Exploring Gut Microbiota and Diet in Autism and ADHD: What Does the Research Say?

In recent years, there has been growing interest in understanding the connection between our gut microbiota (the community of microorganisms in our digestive system) and various neurodevelopmental disorders like autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A new study by Shunya Kurokawa and colleagues dives deeper into this area, comparing dietary diversity and gut microbial diversity among children with ASD, ADHD, their normally-developing siblings, and unrelated volunteer controls. Let's unpack what they found and what it means.

The Study Setup

The researchers recruited children aged 6-12 years diagnosed with ASD and/or ADHD, along with their non-ASD/ADHD siblings and the unrelated non-ASD/ADHD volunteers. The diagnoses were confirmed using standardized assessments like the Autism Diagnostic Observation Schedule-2 (ADOS-2). The study looked at gut microbial diversity using advanced DNA extraction and sequencing techniques, comparing alpha-diversity indices (which reflect the variety and evenness of microbial species within each gut sample) across different groups. They also assessed dietary diversity through standardized questionnaires.

Key Findings

The study included 98 subjects, comprising children with ASD, ADHD, both ASD and ADHD, their non-ASD/ADHD siblings, and the unrelated controls. Here's what they discovered:

Gut Microbial Diversity: The researchers found significant differences in alpha-diversity indices (like Chao 1 and Shannon index) among the groups. Notably, children with ASD had lower gut microbial diversity compared to unrelated neurotypical controls. This suggests disorder-specific differences in gut microbiota, particularly in children with ASD.

Dietary Diversity: Surprisingly, dietary diversity (assessed using the Shannon index) did not differ significantly among the groups. This finding implies that while gut microbial diversity showed disorder-specific patterns, diet diversity itself might not be the primary factor driving these differences.

What Does This Mean?

The study highlights intriguing connections between gut microbiota and neurodevelopmental disorders like ASD and ADHD. The lower gut microbial diversity observed in children with ASD points towards potential links between gut health and the pathophysiology of ASD. Understanding these connections is crucial for developing targeted therapeutic interventions.

Implications and Future Directions

This research underscores the importance of considering gut microbiota in the context of neurodevelopmental disorders. Moving forward, future studies should account for factors like co-occurrence of ASD and ADHD, as well as carefully control for dietary influences. This will help unravel the complex interplay between gut microbiota, diet, and neurodevelopmental disorders, paving the way for innovative treatments and interventions.

In summary, studies like this shed light on the intricate relationship between our gut health, diet, and brain function. By unraveling these connections, researchers are opening new avenues for understanding and potentially treating conditions like ASD and ADHD.

April 9, 2024

Meta-analysis finds no link between maternal exposure to PFAS and offspring ADHD

Meta-analysis Finds No Link Between Maternal Exposure to PFAS and Offspring ADHD

Perfluoroalkylated substances (PFASs) – often described in the popular press as “forever chemicals” – are highly persistent pollutants.

Perfluoroalkylated substances (PFASs), commonly known as "forever chemicals" in the media, are pollutants that do not break down in the environment. Their chemical structure includes fluorine atoms bonded to carbon, which makes them effective at repelling water. This property has led to their use in water-repellent clothing, stain-resistant carpets and furniture, and nonstick cookware.

However, the same chemical structure that makes PFASs useful also makes them a concern for human and animal health, as there are no natural biological processes to remove them from the body. Once ingested, they accumulate and become more concentrated at each level of the food chain. PFASs can also cross the placental barrier, raising concerns about potential harm to developing embryos and fetuses.

A Chinese research team conducted a systematic review of the medical literature to examine if there is a link between maternal exposure to PFASs and an increased risk of ADHD in children. They analyzed data from several studies:

- A meta-analysis of five studies involving 2,513 mother-child pairs found no increase in ADHD risk from exposure to PFOA (perfluorooctanoate) or PFOS (perfluorooctane sulfonate). The consistency across these studies was high, with little variation and no evidence of publication bias.

- Another meta-analysis of three studies with 995 mother-child pairs also showed no increase in ADHD risk from exposure to PFNA (perfluorononanoate) or PFHxS (perfluorohexane sulfonate), with similarly negligible variation between studies and no publication bias.

