Why 12 genetic markers for ADHD are exciting news for New Brain Nutrition

We are finally here: for the first time, genome-wide significant markers are identified that increase the risk for Attention Deficit / Hyperactivity Disorder (ADHD). This research was conducted by an international consortium of more than 200 experts on genetics and ADHD, and includes several researchers that are also involved in our Eat2beNICE project (the scientific basis of this New Brain Nutrition website). The findings were recently published in the prestigious journal “Nature Genetics” and will greatly advance the field of ADHD genetics research.

Why is this finding so important?

The genetics of ADHD are very complex. While ADHD is highly heritable, there are likely to be thousands of genes that contribute to the disorder. Each variant individually increases the risk by only a tiny fraction. To discover these variants, you therefore need incredibly large samples. Only then can you determine which variants are linked to ADHD. The now published study by Ditte Demontis and her team combined data from many different databases and studies, together including more than 55,000 individuals of whom over 22,000 had an ADHD diagnosis.

We can now be certain that the twelve genetic markers contribute to the risk of developing ADHD. Their influence is however very small, so these markers by themselves can’t tell if someone will have ADHD. What’s interesting for the researchers is that none of these markers were identified before in much smaller genetic studies of ADHD. So this provides many new research questions to further investigate the biological mechanisms of ADHD. For instance, several of the markers point to genes that are involved in brain development and neuronal communication.

Why are our researchers excited about this?

A second important finding from the study is that the genetic variants were not specific to ADHD, but overlapped with risk of lower education, higher risk of obesity, increased BMI, and type-2 diabetes. If genetic variants increase both your risk for mental health problems such as ADHD, and for nutrition-related problems such as obesity and type-2 diabetes, then there could be a shared biological mechanism that ties this all together.

We think that this mechanism is located in the communication between the gut and the brain. A complex combination of genetic and environmental factors influence this brain-gut communication, which leads to differences in behaviour, metabolism and (mental) health.genetic markers for adhd

The microorganisms in your gut play an important role in the interaction between your genes and outside environmental influences (such as stress, illness or your diet). Now that we know which genes are important in ADHD, we can investigate how their functioning is influenced by environmental factors. For instance, gut microorganisms can produce certain metabolites that interact with these genes.

The publication by Ditte Demontis and her co-workers is therefore not only relevant for the field of ADHD genetics, but brings us one step closer to understanding the biological factors that influence our mental health and wellbeing.

Further Reading

Demontis et al. (2018) Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics. https://www.nature.com/articles/s41588-018-0269-7

The first author of the paper, Ditte Demontis, also wrote a blog about the publication. You can read it here: https://mind-the-gap.live/2018/12/10/the-first-risk-genes-for-adhd-has-been-identified/

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Breaking news: It has long been assumed that the gut and the brain communicate not only via a slow, hormonal pathway, but that there must be an additional, faster association between gut and brain. Melanie Maya Kelberer and her colleagues from Duke University, NC, now managed to detect this connection. Their paper has just been published in the renowned journal ‘Science’.

By researching a mouse model, they were able to show that the gut and the brain are connected via one single synapse. This is how it works: A cell in the gut (the so-called enteroendocrine cell) transfers its information to a nerve ending just outside the gut. At the connecting nerve ending (the synapse), the neurotransmitter glutamate – the most important excitatory transmitter in the nervous system – passes on the information about our nutrition to small nerve endings of the vagal nerve, which spreads from the brain to the intestines.

Vagal nerveBy travelling along this vagal nerve, the information from the gut reaches the brainstem within milliseconds. The authors now state that a new name is needed for the enteroendocrine cells, now that they have been shown to be way more than that. The name ‘neuropod cells’ has been suggested. The authors interpret their findings as such, that this rapid connection between the gut and the brain helps the brain to make sense of what has been eaten. Through back-signalling, the brain might also influence the gut. In sum, this finding is an important step towards a better understanding of how the gut and the brain communicate. Findings such as this one help us to find ways to positively influence our brain states and our mental health by our food choices.

