and improved attention span, enhanced interpersonal abilities,
eating difficulties may have a higher likelihood of demanding and decreased fear, anxiety, and mood disorders. They
behavior, GI symptoms, co-occurring psychopathology, also linked the behavioral and psychological changes
and sensory abnormalities. The condition known as ASD is with decreased electron chain activity and decreased gene
diverse (45). Research by Hill et al. (46) suggests that children expression in the mitochondria. Several researchers have
with ASD tend to avoid “fruits, vegetables, and whole grains” demonstrated that individuals on a carbohydrate-free diet
in favor of high-energy, low-nutrient diets. Children with develop a dependence on ketones, leading to decreased
autism and ASD, often labeled as “picky eaters”, may have mitochondrial activity and reduced energy levels, which
preferences for specific food types, flavors, and textures, posing may contribute to observable changes in behavior (53,54).
a significant challenge to their parents and caregivers (44). To Additionally, Zeybek and Yurttagul (40) have shown that
address these issues, parents should introduce nutritious diets these screening methods could be useful for tracking growth
to their children during the weaning process. patterns and body types, particularly among teenagers and
In addition, specific diets, limited food preferences, the young adults with ASD. Numerous nutritional therapies
introduction of new meals, or physical activity can often are designed to address ASD by improving physical
sometimes trigger aggressive behavior in children with and physiological health by reducing food allergies and
ASD, leading parents to accommodate their requests (44). intolerances and improving dietary patterns (55). These
Therefore, it is advisable to gradually provide new foods to treatments focus on promoting a moderately nutritious
these children to help them become accustomed to different and healthy diet to improve lipid profiles, body mass index
flavors and textures (8). (BMI), and metabolic status in individuals with ASD (56).
Improving health is a critical aspect when addressing ASD,
as studies have demonstrated the links between eating
Nutrition problems and sensory disorder
behaviors and elevated insulin levels, obesity, chronic
Successful behavioral methods for children with ASD inflammation, and metabolic syndrome in individuals with

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1656 Almohmadi. Nutrients metabolism in autistic children

Table 1 Previous research on metabolic regulation

Summary Sample size (N) References

Discovered that the ketone diet significantly reduces eating, tantrums, and behavior 35 in addition to one case (52)
study

Discovered sensory problems with food and dietary habits. The sensory patterns of these 95 instances compared (8)
children can be completely uncontrollable and dissimilar siblings within the same
family who were not
autistic to autistic children

To alleviate symptoms, a ketogenic diet lowers the expression of the mitochondrial gene – (53)

Due to the decrease in mitochondrial gene expression brought about by a ketogenic diet, – (54)
behavior, hunger, and other major symptoms of autism improved dramatically

Tantrums, expressive language, autism and ASD, and improved PGI-R subscales are all areas 141 (59)
where minerals and vitamins can be helpful

Diets that are vegetarian and gluten-free improve behavioral outcomes – (60)

Alternative and complementary therapies worked better for most children. The greatest 376 (61)
outcomes and fewest adverse reactions came from cutting back on medication and raising
melatonin

A rise in sociability, motor abilities, and physical exercise controls appetite and alters 35 (62)
psychological, emotional, and interpersonal growth
ASD, autism spectrum disorder; PGI-R, patient global impression-revised.

ASD. These conditions can be positively impacted by plants and animals, have microbiota. After birth, bacteria
implementing effective nutritional therapies (57). begin to colonize the body, and by the ages of three to five,
There is a suggestion that a greater frequency of systemic they resemble the mature microbiome, which then stabilizes
inflammation in ASD may lead to various metabolic largely (64). The absorption of drugs and defense against
abnormalities, such as insulin resistance and dyslipidemia, pathogens is influenced by microbiota (65). The microbial
that can be treated with dietary therapies. The approach flora in the stomach affects the regulation of hunger, energy
could be beneficial as individuals with ASD often have utilization, stomach processes, and nutrient uptake (66).
limited dietary intake, with refined foods making up a Many human diseases, such as cancer, metabolic syndrome,
significant portion of their diet, potentially exacerbating bowel inflammation, obesity, and neurological disorders,
the inflammatory response (58). Vitamin D3 and omega-3 have been linked to the disruption or imbalance of the
fatty acids, when consumed as nutrients, have been shown microbiota (67,68).
to reduce inflammatory reactions in individuals with ASD, The brain and the GI tract interact in several significant
potentially improving metabolism (58). ways. One method is through the parasympathetic
Table 1 summarizes a few of the research topics we nervous system’s Vagus nerve. The Vagus nerve serves as
covered. Figure 1 illustrates how controlling metabolism an interface between the brain and the intestinal tract,
through nutrition might improve the lives of kids with distinguishing between harmful and beneficial bacteria
autism and ASD. and transmitting messages with anxiogenic and calming
properties (67). Bacterial species also play a role in
generating immune-regulating metabolites, such as short-
The significance of microbes in nutrient
chain fatty acids produced during the decomposition of
metabolism
carbohydrates. According to Louis et al., short-chain fatty
A population of microbes consisting of bacteria, fungi, viruses, acids like propionic acid (PPA), butyric acid (BA), and acetic
archaea, and parasites is referred to as a microbiome (63). acid (AA) offer various benefits to the host (68), including
All multicellular species that have been studied, including improved lipid profile, colon health, and weight control.