- In an analysis comparing the highest and lowest quartiles of maternal exposure, a slight increase in ADHD risk was observed with PFOA exposure, while a slight decrease was noted with PFOS exposure. Both findings were marginally significant and may be due to the small sample sizes. 

The researchers concluded that more studies are needed to confirm these findings due to the limited evidence available.

May 6, 2024

Meta-analysis confirms association between overweight mothers and ADHD in offspring

Meta-analysis Confirms Association Between Overweight Mothers and ADHD in Offspring

Noting “the incidence of parental obesity has been rising together with the prevalence of mental illness, suggesting a possible link between the two phenomena,” a Chinese study team performed a systematic search of the peer-reviewed literature on that topic.

Noting “the incidence of parental obesity has been rising together with the prevalence of mental illness, suggesting a possible link between the two phenomena,” a Chinese study team performed a systematic search of the peer-reviewed literature on that topic.

Further noting that previous meta-analyses have suggested a link between maternal obesity and increased risk of ADHD in offspring, they set out to also look at paternal obesity.

Only two studies, however, probed the relationship between paternal overweight and obesity and offspring ADHD, making that meta-analysis impractical. A meta-analysis of six studies with a combined total of over a hundred thousand participants found no significant association between overweight or obsess fathers and offspring mental disease of any kind (with all such disorders lumped together). There was no indication of publication bias and little variability (heterogeneity) between studies.

Ten studies with a combined total of over 800,000 participants, however, examined the relationship between overweight and obese mothers and offspring ADHD. Overweight mothers were twenty percent more likely to have offspring with ADHD. Obese mothers were more than fifty percent more likely to have offspring with ADHD. There was absolutely no sign of publication bias in either case. Inter-study heterogeneity was negligible for overweight, and moderate for obesity.

The team concluded, “We found that the most recent evidence indicates the detrimental connections between parental pre-pregnancy overweight/obesity and offspring mental health.” That is perhaps a bit overstated, as the only clear sign was with maternal overweight or obesity.

April 22, 2024

Population Study Finds Association Between ADHD and Obesity in Adolescents

Israeli nationwide population study finds association between ADHD and obesity in adolescents

After noting that the association between ADHD and obesity has been called into question because of small sample sizes, wide age ranges, self-reported assessments, and inadequate attention to potential confounders, an Israeli study team set out "to assess the association between board-certified psychiatrist diagnoses of ADHD and measured adolescent BMI [body mass index] in a nationally represented sample of over one million adolescents who were medically evaluated before mandatory military service."

The team distinguished between severe and mild ADHD. It also focused on a single age group.

All Israelis are subject to compulsory military service. In preparation for that service, military physicians perform a thorough medical evaluation. Trained paramedics recorded every conscript's height and weight.

The study cohort was divided into five BMI percentile groups according to the U.S. Centers for Disease Control and Prevention's BMI percentiles for 17-year-olds, and further divided by sex: <5th percentile (underweight), 5th-49th percentile (low-normal), 50th-84th percentile (high normal), 85th-94th percentile (overweight) and ≥95th (obese). Low-normal was used as the reference group.

Adjustments were made for sex, birth year, age at examination, height, country of birth (Israeli or other), socioeconomic status, and education level.

In the fully adjusted results, those with severe ADHD were 32% more likely to be overweight and 84% more likely to be obese than their typically developing peers. Limiting results to Israeli-born conscripts made a no difference.

Male adolescents with mild ADHD were 24% more likely to be overweight, and 42% more likely to be obese. Females with mild ADHD are 33% more likely to be overweight, and 42% more likely to be obese. Again, the country of birth made no difference.

The authors concluded, that both severe and mild ADHD was associated with an increased risk for obesity in adolescents at the age of 17 years. The increasing recognition of the persistence of ADHD into adulthood suggests that this dual morbidity may have a significant impact on the long-term health of individuals with ADHD, thus early preventive measures should be taken.