Read the original paper here: http://science.sciencemag.org/content/361/6408/eaat5236.long

Kaelberer, M.M., Buchanan, K. L., Klein, M. E., Barth, B. B., Montoya, M. M., Shen, X., and Bohórquez, D. V. (2018), A gut-brain neural circuit for nutrient sensory transduction, ​Science,
​ Vol. 361, Issue 6408

 

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Maladaptive or uncontrolled impulsivity and compulsivity lead to emotional and social maladjustment, e.g. addiction and crime, and underlie psychiatric disorders. Recently, alterations in microbiota composition have shown to have implications for brain and social behaviors as we have been explaining in our lasts blogs. The microbiota-gut-brain axis may be involved in this process but the mechanisms are not fully identified (1). The supplementation of probiotics can modulate the microbial community and now has been suspected to contribute to ameliorating symptoms of a psychiatric disease with possible influence on social behaviors (2). To date, no randomized controlled trial has been performed to establish feasibility and efficacy of this intervention targeting the reduction of impulsivity and compulsivity. This gave us the idea to perform a study to investigate the effects of supplementation with probiotics, working with adults with Attention Deficit Hyperactivity Disorder (ADHD) and Borderline Personality Disorder (BPD) which in most cases present high levels of impulsivity, compulsivity and aggression.

Probiotics for healthWe call our project PROBIA, which is an acronym of “PROBiotics for Impulsivity in Adults”. This study will be performed in three centers of Europe including, Goethe University in Frankfurt, Semmelweis University in Budapest and Vall d’Hebron Research Institute (VHIR) in Barcelona, the coordinator of the clinical trial. We are planning to start recruiting patients in January of 2019 and obtain the results in 2021. In our study, we will explore the effects of probiotics by measuring the change in ADHD or BPD symptoms, general psychopathology, health-related quality of life, neurocognitive function, nutritional intake, and physical fitness. The effect of the intervention on the microbiome, epigenetics, blood biomarkers, and health will be also explored by collecting blood, stool, and saliva samples.

We are looking forward to having the results of this amazing study in order to understand the mechanisms involved in the crosstalk between the intestinal microbiome and the brain. If improvement effects can be established in these patients, new cost-effective treatment will be available to this population.

 This was co-authored by Josep Antoni Ramos-Quiroga, MD PhD, psychiatrist and Head of Department of Psychiatry at Hospital Universitari Vall d’Hebron in Barcelona, Spain. He is also professor at Universitat Autònoma de Barcelona.

Sources

  1. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. Microbiota is essential for social development in the mouse. Mol Psychiatry [Internet]. The Author(s); 2013 May 21;19:146. Available from: http://dx.doi.org/10.1038/mp.2013.65
  2. Felice VD, O SM. The microbiome and disorders of the central nervous system. 2017 [cited 2017 Oct 16]; Available from: https://ac.els-cdn.com/S0091305717300242/1-s2.0-S0091305717300242-main.pdf?_tid=b52750d8-b2ae-11e7-819b-00000aab0f02&acdnat=1508185089_58e99184d2c0f677d79ff1dd88d02667

 

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Have you experienced drowsiness after eating a large meal? Has an important presentation made your stomach turn? Seeing a special someone made you feel butterflies in your stomach? If you have (and you most likely have), then you know how strong the connection between the brain and the gut is.

Scientists have found that many chronic metabolic diseases, type 2 diabetes, mood disorders and even neurological diseases, such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders (1). The importance of the association between the gut and the brain is gaining momentum with each new study. However, the way HOW the signaling between these two integral parts of the body exactly works hasn’t been clear until recently.

It was thought for a long time that the only “communication channel” between the gut and the brain was the passive release of hormones stimulated by the consumed nutrients. Hormones entered the bloodstream and slowly notified the brain that the stomach is full of nutrients and calories. This rather slow and indirect way of passing messages takes from minutes to hours.

But now, a recent study (2) has elegantly proven that the gut can message the brain in seconds! Using a rabies virus enhanced with green fluorescence, the scientists traced a signal as it traveled from the intestines to the brainstem of mice, crossing from cell to cell in under 100 milliseconds – faster than the blink of an eye.

The researchers had also noticed that the sensory cells lining the gut were quite similar to the receptors in the nose and on the tongue (3). The effects, however, differ. In the mouth, the taste of fatty acids triggers signals to increase hunger, whereas in the small intestine, fatty acids trigger signals of satiety. This means that the discovered “gut feeling” might be considered as a sixth sense, a way of how the brain is being signaled when the stomach is full.