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Translational Pediatrics, Vol 13, No 9 September 2024 1657

Probiotics

Decreased glucose induced

mitochondria dysfunction
Autism
disorder
Vitamins

Minerals

Strategy to reduce the autism

Immune Increase oxidative
impairment stress Ensconced microbiota community

in children
Gastrointestinal Inflammation
disease Higher levels of vitamin and
minerals
Eating behavior
Epilepsy
disorder

Decreased of gluten free diet

Insufficient of vitamin Communication
and minerals skill impairment

Camel milk
Cardiovascular Reduce the carbohydrates
Hyperactivity disease

Figure 1 Nutritional control of metabolism in children with ASDs. ASD, autism spectrum disorder.

However, the accumulation of these acids, particularly with autism can alter the metabolism and functionality of
PPA, can also impact the neurological system and has been neurons such as 5-HT and catecholamines, exacerbating
linked to ASD (69-72). symptoms associated with serotonergic structure
Propionate reduces serotonin (5-hydroxytryptamine, or malfunction (76,77). Approximately 30% of children with
5-HT) release in the gut. It affects the functioning of the autism have high levels of 5-HT in their red blood cells
central nervous system and acts as a neurochemical. Low and blood cells, making 5-HT a potential indicator for
levels of dopamine and 5-HT in the brain are believed the presence of ASD (78). Intestinal permeability may
to be responsible for these effects (73). Additionally, they allow 5-HT to enter the bloodstream and elevate blood
may have a role in hyperserotonemia (excessive serotonin levels of the hormone (78,79). Furthermore, reduced
production) that is seen in autistic children (74). Certain 5-HT inactivation can lead to increased 5-HT levels,
symptoms of ASD may arise due to the displacement of the which are associated with intestinal inflammation and may
brain by transporters or passive diffusion through the blood- contribute to the inflammatory response (80). Contrary to
brain barrier of higher levels of microorganisms that produce popular belief, the availability of tryptophan and serotonin
short-chain fatty acids (such as Clostridia, Desulfovibrio, and synthesis can be affected by an imbalance (disturbance of
Bacteroides) found in autistic individuals (75). While the the microbiome) that reduces the absorption of amino
exact mechanism of how short-chain fatty acids affect acids from food. A decrease in tryptophan levels is linked
behavior is still unclear, both epigenetic modifications to the exacerbation of repetitive behaviors observed in
and mitochondrial dysfunction (Krebs cycle) may be individuals with ASD (81). As Rodop et al. (15) emphasized,
involved (Figure 2) (73). Another important factor for dietary habits are crucial for individuals with ASD or other
social interaction and repetitive behaviors is 5-HT. Due systemic symptoms to maintain a better quality of life and
to its high production in the gut and metabolism by slow the progression of their condition. Various diets have
intestinal microbiota, 5-HT is implicated in regulating been explored to alleviate ASD symptoms, with a focus on
neurodevelopment (76). addressing digestive issues in individuals with ASD (82).
According to reports, certain bacterial species (Lactobacillus Many dietary regimens have been designed with the gut-
and Clostridium spp.) found in the feces specimens of children brain-microbiota axis in mind.

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1658 Almohmadi. Nutrients metabolism in autistic children

Gut microbiota

Immune system

Neuroendocrine system

Circulatory system

Enteric nervous system

Microbiota dysbiosis

Figure 2 An illustration of the relationship between the axis of gut and brain. The gut-brain axis may influence both gastrointestinal and
the brain’s operation through bilateral interaction. This unidirectional transmission is mostly controlled by the gut microbiota, which is
regulated by dietary interventions.