January 6, 2022

Study: Methylphenidate Reduces Traffic Accidents in Persons with ADHD

Nationwide cohort study: methylphenidate reduces traffic accidents in persons with ADHD

Taiwan has a single-payer healthcare system that covers virtually every inhabitant (99.5%). That makes it relatively easy to track healthcare issues using its comprehensive National Health Insurance Research Database.

This database maintains a subset, the Longitudinal Health Insurance Database (LHID), consisting of a million persons, with no significant differences in sex, age, or healthcare use from the parent database.

A Taiwanese research team used the LHID to identify 114,486 individuals diagnosed with ADHD from 1997 to 2013. It then compared their motor vehicle (including motorcycles, which are extremely common in Taiwan) crash patterns with 338,261 normally developing controls from the same database.

Adjusting for sex, age, and psychiatric comorbidities, persons with ADHD were about a fifth (19%)more likely to be in traffic crashes. Breaking it down further by sex, women with ADHD were no more likely to be in crashes, but men with ADHD were about a quarter (24%) more likely than their healthy counterparts.

Since the database also tracks pharmaceutical prescriptions, the team also looked into the effect of methylphenidate (MPH), the medication that is the first-line treatment for ADHD under Taiwanese guidelines, and the only approved stimulant. Atomoxetine, a non-stimulant, is used where MPH is either ineffective or not indicated for any other reason and is only used in 4% of all cases.

Of the 114,486 persons diagnosed with ADHD, 89,826 used MPH, and 24,660 did not.

Compared with persons with ADHD who were not on methylphenidate, those with ADHD who were on MPH for 180 days (roughly half a year) or less had 77% fewer accidents, and those on MPH for over 180 days had 93% fewer accidents. This strong dose-response relationship is suggestive of a causal relationship, with MPH perhaps reducing impulsive behavior, particularly among young men with ADHD.

The team also conducted within-person analyses, comparing times when persons with ADHD were taking MPH with periods when they were not. These showed no effect within 30 days of use, rising to a 65%reduction in crashes within 60 to 90 days of use, which was barely outside the 95% confidence interval (p = .07), very likely because of "the extremely low incidence of transport accidence (i.e. 0.6%)enlarged the confidence interval."

The authors concluded, "All registration medical claim data came from the nationally-representative sample of NHI, minimizing the selection and recall bias. By excluding transport accidents before ADHD diagnosis, we have precluded the reverse association between ADHD and road traffic accidents as much as possible. The advantage of the between-subjects comparison was that we were able to examine the MPH effect in different dose groups. However, confounding by indication cannot be eliminated. For example, those with a severe degree of ADHD symptoms, an exhibition of risky behaviors, or comorbid with other psychiatric illnesses were more likely to be prescribed medication. Hence, we also performed within-subject comparisons to adjust for time-invariant factors."

Transport safety thus offers another compelling reason to treat ADHD symptoms. Methylphenidate in particular seems to be especially effective in reducing traffic fatalities and injuries.

December 11, 2021

Meta-analyses Suggest Physical Exercise is Effective Tool in Treating ADHD

Two meta-analyses suggest physical exercise is an effective tool in treating ADHD

Two recent meta-analyses, one by an Asian team, and the other by a European team, have reported encouraging results on the efficacy of physical exercise in treating ADHD among children and adolescents.

One, a Hong Kong-based team (Liang et al. 2021) looked at the effect of exercise on executive functioning.

The team identified fifteen studies with a combined total, of 493 participants that met the criteria for inclusion. As the authors noted, "only a few studies successfully blinded participants and therapists, due to the challenges associated with executing double-blind procedures in non-pharmacological studies."

After adjusting for publication bias, the meta-analysis of the fifteen studies found a large improvement in overall executive functioning.

The studies varied in which aspects of executive functioning were addressed. A meta-analysis of a subset of eleven studies encompassing 406 participants found a large improvement in inhibitory control. A meta-analysis of another subset, of eight studies with a total of 311 participants, found a large improvement in cognitive flexibility. Finally, a meta-analysis of a subset of five studies encompassing 198 participants found a small-to-medium improvement in working memory.

