This week, my lab at the University of Canterbury published the first investigation1 into whether a mineral-vitamin supplement could change the bacteria in the microbiome of children with ADHD. Our preliminary data, based on our sample of 17 kids (half of whom were given micronutrients and half were given placebo for 10 weeks), hints at increased diversity and changes in the types of bacteria contained in the microbiome of the children exposed to the micronutrients. This type of study starts to moves us beyond the efforts to show that micronutrients benefit some people with psychiatric symptoms, and towards figuring out why they might exert their influence. So what does this mean?

First off, what is the microbiome?

The gut microbiome is defined as the trillions of microbes that inhabit the human digestive tract. In additional to playing a crucial role in digesting food, they also play pivotal roles in immune and metabolic functioning, gene expression, as well as playing a role in the expression of psychiatric symptoms through the gut-brain connection.2 We also know that they generate essential vitamins. When our microbiome gets into a state of dysbiosis (microbial imbalance), in addition to the physical symptoms like reflux, poor digestion, pain, constipation and/or diarrhoea, it is thought that dysbiosis can also lead to increased permeability of the gut wall, increased production of endotoxins, increased inflammation and decreased nutrient synthesis.

How do we learn about what bacteria are within and on us?

Research on the human microbiome has grown exponentially in the past decade. However, it was only recently that we could fairly cheaply quantify and describe the bugs contained within us. 16S rRNA sequencing (the technology we used) is a key methodology in identifying bacterial populations and allows scientists to easily and reliably characterize complex bacterial communities.3 This methodology is a simple and effective alternative to microbial culture, and provides detailed information about the various species of bacteria that are contained within our microbiome. The sequencing gives information on bacterial diversity, as well as details about the specific family (e.g., Bifidobacteriaceae), genus (e.g., Bifidobacterium), and species (e.g., Bifidobacterium Longom).

What about the microbiome of kids with ADHD?

What scientists are now wondering is whether people who suffer from specific psychiatric symptoms, like those associated with ADHD, have a different bacterial composition than those who don’t have these symptoms and whether these differences can help us understand the severity of the symptoms. In other words, is it possible that our bugs can make us impulsive? And if so, if we changed the bugs, can we become less impulsive?

There isn’t a huge literature exploring this topic in ADHD. Preliminary studies suggest that antibiotics in the first 6 months of life may increase risk of ADHD symptoms at 11 years of age,4 although this finding hasn’t been replicated.5 Another study found that the Phylum Actinobacteria is overrepresented in ADHD compared with controls.6 Other research suggests that reduced alpha diversity may exist in young patients with ADHD, specifically that boys with ADHD had more Bacteroidaceae relative to controls, with the species Neisseriaceae identified as a particularly promising ADHD-associated candidate.7 Although this finding of reduced alpha diversity was not observed in treatment-naïve children with ADHD, Jiang and colleagues noted that the more an individual had the species Faecalibacterium, the lower their ADHD severity.8

Overall, there are intriguing signals but the signals are not always replicating. Much more research with larger samples is needed to try to determine if there are reliable bacterial biomarkers. We also need to parse out the effect of diet, medications, age, ethnicity and gender on the results that have been reported. Further, we don’t know whether these differences are causal or a result of ADHD or completely irrelevant to the expression of the symptoms.

We still don’t know if changing the relative amount of a bacteria can change psychiatric symptoms. We know that diet manipulation can change levels of bacteria but whether those changes in bacteria are necessary for improvement in psychological states requires much more research.

So what did we find?

Looking at the microbiome over a short period of time with a small sample is challenging. There is such diversity in the bacteria within us and between us that it is a challenge to explore changes and also whether changes are meaningful. But we did observe some intriguing effects:

  1. The observed taxonomic units (OTU), a measure of community richness, significantly increased in treatment group but not in placebo group. We think this is a good thing.
  2. We observed significant greater decrease in abundance of genus Bifidobacterium from phylum Actinobacteria in active versus placebo and that the more it decreased, the more the ADHD symptom scores dropped. If Bifodobacterium is contributing to the symptoms of ADHD, this is a good thing.
  3. We also observed a significant positive correlation between Actinobacterium abundance and Clinician ADHD IV-RS rating scale before the intervention was introduced, which suggests that Actinobacterium may play a role in the expression of ADHD.

What does this mean?

The small sample makes it difficult to generalize from this study. However, these novel results provide a basis for future research on the biological connection between ADHD, diet and the microbiome. Previous research from our lab has shown that micronutrients do exert some positive effects on ADHD and associated symptoms.9 10 These findings suggest that micronutrient treatment may result in a more diverse microbiome which may in turn, have a positive effect on brain health.

What next?

