In this week’s article on the gut-brain axis, we address autism and the gut. The gut and the brain are linked, with the gut-brain axis regulating brain function and behavior (Chunlong Mu, 2016). For a full explanation of the gut brain axis, please see our first article on anxiety and the gut.
The gut-brain axis plays a critical role in many neurological disorders. It affects neuropsychiatric disorders like anxiety, depression, schizophrenia and dementia (Kim YK, 2018), as well as neurodevelopmental disorders in children including autism, ADHD, learning disabilities, intellectual developmental disorder, motor disorders, and specific learning disorders (EPA, 2015).
In this article, we will explore the link between autism and the gut brain axis. Autism, or autism spectrum disorder (ASD), is a brain developmental disorder (Li Q, 2017).
ASD is defined by significant social, communication and behavioral challenges, often with a pattern of stereotyped repetitive behaviors, speech and nonverbal communication behaviors and challenges with communication and social interaction (Li Q, 2017).
As autism is classified as a spectrum disorder, it affects sufferers differently (Autism Speaks, 2019). Cognitive abilities of people with ASD range from extremely gifted to severely challenged. Some with ASD need significant support in daily life, while others need less and some can live entirely independently.
ASD is often accompanied by sensory sensitivities, gastrointestinal (GI) disorders, immune deficits, anxiety, depression, sleep disturbances, seizures and attention issues (Lyall K, 2017).
A diagnosis of ASD now includes several conditions that used to be diagnosed separately: autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. These conditions are now all called autism spectrum disorder (Centers for Disease Control and Prevention, 2018).
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Important facts about ASD:
- The prevalence is increasing (Autism Speaks, 2019). According to the CDC (Centers for Disease Control and Prevention, 2019):
- In 2004, 1 in 166 children had ASD.
- In 2006, 1 in 150 children had ASD.
- In 2016, 1 in 68 children had ASD.
- In 2018, 1 in 59 children had ASD, according to Autism Speaks, who used data from the CDC (Autism Speaks, 2018).
- However, according to Pediatrics journal, using data from the 2016 National Survey of Children’s Health (NSCH), in 2018, 1 in 40 children had ASD (Kogan MD, 2018).
- Some of this increase is due to better and earlier diagnosis, but there is debate about whether this explains all of the increase in ASD rates. This will become clear when we discuss causes. Our genes have not and cannot change so quickly, but our environment has. Thus some environmental changes or triggers are thought to be partially driving the increases seen.
- Boys are four times more likely to be diagnosed with autism than girls (Centers for Disease Control and Prevention, 2019). Of the 1 in 59 children diagnosed with ASD in 2018: 1 in 37 are boys and 1 in 151 are girls.
- However, the gender gap in autism has decreased (Autism Speaks, 2018). While boys were 4 times more likely to be diagnosed than girls in 2014, the difference was narrower than in 2012, when boys were 4.5 times more frequently diagnosed than girls (Autism Speaks, 2018). This is likely due to improved identification of autism in girls, who often do not manifest the stereotypical symptoms of autism seen in boys.
- 31% of children with ASD have an intellectual disability (with an IQ <70), 25% are in the borderline range (IQ 71–85), and 44% have IQ scores in the average to above average range (IQ >85) (Autism Speaks, 2019).
- ASD is one of the most serious neurodevelopmental conditions in the U.S. It has significant caregiver, family, and financial burdens. The annual total costs associated with ASD in the U.S. have been estimated to be approx. $250 billion (Lyall K, 2017). Lifetime individual ASD-associated costs are in the $1.5 to $2.5 million range (estimates in 2012 U.S. dollars) (Lyall K, 2017).
Most children are still being diagnosed after age 4, though autism can be reliably diagnosed as early as age 2 (Autism Speaks, 2019). Diagnosing ASD can be difficult. There is no medical test, such as a blood test, to diagnose it (Centers for Disease Control and Prevention, 2018).