Different types of treatment for metabolic status and outdoors, are among the physical activities most
in ASD frequently prescribed for individuals with ASD. In the
study of Shahrasfenghar et al. (87), these exercises can have
Increasing the levels of physical activity seems to be an
greater positive effects, particularly when recommended
effective additional treatment to improve the metabolic
for longer periods. They may improve physical fitness and
state in individuals with ASD and enhance dietary
metabolic conditions in people with ASD. When combined
conditions. Since ASD is more prevalent in individuals
with dietary therapies such as vitamin D3 supplements,
who are overweight and have lower levels of the hormone’s
aquatic sports can be an effective way to enhance the
adiponectin, ghrelin, and leptin, this health concern is
becoming more significant (83). Various physical exercise metabolic state of individuals with ASD (58).
strategies are recommended as beneficial activities for Recently, there has been a notable increase in the
individuals with ASD; however, it is crucial to consider that popularity of aquatic physical exercise, and several
ASD has specific needs. Therefore, some activities that are therapies, such as combining it with vitamin medication,
recommended or utilized may not be suitable for individuals are beneficial for reducing inflammation and enhancing
with ASD. metabolic conditions in people with ASD (55). An improved
Moderate-intensity physical activity has been demonstrated inflammatory reaction could result in an improved
to enhance metabolic reactions and inflammatory responses, metabolic state. Following Mazahery et al. (58), there is
even without changes in adipose tissue. Regular evidence to suggest that incorporating water-based activities
participation in higher-intensity physical activity has been with the addition of vitamin D3 may enhance the BMI,
linked to multiple reported benefits (84,85). The optimal waist-to-hip ratio (WHR), and other demographic metrics,
amount of physical activity is still debated in several studies. including cholesterol levels, in individuals with ASD.
Some studies suggest that higher-intensity physical activities Other therapeutic techniques for enhancing
may increase inflammation, and longer rest intervals may cardiovascular alterations in cholesterol levels and metabolic
have the opposite effect (86). This finding seems to improve states in ASD include coordinated physical activity (88).
the metabolic condition of individuals with ASD. There is Additional physical activity interventions could involve
growing interest in the impact of different types of sports indoor and home-based activities, which were particularly
on the health of individuals with ASD. important throughout the coronavirus disease 2019
Aerobic exercises, which can be performed both indoors (COVID-19) pandemic. Individuals with ASD spent more

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Translational Pediatrics, Vol 13, No 9 September 2024 1659

time at home due to quarantines and lockdowns. Given the to moderate improvements (92).
poor physical fitness of many individuals with ASD, this In another study, a child who experienced both seizures
kind of physical activity has concentrated on improving and autism was placed on a KD with a fat ratio of 1.5 to
strength and flexibility in a safe, comfortable setting under protein and carbohydrates. Several benefits were observed
the guidance of a therapist. Typically, these exercises are following the diet, including improvements in behavioral
recommended to enhance body composition, manage features and reversal of morbid obesity and dementia.
weight, and prevent metabolic illnesses (89,90). After adhering to a similar diet for a few years, the
child’s IQ increased by 70 points, and his severe autism
classification changed to a non-autistic condition as his
Some diets that affect ASDs
CARS rating decreased from 49 to 17 (30). Seizures also
KD ceased after following the diet for 14 months. Although
the KD was originally developed for treating EL seizures,
A KD consists of very low carbohydrates, adequate protein,
it requires a high-fat content, moderate carbohydrates,
and high fat. It has a proven track record of working for and adequate protein. Studies have shown that the KD
patients who are resistant to anticonvulsant medication reduces repetitive movements and promotes social
therapy, particularly those with epilepsy (91). Studies have interactions in mice and rats.
also shown that a KD can reduce the severity of behavioral Furthermore, children on the KD exhibited higher IQ
issues and seizures in patients with mild to severe ASD scores and lower CARS scores. Conducting further research
(92,93). In one study, pregnant Swiss rats were injected with on the efficacy of the KD for ASD will help establish the
valproic acid (VPA) on the eleventh day of pregnancy at a correlation between the two. Additionally, parents of the
dose of 600 mg/kg. The rats were divided into two groups: children noted reductions in common ASD symptoms such
a control group that did not receive VPA and a treatment as inattention, speech difficulties, attention issues, and gaze
group that did. Half of each group was fed a KD, while problems (96).
the other half was fed a standard diet (SD). After 70 days, In another trial, 15 children with ASD received extra
a significant difference in social behavior was observed medium-chain triglycerides oil and a modified ketogenic,
between the VPA mice that received SD and those that gluten-free meal. This intervention was implemented due to
were treated with KD (94). the presence of both primary and secondary mitochondrial
In another study, male and female epileptic (EL) mice issues in individuals with ASD. After 3 months, the children
with ASD and epilepsy were evaluated for their behavior, as showed significant improvements in their Impact on Society
they are commonly used in models of autism and epilepsy. and Total Plan-2 scores for ASD monitoring. Furthermore,
Three different diet regimens were tested for 3 to 4 weeks: parents of these children observed reductions in common
one SD and two KD, with one KD having a higher fat ratio. ASD symptoms, including inattention, speech difficulties,
In the social recognition test, male and female mice in the attention issues, and gaze problems (96).
KD-fed groups spent more time interacting with a foreign Diet is crucial for treating GI issues that individuals
mouse. It was recently discovered that preferences for with ASD experience (15). Several dietary regimes have
novel mice increased, especially in females on a higher-fat been developed with the gut-brain-microbiota axis
KD. Meanwhile, self-grooming, a repetitive behavior test, kept in mind. Some studies have examined how ASD
significantly decreased in male mice. According to Ruskin and neurodevelopmental problems are affected by the
et al. (95), the decrease in self-grooming activity among Mediterranean diet, the low-oxalate diet, camel’s milk,
females was not statistically significant. the gluten-free/casein-free eating habits, and the KD.
In a human pilot study, thirty children diagnosed with Nevertheless, the investigation provides scant evidence
ASD were examined. They followed a diet consisting of to support the efficacy of these diets. Table 2 provides
30% medium-chain triglycerides, 30% heavy cream, 11% an overview of the studies covering the impact of KD
saturated fat, 19% carbohydrates, and 10% protein for treatment on autism.
6 months. Forty percent of the children either could not
tolerate the diet or did not adhere to it. Only two children
Probiotics supplementation
showed significant improvements on the Childhood Autism
Rating Scale (CARS), while the rest demonstrated modest Probiotic treatment for individuals with ASD is a new