The field of the microbiome is literally exploding with new studies out every day. The focus currently is trying to find ways to manipulate the microbiome for positive response. This has mainly been explored through either adding in bacteria (in the form of probiotics or psychobiotics if targeting psychological symptoms), diet manipulation, or more recently, fecal microbiota transplants. I do worry a bit that this search for the magic-bullet bacteria that causes distress may turn out to be as disappointing as the search was for candidate genes, but it is worth some effort to figure out if this is an important lead.

Eat2BeNice (New Brain Nutrition) plans to explore the role of the microbiome in multiple ways, including determining whether individuals with high impulsivity/compulsivity have a unique microbiome profile, whether targeted probiotics can improve impulsivity/compulsivity symptoms, and also whether improvement in impulsivity/compulsivity symptoms from diet manipulation and via the use of supplements can be explained via changes in the microbiome. Watch this space!

REFERENCES 

  1. Stevens AJ, Purcell RV, Darling KA, et al. Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder. Sci Rep 2019;9(1):10128.
  2. Frye RE, Slattery J, MacFabe DF, et al. Approaches to studying and manipulating the enteric microbiome to improve autism symptoms. Microb Ecol Health Dis 2015;26:26878-78.
  3. Ames NJ, Ranucci A, Moriyama B, et al. The Human Microbiome and Understanding the 16S rRNA Gene in Translational Nursing Science. Nurs Res 2017;66(2):184-97.
  4. Slykerman RF, Coomarasamy C, Wickens K, et al. Exposure to antibiotics in the first 24 months of life and neurocognitive outcomes at 11 years of age. Psychopharmacology (Berl) 2019;236(5):1573-82.
  5. Axelsson PB, Clausen TD, Petersen AH, et al. Investigating the effects of cesarean delivery and antibiotic use in early childhood on risk of later attention deficit hyperactivity disorder. J Child Psychol Psychiatry 2019;60(2):151-59.
  6. Aarts E, Ederveen THA, Naaijen J, et al. Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One 2017;12(9):e0183509.
  7. Prehn-Kristensen A, Zimmermann A, Tittmann L, et al. Reduced microbiome alpha diversity in young patients with ADHD. PLoS One 2018;13(7):e0200728.
  8. Jiang HY, Zhou YY, Zhou GL, et al. Gut microbiota profiles in treatment-naive children with attention deficit hyperactivity disorder. Behav Brain Res 2018;347:408-13.
  9. Rucklidge JJ, Eggleston MJF, Johnstone JM, et al. Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry 2018;59(3):232-46.
  10. Rucklidge JJ, Frampton CM, Gorman B, et al. Vitmain-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised palcebo-controlled trial. The British Journal of Psychiatry 2014;204:306-15.
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A team of Iranian researchers recently published a meta-analysis seeking to determine what, if any, association there may be between low Vitamin D levels and ADHD in children and adolescents.

Combining the results from thirteen studies with 10,334 participants, they found that youth with ADHD had “modest but significant” lower serum concentrations of 25-hydroxyvitamin D than normally developing children. The weighted mean difference was just under 7 nanograms per milliliter. The odds of obtaining such a result by chance would be less than one in a thousand (p < .001). There was little to no sign of publication bias. Between-study heterogeneity, however, was very high (I2 = 94).

Vitamin D and ADHDThese results suggest an association. But are low serum levels of Vitamin D a cause or effect of ADHD? Causation is vastly more difficult to establish than association. To begin to tease this out, the researchers identified four prospective studies that compared maternal Vitamin D levels with the subsequent development of ADHD symptoms in their children. Two of these used maternal serum levels, and two used umbilical cord serum levels. Together, these studies found that low maternal Vitamin D levels were associated with a 40% higher risk of ADHD in their children. Whether maternal serum or umbilical cord serum measurements were used had little or no effect on the outcome. Study heterogeneity was negligible. But the authors noted that this result “should be considered with caution” because it was heavily dependent on one of the prospective studies included in the analysis. All of which suggests a need for further prospective studies.

In the meantime, the authors suggest it would be prudent to increase sun exposure and Vitamin D supplementation given the prevalence of Vitamin D deficiency.

REFERENCES

Yadollah Khoshbakht, Reza Bidaki, and Amin Salehi-Abargouei, “Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies,” Advances in Nutrition, vol. 9, issue 1, p. 9-20 (2018).

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Mediterranean diet could prevent depression, new study finds” [CNN]; “Mediterranean diet ‘may help prevent depression‘” [BBC]. The publication of Lassale and her colleagues in the prestigious scientific journal Molecular Psychiatry on the association between Mediterranean Diet and depression, received a lot of attention in the media last week.

So, can diet really influence your mental health? The publication of Lassale shows that there are indications that what you eat is related to how you feel. But because this study is an observational study, we can’t conclude anything yet about causation. In other words, we don’t know yet whether eating healthy causes you to feel less depressed, or whether feeling depressed causes you to eat unhealthy.