Doctors look at the child’s behavior and development to make a diagnosis. It can sometimes be detected at 18 months or younger. By age 2, a diagnosis by an experienced professional can be considered to be very reliable (Centers for Disease Control and Prevention, 2018).
What are the CAUSES or Contributing Factors?
The causes of ASD are not completely understood. Studies on twins suggest that both genes and environment play roles in the development of ASD (Modabbernia A, 2017). The developing brain is vulnerable to environmental factors, which explains the causative association between environmental factors and ASD (Modabbernia A, 2017).
Some studies show ASD is primarily driven by genetic influences, and others report a nearly equal contribution from heritable genetic and non-heritable environmental factors (Lyall K, 2017). One study found that up to 40-50% of autism spectrum disorder (ASD) liability might be determined by environmental factors (Modabbernia A, 2017). Because environmental and epigenetic influences are not as well studied as genetic ones, there may be a much greater impact of environment than has appeared in studies so far.
Metabolism, gut, immune and mitochondrial dysfunction are frequent in ASD (Lyall K, 2017). Among children with ASD, gastrointestinal symptoms have also been associated with more frequent challenging behaviors (Lyall K, 2017).
It is clear that there are three areas to look at to explain ASD:
- Gut health
Genes – It is possible to have a genetic disposition to the condition. The fact that genes partly contribute to ASD is strongly supported by twin and family studies (Lyall K, 2017). Several genes have been identified in ASD; post-synaptic scaffolding genes, i.e. SHANK3, contactin genes, i.e. CNTN4, neurexin family genes, i.e. CNTNAP2, and chromatin remodeling genes, i.e. CHD2 (Lyall K, 2017). The specific genes involved are part of common genetic pathways involved in ASD (Lyall K, 2017). The cumulative effect of multiple common gene issues, i.e. the polygenic risk, is now becoming recognized as an important risk factor for ASD and other psychiatric disorders (Lyall K, 2017).
Epigenetics is the study of gene-environment interaction. Unfortunately there is little information on gene-environment interaction in ASD causality, as only a few studies have been published to date (Lyall K, 2017).
Some epigenetic changes have been found in the brains of people with ASD, including hypo- and hyper-methylation, i.e. related to the MTHFR gene, and spreading of histone 3 lysine 4 trimethylation marks (Lyall K, 2017). We talked in detail about MTHFR here.
Research has found an increased risk of ASD associated with common mutations affecting the folate/methylation cycle i.e. the MTHFR mutation (El-Baz F, 2017). A significant association between severity and occurrence of autism has been found with two common MTHFR gene mutations, called C677T and A1298C (El-Baz F, 2017). Further studies are needed to explore other gene mutations that may be associated with autism, to establish the genetic basis of autism. (El-Baz F, 2017)
Other genetic variants for ASD implicate chromatin remodeling, another aspect of epigenetic regulation (Lyall K, 2017). Other reports suggest interactions between gene risk and prenatal exposure to air pollutants, genes in the one carbon metabolism pathway and maternal use of prenatal vitamins, and genetic variations and maternal prenatal infection (Lyall K, 2017).
Environment – This can be an outright cause or a trigger of ASD. Systematic reviews of the available research suggest more than 20 individual, familial, pre-, peri- and neo-natal factors with some evidence for ASD risk (Lyall K, 2017).
The maternal environment is especially important for the risk of developing autism spectrum disorders. In particular infections present in a mother during pregnancy, micronutrient deficiencies, obesity, and toxic exposures are likely to interact with genetic risk factors to disrupt fetal brain development (Nuttall, 2017).
One study suggests that approximately 75-80% of the observed increase in ASD since 1988 is due to an actual increase in the disorder rather than to changing diagnostic criteria (Nevison, 2014). It attributes the increase to environmental factors driving this increase (Nevison, 2014).