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1660 Almohmadi. Nutrients metabolism in autistic children

Table 2 Earlier studies on the impact of KD treatment on autism

Results and conclusions Method Sample References

The KD and SD groups experienced a novel environment, KD “(7.2 kcal/g energy, 3.3% cho, 19 Mecp2 mice, (97)
which resulted in enhanced motor behavior and reduced 16.7% pro, 80% fat) and SD (4.1 kcal/g 12 controls, and
anxiety. In KD, limiting calories is more crucial than food energy, 65.0% cho, 28.1% pro, 6.9% an RTT model
composition fat)” for 30 days

It is believed that KD considerably reduces seizures, which is utilizing reports from parents to record One hundred (98)
greater than the GFCF diet seizures and the basic symptoms forty-six children
of ASD (attention, behavior, with ASD who
communication, etc.) while putting KD had seizures and
into practice a control group

KD helps the mice exhibit fewer autistic behaviors. Mice KD or a control diet Mice model (99)
administered KD have shown to be more gregarious BTBR

In terms of bioenergetic disorder, KD could get well. KD has Control and KD Mice model (100)
changed complex behaviors and metabolism of mitochondria,
and this change may be useful in the treatment of ASD

The KD-fed mice showed a rise in brain norepinephrine, but KD or a control diet Adult engrailed (101)
there was no alteration in peripheral monoamine levels two null mice,
wild-type mice

KD modulated motor input and corrected reduced motion In this research, the BTBR mice’s BTBR mice (102)
thresholds baseline system excitability was model
examined

VPA-KD enhanced several social behaviors. Compared to Four groups were investigated in this Mice model (94)
VPA-SD, VPA-KD scored higher in friendliness and social investigation: (I) supplemented with
novelty ratings SD, (II) VPA mice fed with SD (VPA-
SD), (III) VPA mice fed with KD (VPA-
KD), and (IV) fed with KD

In mice, KD has reduced several neurological signs linked to For 10–14 days, use either SD or KD BTBR and (103)
ASD (75% kcal fat) C57BL/6 (B6)
mice

There was reduced habitual conduct and increased social KD and SD for 3–5 weeks. KD: 3.2% 28 control, 30 (95)
behavior and interaction in mice fed KD cho, 75.1% fat, 8.6% pro, 7.24 kcal/g BTBR mice
energy. SD: 57.9% cho, 5% fat,
23.9% pro, 3.02 kcal/g energy

Following KD medication, ASD impairments related to myelin Investigated alterations in gene BTBR mice (104)
production and white matter growth improved in both brain expression in BTBR mice after KD
areas therapy

For men, KD eating completely or partially corrected all KD or control diet for 3 weeks Young adult (105)
MIA-induced behavioral problems; female behavior was C57Bl/6 mice
unaffected. KD decreased MIA-elevated self-directed
repetitive behavior

In Glut3+/− males, but not in females, enhanced synaptic Assessed sociability and Glut3+/− mice (106)
protein levels and spontaneous excitatory postsynaptic electroencephalogram seizures in KD
activity decrease hippocampal glucose concentration and patients
brain amyloid β1-40 accumulation. KD somewhat restores
social skills, although vocalization or cognitive deficiencies
are not
KD, ketogenic diet; SD, standard diet; cho, carbohydrates; pro, protein; RTT, Rett syndrome; GFCF, gluten-free casein-free; ASD, autism
spectrum disorder; VPA, valproic acid; MIA, maternal immune activation.