Nine studies involved acute (singular) exercise interventions lasting 5 to 30 minutes, while twelve studies involved chronic (regular) exercise interventions ranging from 6 to 12 weeks, with a total duration of 12 to 75 hours. The chronic exercise was more than twice as effective as acute exercise. The former resulted in large improvements in overall executive functioning, the latter in small-to-medium improvements.

No significant differences were found between aerobic exercises (such as running and swimming) and cognitively engaging exercises(such as table tennis and other ball games, and exergaming ... video games that are also a form of exercise, relying on technology that tracks body movements).

The authors concluded that "Chronic sessions of exercise interventions with moderate intensity should be incorporated as a treatment for children with ADHD to promote executive functions."

Meanwhile, a German study team (Seiffer et al. 2021) looked at the effects of regular, moderate-to-vigorous physical activity on ADHD symptoms in children and adolescents.

They found eleven studies meeting their criteria, with a combined total of 448 participants. A meta-analysis of all eleven studies found a small-to-moderate decline in ADHD symptoms. However, the three studies with blinded outcome assessors found a large and statistically highly significant decline in symptoms, whereas the eight studies with blinded outcome evaluators found only a small decline that was not statistically significant.

When compared with active controls using pharmacotherapy in a subgroup of two studies with 146 participants, pharmacotherapy held a small-to-moderate advantage that fell just short of statistical significance, most likely because of the relatively small sample size.

The authors concluded that moderate to vigorous physical activity (MVPA) "could serve as an alternative treatment for ADHD," but that additional randomized controlled trials "are necessary to increase the understanding of the effect regarding frequency, intensity, type of MVPA interventions, and differential effects on age groups."

December 5, 2021

Swedish Twin Study Finds Association Between Diet and ADHD

Associations between diet and ADHD emerge from Swedish population-based twin study

Sweden has a national single-payer health insurance system that includes virtually the entire population. It also has a system of national registers that track every resident from birth to death. That makes it possible to conduct nationwide population studies with a very high degree of precision and reliability.

In addition, one of the national registers is the Swedish Twin Register. Tracking all twins in the population enables studies to evaluate the degree to which observed associations may be attributable to genetic influences and to familial confounding. The twin method relies on the different levels of genetic relatedness between monozygotic ("identical") twins, who are genetically identical, and dizygotic ("fraternal") twins, who share on average half of their genetic variation (as do ordinary full siblings).

A Swedish team of researchers identified 42,582 Swedish twins born between 1959 and 1985, and who were, therefore, adults by the time of the study (20-47 years old). Of these, 24,872 (three out of five) completed a web-based survey with 1,300 questions covering lifestyle and mental and physical health. Out of this group, 17,999 provided information on ADHD symptoms and food frequency.

Self-reported ADHD symptoms came from nine inattention components and nine hyperactivity/impulsivity components, covering the 18 DSM- IV symptoms of ADHD.

The food frequency questionnaire included 94 food items, with the following frequency categories: never, 1-3 times/month, 1-2 times/week, 3-4 times/week, 5-6 times/week, 1 time/day, 2 times/day, 3 times/day.

In the raw data, the two subtypes of ADHD exhibited very similar associations. Both had significant associations with unhealthy diets. Both were more likely to be eating foods high in added sugar, and neglecting fruits and vegetables while eating more meat and fats.

After adjusting for the degree of relatedness of twins (whether monozygotic or dizygotic) and controlling for the other ADHD subtype, the associations remained statistically significant for inattention, but diminished to negligible levels or became statistically non-significant for hyperactivity/impulsivity.

Even for persons with inattention symptoms, adjusted correlations were small (never exceeding r = 0.10), with the strongest associations being for overall unhealthy eating habits (r = 0.09), eating foods high in added sugar (r = 0.10) or high in fat (r = 0.05), and neglecting fruits and vegetables (r = 0.06). All other associations became statistically non-significant.

For persons with hyperactivity/impulsivity symptoms, the only associations that remained statistically significant ­- but at tiny effect sizes - were unhealthy dietary patterns (r = 0.04) and consumption of foods high in added sugar (r = 0.03).