Causal links between diet and mental health

Diet and mental healthThe researchers of the European consortium Eat2beNICE are investigating exactly this causal link. The way we do this is through clinical trials. In this way, we first let chance decide whether a person receives a particular diet or is part of the control group. Through this randomization we can be sure that the differences that we find between the two groups are really due to the dietary intervention that people received, because all other factors are the same between the two groups.

Specifically for the effects of the Mediterranean diet on behaviour, in the Eat2beNICE project we are using the information and measurements available from the PREDIMED-PLUS trial. In this study, we are looking specifically for the effect of a calorie-restricted Mediterranean diet, combined with physical activity, on several behavioral outcomes related with several psychiatric diseases of adults at high cardiovascular risk.

At the same time, we are conducting three other clinical trials:

  1. In Nijmegen (The Netherlands), we investigate the effects of a very strict, hypo-allergenic diet on behavioural problems in children with ADHD.
  2. We are investigating the effects of vitamin supplements in a clinical trial that will be conducted in Mannheim(Germany) and Groningen(The Netherlands).
  3. Researchers in Barcelona (Spain) and Frankfurt (Germany) are investigating the effects of probiotics (i.e. bacteria that are good for you) on mental health in adults that are highly impulsive and/or aggressive.

Through these studies we hope to be able to identify if these types of food improve mental health and in which circumstances. This can have big implications for psychiatry, where putting someone on a specific, personalised diet may be a way to improve treatment. Also, people who are at a risk for developing mental health problems may benefit from specific diets to reduce this risk. But before this can be put into action, we first need good scientific data on what really works.

How can food drive human behaviour?

A second aim of our large research consortium is to identify the mechanisms between nutrition and the way the brain works. We think that the bacteria that live in your gut play a large role in this, as they interact with other systems in your body, including your brain. So we are collecting poop samples of the people that are participating in our clinical trials to identify which bacteria are more or less common in our participants compared to the control population. We are also measuring our participants’ behaviour and we will scan their brains. We hope that this will help us understanding better why certain types of food can be beneficial for mental health, and why some others increase the risk for mental health problems. This too will help to elucidate, and understand, the causal links between food and behaviour.

In short, we are very thankful for the study of Lassale and her colleagues, for backing up the evidence that what you eat is related to how you feel and behave. Now there’s work for us to do to prove the causal and mechanistic links. We’ll keep you posted here!

 

Authors Jeanette Mostert and Alejandro Arias-Vasquez work at the department of Genetics at the Radboud University Medical Center in Nijmegen, The Netherlands. Alejandro Arias-Vasquez is the project coordinator of the Eat2beNICE project. Jeanette Mostert is the dissemination manager.

 

Further reading

Lassale C, Batty GD, Baghdadli A, Jacka F, Sánchez-Villegas A, Kivimäki M, Akbaraly T. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Mol Psychiatry. 2018 Sep 26. doi: 10.1038/s41380-018-0237-8.

 

Blog by Jordi Salas explaining the Lassale paper and the PREDIMED trial:
http://newbrainnutrition.com/category/nutrition/mediterranean-diet/

Blog by Jolanda van der Meer on hypo-allergenic diet (TRACE study): http://newbrainnutrition.com/adhd-and-food-elimination-diet/

Blog by Julia Rucklidge on trials with vitamin supplements: http://newbrainnutrition.com/micronutrients-and-mental-health/

Blog by Judit Cabana on the Gut-Brain axis: http://newbrainnutrition.com/the-gut-brain-axis-how-the-gut-relates-to-psychiatric-disorders/

 

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Vitamin B and ADHDThere is a well-documented relationship between dietary factors, health and human behavior. Severe malnutrition produces neurological and psychiatric symptoms. It is also assumed that dietary factors play a role in common mental disorders, such as ADHD, but this is less established and more difficult to investigate. A few studies have documented a beneficial effect of dietary interventions and vitamin supplements in ADHD in children and adults. To examine the nutritional status in ADHD, Landaas et al.(1) recently compared blood vitamin levels in 133 adult ADHD patients and 131 healthy controls. In the ADHD group there was a clear overrepresentation in the group with low levels of vitamins B2, B6 and B9.

It is yet unclear whether these vitamin levels are a) associated with ADHD symptoms, or b) whether they are the result of altered dietary intake, or c) metabolism in ADHD patients. However, it is possible that the differences reflect dietary habits that are different in a subgroup of ADHD patients and controls. Dietary habits are established early during life and may last into adulthood. It is possible that suboptimal dietary habits may precipitate, exacerbate or maintain symptoms of ADHD. More research in larger samples is obviously needed to clarify these issues. Over the next five years in our project, entitled “Effects of Nutrition and Lifestyle on Impulsive, Compulsive, and Externalizing behaviours,” we expect to gain much more insight into these connections.  We will share our findings with you.  Stay tuned!!

(1) BJPsych Open. 2016 Nov; 2(6): 377–384. Published online 2016 Dec 13. doi:  10.1192/bjpo.bp.116.003491
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153567/ 

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