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Translational Pediatrics, Vol 13, No 9 September 2024 1661

area of research and interest. Currently, there are very gut health to human illnesses (117). To determine if adding
few investigations on the benefits of probiotics in people probiotics can be beneficial for pregnant mothers as a
with ASD. This is compounded by the wide variety of preventive measure for ASD, more research is needed.
probiotics available and the lack of knowledge regarding Despite varying opinions and conclusions, the response has
side effects, therapeutic benefits, proper dosage, and strains been cautiously optimistic. One group has stated that there
that are beneficial for individuals with ASD. Probiotics is currently no conclusive evidence of the beneficial impact
can influence the gut microbiota and potentially reduce of oral probiotics on ASD. However, many studies on similar
gut permeability and GI inflammation (107). One study topics have indicated the need for further research (118).
involved administering probiotics to children with ASD On the other hand, some argue that probiotic supplements
aged between two and nine. The results showed a decrease could be an adjunct treatment (110). More research is
in intestinal inflammation and restoration of the abnormal needed to fully understand the role of probiotics as a
GI microbiome (108). Several other studies have also therapeutic option for ASD.
demonstrated reductions in ASD symptoms and GI
issues (109,110). Another study suggested that probiotic
Specific carbohydrate diet (SCD)
supplementation may reduce the risk of developing
neuropsychiatric disorders later in childhood through Sidney Haas developed the strict SCD in the 1920s to treat
mechanisms beyond gut microbiota composition (111). celiac disease. Later, the mother of an individual cured
Multiple ideas support the possible processes underlying by Haas of irritable bowel syndrome promoted it (119).
probiotics and their relationship with ASD. Firstly, the The goal of SCD is to restrict the intake of complex
opioid-excess explanation explains why the gluten-free carbohydrates, starches, and disaccharides such as lactose,
casein-free (GFCF) dietary is effective. It proposes that maltose, and sucrose to reduce the symptoms of gut
probiotics can aid in digesting gluten products without microbial overgrowth and carbohydrate digestion. Instead,
significantly altering intestinal permeability, preventing the diet recommends foods high in monosaccharides such as
peptide leakage, and fortifying the blood-brain barrier glucose, fructose, and galactose, including fruits, vegetables,
(112,113). This finding is also supported by the second honey, meats, eggs, nuts, and certain legumes. Foods like
theory, which deals with dietary protein allergies. According grains and potatoes, sugar, dairy products, and refined foods
to this notion, probiotics’ anti-inflammatory properties may are examples of restricted foods.
be able to mitigate the inflammatory and immunological Studies showing dysbiosis and reduced absorption
responses that people with ASD experience, possibly even and digesting of carbohydrates in individuals with ASD
helping with behavioral issues related to the disorder (114). provide support for the use of SCD for autism (120,121).
The last theory is based on using probiotics to treat It is thought that these disruptions in the microbiota may
gut dysbiosis and decrease endotoxin generation. This contribute to the coexisting GI symptoms and possibly
would lessen gut permeability and inflammation and even the behavioral symptoms. However, there is a lack
stop endotoxins from damaging the central nervous of published data supporting the safety or effectiveness of
system (107). This notion has been validated by multiple SCD in individuals with ASD, as it is a commonly used
research projects, which have also shown a linked finding of dietary therapy with and without professional guidance.
enhanced behavioral results (115). The authors investigated the use of SCD for treating
Additionally, Iovene et al. (116) discovered that gut GI issues in a person with fragile X syndrome and ASD.
dysbiosis in ASD patients is indicated by a drop in They observed improvements in behavioral, nutritional,
Lactobacillus and Clostridium spp. and a rise in invasive and GI aspects, and the nutritional intervention was well-
Candida spp. This dysbiosis raises intestinal permeability received (122). Despite these positive results, there are
and has a significant relationship with the intensity of ASD concerns about potential nutritional deficiencies that may
symptoms. Questions have been raised about supplementing arise from restrictive dietary therapies, especially in cases
mothers with probiotics to prevent ASD and other disorders where professional supervision is lacking or in individuals
based on the benefits of probiotics. It is reasonable to with limited dietary variety and selective eating habits.
hypothesize that prescribing probiotics to mothers could These findings highlight the need for further research
be a significant area of research for preventing disorders before implementing the SCD regimen in individuals
in individuals, especially ASD, as there is evidence linking with ASD.