For example, polybrominated diphenyl ethers (used in flame retardants, building materials, electronics, furnishings, motor vehicles, airplanes, plastics, polyurethane foams, and textiles), aluminum adjuvants (used in vaccines), and the herbicide glyphosate have increasing trends that correlate positively to the rise in autism (Nevison, 2014).
Environmental factors driving ASD risk include:
- Parental age: Every 10-year increase in maternal and paternal age increases the risk of ASD in the offspring by 18 and 21% respectively (Modabbernia A, 2017).
- Inter-pregnancy interval: Increases in risk of ASD with a short (<12 months) period between pregnancies have been consistently reported. Reasons for this are not clear but relate to maternal nutrient deprivation, inflammation, and stress (Lyall K, 2017). Adequate recovery time between pregnancies is recommended.
- Pregnancy-related complications: Abnormal or breech presentation, cord complications, fetal distress, multiple births, low birth weight <1500 g, small for gestational age, congenital malformations, birth injury or trauma, hyperbilirubinemia, earlier birth (first vs. third born) and feeding difficulties at birth can all play a role (Modabbernia A, 2017).
- Immune factors: Maternal hospitalization with infection (bacterial or viral) during pregnancy has been associated with increased risk of ASD (Lyall K, 2017). Familial history of autoimmune disease has also been associated with increased risk of ASD (Lyall K, 2017).
- Medication use during pregnancy: Antidepressants, anti-asthmatics, and anti-epileptics (especially maternal valproate use for epilepsy and bipolar disorder) are associated with ASD in the children (Modabbernia A, 2017). Some association with SSRI anti-depressants exist but are not fully established in the research (Modabbernia A, 2017). However, these drugs can cross the placenta and blood brain barrier (BBB), as well as be transferred to the child through breast milk (Lyall K, 2017).
- Nutrient deficiencies: Research has looked at folate, vitamin D, omega 3, iron and zinc deficiencies with some links to ASD (Modabbernia A, 2017). One paper finds that zinc, copper, iron, and vitamin B9 are specific micronutrients related to ASD (Nuttall, 2017). Specific toxins can induce a maternal inflammatory response which leads to fetal micronutrient deficiencies in these nutrients (Nuttall, 2017). The fetal deficiencies disrupt development of the early brain (Nuttall, 2017). Maternal micronutrient supplementation is advised as it is associated with reduced risk of ASD (Nuttall, 2017). Higher maternal intake of certain nutrients and supplements has been associated with reduction in ASD risk, with the strongest evidence for taking folate supplements before conception (Lyall K, Schmidt RJ, 2014). In later life, vitamin D deficiency seems to be quite common in children with ASD (Modabbernia A, 2017).
- Environmental chemicals: We are exposed to a vast, almost countless, number of environmental and industrial chemicals in today’s world. Certain environmental chemicals exposures during the pre-natal period interfere with and disrupt normal brain development in the fetus. These chemicals can cross the placenta and the blood brain barrier, accumulating in developing brains (Lyall K, 2017). Others disrupt hormone pathways or act on inflammatory pathways that may have negative effects on brain development (Lyall K, 2017). Prenatal exposure to air pollution has emerged as a risk factor for ASD. These are hazardous air pollutants, such as chlorinated solvents, methylene chloride and diesel particulate matter and others (Lyall K, 2017). Chemicals in flame retardants can result in mitochondrial toxicity and lead to issues with energy balance in the brain (Modabbernia A, 2017). In general, chemicals can contribute to the mitochondrial dysfunction that is well documented in people with ASD (Modabbernia A, 2017).
— To Be Continued —
Due to the complexity of ASD, we can’t cover all of the factors contributing to ASD in one blog post. So please tune in again next week for ASD: Part 2 where we will continue with the environmental factors that contribute to ASD. We will also discuss gut health and how it contributes to ASD. Finally, in ASD: Part 3, we will outline what diet, supplements and lifestyle action steps you can take to address ASD.
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