The further genetic analysis, therefore, focused on the strongest associations, between ADHD subtypes on the one hand, and unhealthy dietary patterns and eating foods high in added sugar on the other hand. The heritability estimates (the fraction of phenotypic covariance explained by genetic influences) were 44%, 40%, and 37% for inattention and high-sugar food, inattention and unhealthy dietary patterns, and hyperactivity/impulsivity and high-sugar food, respectively.

 When examining only differences between pairs of monozygotic("identical") twins, the correlations became stronger for inattention, rising to r = 0.12 for unhealthy eating habits and r = 0.13 for consumption of foods high in added sugar. For hyperactivity/impulsivity symptoms, the association with unhealthy eating habits was weaker, and the association with consumption of foods high in added sugar became statistically insignificant.

The authors concluded, "we identified positive associations between self-reported trait dimensions of ADHD and intake of seafood, high-fat food, high-sugar food, high-protein food, and an unhealthy dietary pattern, and negative associations with consumption of fruits, vegetables, and a healthy dietary pattern. However, all the associations are small in magnitude. These associations were stronger for inattention compared to hyperactivity/ impulsivity. This pattern of associations was also reflected at the etiological level, where we found a slightly stronger genetic correlation between inattention with dietary habits and hyperactivity/impulsivity with dietary habits. Non-shared environmental influences also contributed to the overlap between ADHD symptom dimensions and consumption of high-sugar food and unhealthy dietary pattern. However, shared environmental influences probably contributed relatively little to the associations between ADHD symptoms and dietary habits. ... significant MZ twin intraplate differences also provided support for a potential causal link between inattention and dietary habits.

November 29, 2021

Is There Any Relationship Between Artificial Food Colors and ADHD?

Is there any relationship between artificial food colors and ADHD?

Several meta-analyses have assessed this question by computing the standardized mean difference or SMD statistic.  The SMD is a measure that allows us to compare different studies. For context, the effect of stimulant medication for treating ADHD is about 0.9.  SMDs less than 0.3 are considered low, between 0.3 to 0.6 medium, and anything greater than high.
A 2004 meta-analysis by Schab and Trinh combined the results of fifteen studies with a total of 219 participants and found a small association(SMD = .28, 95% CI .08-.49) between consumption of artificial food colors by children and increased hyperactivity. Excluding the smallest and lowest quality studies further reduced the SMD to .21, and a lower confidence limit of .007 also made it barely statistically significant. Publication bias was indicated by an asymmetric funnel plot. No effort was made to correct the bias.
A 2012 meta-analysis by Nigg et al. combined twenty studies with a total of 794 participants and again found a small effect size (SMD =.18, 95% CI .08-.29). It likewise found evidence of publication bias. Correcting for the bias led to a tiny effect size at the outer margin of statistical significance (SMD = .12, 95% CI .01-.23). Restricting the pool to eleven high-quality studies with 619 participants led to a similarly tiny effect size that fell just outside the 95% confidence interval (SMD = .13, CI =0-.25, p = .053). The authors concluded, "Overall, a mixed conclusion must be drawn. Although the evidence is too weak to justify action recommendations absent a strong precautionary stance, it is too substantial to dismiss."
In 2013 a European ADHD Guidelines Group consisting of 21 researchers (Sonuga-Barke et al.) performed a meta-analysis of eight studies involving 294 participants that examined the efficacy of excluding artificial colors from the diets of children and adolescents as a treatment for ADHD. It found a small-to-medium effect size (SMD = .32, 95% CI .06-.58), with less than one in fifty probability that such a result would occur by chance. Yet "Restricting the probably blinded assessment analysis to the four no/low medication trials reduced the standardized mean difference (0.32) to non-significant levels (95%CI=-0.13, 0.77)."
On balance, the research to date suggests a small effect of artificial food colors in aggravating symptoms of hyperactivity in children, and a small beneficial effect of excluding these substances from the diets of children and adolescents, but the evidence is not very robust. More studies with greater numbers of participants, and better control for the effects of ADHD medications, will be required for a more definitive finding.
In the meantime, given that artificial food colors are not an essential part of the diet, parents should consider excluding them from their children's meals, since doing so is risk-free, and the cost (reading labels) negligible.

June 22, 2021