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1662 Almohmadi. Nutrients metabolism in autistic children

Dietary supplements vitamins may be a mechanism between vitamin A deficiency and

ASD, with the b-CD38-oxytocin retinal transporter axis,
Vitamin A
also known as the oxytocin-CD38-vitamin A axis, being a
The cause of ASD is also linked to several other nutritional
promising potential mechanism. However, supplementing
deficits, including hemoglobin and the vitamins A, C,
to address a vitamin A deficiency has not been shown to be
B6, B12, folate, and D. These potential deficiencies have
an effective therapy for ASD symptoms in recent research.
prompted several supplement studies aimed at addressing
ASD symptoms. Like polyunsaturated fatty acids (PUFAs),
Vitamin C
several research studies have shown that vitamin A
Many studies on vitamin C and ASD approach the subject
insufficiency is frequently observed in children with ASD
from the perspective of nutritional deficiency, as individuals
diagnoses (123). In China, 154 children participated in a
with ASD are particularly prone to eating difficulties and
nationwide survey, which revealed that the incidence of
inadequate nourishment. A case report implemented by
blood vitamin A deficiency was low among children with
Rafee et al. (131) highlighted a patient with significant
ASD. Still, it was adversely connected to CARS ratings dietary selectivity leading to severe vitamin C deficiency;
(P=0.021) (124). Regarding potential pathologies linked another case involved a 10-year-old boy with scurvy and
to a lack of vitamin A for ASD, especially those connected anemia (132).
to the pregnant woman’s oxytocin-CD38-vitamin A Remarkably, scurvy has been frequently shown in
pathway, authors of additional research have called for the children with ASD, with seven cases reported at Boston
establishment of standards for vitamin A in infants and Children’s Hospital among patients with developmental
expectant mothers (125). disorders (133). Similar findings have been reported
Additionally, studies (126,127) found that a vitamin A in other studies (134,135). Likewise, a comparison of
deficiency could cause ASD in rats. When puppies with nutritional intake between 50 typically developing children
gestational vitamin A insufficiency were given vitamin and 63 children with ASD revealed that a higher proportion
A supplements, their autistic-like behaviors improved. of children with ASD had lower vitamin C intake (136).
This suggests that the deficiency inhibits the retinoic acid A controlled trial involving male children and teenagers
receptors b signal transmission. diagnosed with ASD, along with findings from comparison
Research on vitamin A supplementation in children research conducted in Valencia, Spain (137), further
with ASD has been limited or accompanied by caution. supported these findings.
Guo et al. (123) found that supplementing with vitamin Additionally, data showed that supplementation led to
A significantly reduced autism symptoms. Still, they also excessive vitamin C in 2- to 3-year-old children with ASD (128).
cautioned that some children with ASD may benefit more The long-term investigation on dietary supplements
from daily vitamin doses than others. Similarly, researchers in children with ASD (n=288) highlighted the issue of
stressed the need for more research to determine the overconsumption of micronutrient supplements among
process supporting the link between ASD and vitamin children diagnosed with ASD, particularly in the case
A before drawing firm conclusions from another study. of vitamin C (128). However, the Chinese study on the
It is important to note that vitamin A supplementation relationship between symptoms and nutrition in ASD did
increased vitamin A intake, which may not be desirable, not specifically examine vitamins (124). Scientifically, it has
according to a continuous investigation into nutritional been hypothesized that these increased vitamin C levels
supplements in children with ASD. These findings were might be advantageous in addressing oxidative stress. In a
supported by another study, which found that certain age randomly assigned, blinded, placebo-controlled mineral and
groups of children with ASD consumed excessive amounts vitamin treatment research, children with ASD who received
of vitamin A (128). vitamin C showed a significant reduction in oxidative damage
Additionally, based on the findings of a study examining [measured by the glutathione disulfide (GSSG), ratio to
the effects of vitamin A supplementation on gut microbes, decreased glutathione (GSH)]. It was proposed that these
researchers hypothesized that while vitamin A may influence elevated vitamin C levels helped these individuals experience
autistic symptoms (129), there is no clear relationship a considerable decrease in oxidative stress (59).
between vitamin A levels, supplementation, and ASD Additionally, micronutrients such as folate, vitamins B6,
symptoms (130). Overall, these results suggest that there and B12 are involved in methylation and transculturation

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Translational Pediatrics, Vol 13, No 9 September 2024 1663

processes. Methylation-dependent epigenetic control, production of neurotransmitters (59). However, researchers

involving the methylation of DNA and histone proteins, is a found that supplementing with B6 and magnesium did not
key component of the programmed changes in gene expression significantly improve symptoms of ASD in a 2017 evaluation
that characterize healthy neurodevelopment (138). Low of seven randomized controlled trials (RCTs) (146).
GSH and oxidative stress levels are linked to deficiencies in The limited number of available high-quality trials led
methylation status in ASD, supporting the idea of dietary to a similar conclusion: there was insufficient data to
supplements containing micronutrients that promote support the effectiveness of the therapy (147). It’s crucial
methylation (139). to remember that the American Psychiatric Association
and the American Academy of Pediatrics have stated that
Vitamin B megavitamin treatment for learning disabilities and autism
The transsulfuration pathway connects the methylation is not justified when discussing the use of vitamin B6 and
process from MET to GSH production by converting magnesium supplementation (148). This may explain the
homocysteine (HCY) to CYS. Folate, also known as lack of current studies on their effectiveness (148). However,
5-methyltetrahydrofolate (5-MTHF), and vitamin B12, or a study suggests that plasma glutamine concentrations could
methylcobalamin (methyl-B12), are necessary cofactors for predict the response to vitamin B6 in individuals with ASD.
MET synthase (MTR) to convert HCY to MET. Vitamin However, the study had limitations, such as a small sample
B12 is particularly vulnerable to oxidation as it awaits the size and a low percentage of B6 sensitivity in ASD (149).
replacement of the methyl group by 5-MTHF during the Despite this, research has shown that children with ASD
catalytic cycle of MTR (140). often have low B6 intake (129).
Oxidative stress can exacerbate the inactivation of MTR,
which leads to an overproduction of HCY. This excess Camel milk
HCY can be redirected to the transsulfuration route, which With only 2 percent fat, camel milk is primarily made up of
boosts the production of GSH, a type of antioxidant. polyunsaturated fats with long chains, which are essential
The interplay between oxidative stress and methylation for brain growth. Camel milk tastes watery because of its
processes can impact regulatory functions, as vitamin B12 low-fat content (150). Camel milk has a similar protein
serves as a sensor of cellular redox status. Therefore, the level (3.2%) to cow’s milk. However, camel milk does not
presence of oxidative stress in ASD is likely to disrupt include the allergens beta-lactoglobulin and beta-casein
neurodevelopment regulated by epigenetic mechanisms. found in cow’s milk. Incorrect separation of these caseins
Vitamin B6 is an important cofactor for the transsulfuration can lead to the synthesis of opioids (casomorphin) in
pathway proteins cystathionine-β-synthase (CBS) and children with autism (151). According to the research of
cystathionine-γ-lyase, also known as cystathionase (CSE). Shabo et al. (152), the absence of these caseins in camel milk
Vitamin D stimulates the development of both CBS and can inhibit the onset of symptoms associated with autism.
CSE (141). Evidence suggests that brain cells could Camel milk contains bacterial immune system enzymes
lack a transsulfuration mechanism, as evidenced by the and defense proteins that have beneficial and antibacterial
significant finding that CBS expression is limited to properties (153). Additionally, camel milk includes insulin.
astrocyte cells (142). Reduced cystathionine concentrations Despite camel milk and cow’s milk having similar amounts
suggest that human brain CSE action is low, particularly of lactose, camel milk is suitable for consumption by
in younger age groups, but increases beginning in the individuals who are lactose intolerant.
fifth decade of life (143), TNF-α, or TNF, a cytokine Additionally, it is an excellent supply of vitamin C,
whose concentrations rise with aging (144), induces CSE calcium, and iron. Its high vitamin C content ensures a
expression. Cysteine concentrations in the spinal canal are low pH, which helps in the more effective absorption
higher compared to those in the cerebral cortex of young of calcium and iron (150). Camels have a unique heavy-
children with ASD, which is compatible with premature chain antibody construction, which lacks a light-
CSE production induced by TNF-α (145). chain antibody organization, making their antibodies
From a molecular standpoint, it has been suggested that distinct from other types. These antibodies are active
certain indications of ASD might be due to inadequacies against numerous viral illnesses and can effectively
in the neurotransmitter system and that vitamin B6 could neutralize enzymes, giving them an advantage over
improve these mechanisms due to its involvement in the human antibodies. Camel serum contains antibodies

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1664 Almohmadi. Nutrients metabolism in autistic children

against ‘IgM, IgG, IgA, and IgD’ (154). Individuals with social interaction, while dietary therapies for GI disorders
weakened immune systems may benefit from the smaller have garnered significant interest. However, there is a lack
size of camel antibodies (152). The immunoglobulins in of scientific research on the effects of therapeutic diets on
camel milk are absorbed by the recipient, impacting tissues autism, leading to no definitive dietary recommendations.
and potentially affecting autoimmune disorders like ASD. Dietary supplements have shown promising results in
Improper breakdown of casein in camel milk can lead to the addressing GI issues and behavior in individuals with
production of opioid casomorphin, which can compromise ASD. Nevertheless, the efficacy of these therapies is often
the body’s defenses and result in brain injury, leading to inconsistent due to the lack of blind studies, control groups,
behavioral and cognitive abnormalities (150). and high expectations. Additionally, the use of various
There is a theory that autoimmune diseases and autism outcome measures, such as questionnaires and diagnostic
may be related. Intravenous immunoglobulin therapy tools, can skew results, and small sample sizes limit the
(IVIGT) is linked to a decrease in the intensity of mental generalizability of findings. It is essential to standardize
and emotional signs. Children under ten have shown full the assessment of ASD symptoms and evaluation methods.
recovery after receiving camel milk or IVIGT therapy. When Nutritional interventions can complement integrated
IVIGT or camel milk therapies were stopped in children psychological treatment, occupational therapy, speech
above the age of 15 years, it was seen that the same symptoms and language therapy, and educational programs. Further
reappeared. Eliminating cow’s milk from the diet suppresses research is needed to identify the factors contributing to
symptoms but does not cause the condition to reverse. positive and negative outcomes and develop effective and
Parents have noticed that younger children respond more straightforward therapies to improve symptoms.
positively to camel milk than older children, suggesting that
camel milk may help prevent brain damage from developing
Acknowledgments
at a young age (150). In animals used for research, the idea
that morphine-like effects result from milk casein breaking The author thanks Umm Al-Qura University for their
down abnormally in autistic children was accepted. Beta- support.
casomorphin-7 was administered to rats (155). The booming Funding: None.
injection-related bell did not pique the curiosity of the rats
who had watched it ring. The analysis of the brain tissues
Footnote
from laboratory animals, 32 different brain areas contained
beta-casomorphine-7, which is involved in vision, hearing, Peer Review File: Available at https://tp.amegroups.com/
and communication (150). article/view/10.21037/tp-24-182/prf
Randomized trials were done to explore how camel milk
intake affected the indicators of oxidative stress in kids with Conflicts of Interest: The author has completed the ICMJE
autism. Sixty autistic children participated in this study. uniform disclosure form (available at https://tp.amegroups.
These children were divided into three groups at random: com/article/view/10.21037/tp-24-182/coif). The author has
those who drank raw camel milk, those who drank cooked no conflicts of interest to declare.
camel milk, and those who drank cow’s milk, which was
used as a placebo. Each child drank 500 cc of milk regularly Ethical Statement: The author is accountable for all
for 2 weeks. The Childhood Autism Assessment Scale aspects of the work in ensuring that questions related
(CAAS) improved, and ‘plasma glutathione, superoxide to the accuracy or integrity of any part of the work are
dismutase, and myeloperoxidase levels’ rose in groups that appropriately investigated and resolved.
drank camel milk. According to Al-Ayadh and Elamin (156),
these results suggest that camel milk can help improve Open Access Statement: This is an Open Access article
autistic behaviors by reducing oxidative stress associated distributed in accordance with the Creative Commons
with autism (157). Attribution-NonCommercial-NoDerivs 4.0 International
License (CC BY-NC-ND 4.0), which permits the non-
commercial replication and distribution of the article with
Conclusions
the strict proviso that no changes or edits are made and the
Behavioral and speech interventions for ASD aim to improve original work is properly cited (including links to both the

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Translational Pediatrics, Vol 13, No 9 September 2024 1665

formal publication through the relevant DOI and the license). disorder: A case-control study. Res Autism Spectr Disord
See: https://creativecommons.org/licenses/by-nc-nd/4.0/. 2018;50:51-9.
12. Leader G, Tuohy E, Chen JL, et al. Feeding Problems,
Gastrointestinal Symptoms, Challenging Behavior and
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Cite this article as: Almohmadi NH. Brain-gut-brain axis,

nutrition, and autism spectrum disorders: a review. Transl
Pediatr 2024;13(9):1652-1670. doi: 10.21037/tp-24-182

© AME Publishing Company. Transl Pediatr 2024;13(9):1652-1670 | https://dx.doi.org/10.21037/tp-24-182