This new knowledge will help to understand the mechanism of appetite, develop new and more effective appetite suppressants and help those struggling with weight and problematic eating patterns.

REFERENCES
(1) Pellegrini C et al (2018) Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases? Acta Neuropathol 136:345. doi:10.1007/s00401-018-1856-5

(2) Kaelberer et al (2018) A gut-brain neural circuit for nutrient sensory transduction. Science 361(6408):eaat5236. doi:10.1126/science.aat5236

(3) Bohórquez and Liddle (2015) The gut connectome: making sense of what you eat. J Clin Invest 125(3):888–890. doi:10.1172/JCI81121

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A hot topic these days, that one can hear more and more information about is the microbiota-gut-brain axis, the bidirectional interaction between the intestinal microbiota and the central nervous system nowadays, this has become a hot topic. We are becoming increasingly aware that gut microbiota play a significant role in modulating brain functions, behavior and brain development. Pre- and probiotics can influence the microbiota composition, so the question arises, can we have an impact on our mental health by controlling nutrition and using probiotics?

Burokas and colleagues aimed to investigate this possibility in their study (2017), where the goal was to test whether chronic prebiotic treatment in mice modifies behavior across domains relevant to anxiety, depression, cognition, stress response, and social behavior.

In the first part of the study, the researchers fed mice with prebiotics for 10 weeks. They were administered the prebiotics fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), a combination of both, or water. FOS and GOS are soluble fibers that are associated with the stimulation of beneficial bacteria such as bifidobacterium and lactobacillus.

Behavioral testing started from the third week including

  • the open field test (anxiety – amount of exploratory behavior in a new place),
  • novel object test (memory and learning – exploration time of a novel object in a familiar context), and
  • forced swimming test (depression-like behavior – amount of activity in the cylinder filled water).

Meanwhile, plasma corticosterone, gut microbiota composition, and cecal short-chain fatty acids were measured. Taken together, the authors found that the prebiotic FOS+GOS treatment exhibited both antidepressant and anxiolytic (anti-anxiety) effects. However, there were no major effects observed on cognition, nociception (response to pain stimulus), and sociability; with the exception of blunted aggressive behavior and more prosocial approaches.

In the second part, FOS+GOS or water-treated mice were exposed to chronic psychosocial stress. Behavior, immune, and microbiota parameters were assessed. Under stress, the microbiota composition of water-treated mice changed (decreased concentration of bifidobacterium and lactobacillus), which effect was reversed by treatment with prebiotics.

Furthermore, it was found that three weeks of chronic social stress significantly reduced social interaction, and increased stress indicators (basal corticosterone levels and stress-induced hyperthermia), whereas prebiotic administration protected from these effects.

After stimulation with a T-cell activator lectin (concanavalin A), the stressed, water-treated mice group presented increased levels of inflammatory cytokines (interleukin 6, tumor necrosis factor alpha), whereas in animals with prebiotics had these at normal levels.

Overall, these results suggest a beneficial role of prebiotic treatment in mice for stress-related behaviors and supporting the theory that modifying the intestinal microbiota via prebiotics represents a promising potential for supplement therapy in psychiatric disorders.

Watch YouTube Video:
https://youtu.be/E479yto8pyk

REFERENCES
Burokas, A., Arboleya, S., Moloney, R. D., Peterson, V. L., Murphy, K., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2017). Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice. Biological Psychiatry, 82(7), 472–487. https://doi.org/10.1016/j.biopsych.2016.12.031

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Recently, the idea that gastrointestinal microbiota are able to affect host behaviour is gaining momentum and it is based on studies conducted with animal models but also in humans with neurological disorders. However, the mechanisms that underlay this complex interplay between gut, brain and microbiota are not completely understood. Here we discuss recent findings on how microbial products could potentially affect the gut-brain axis.

Intestinal microbiota grow through the fermentation of undigested carbohydrates that end up in the large intestine. It was shown that absence of microbes or disruption of the microbiota, led to increased populations of impaired microglia cells in mice. Microglia cells are the primary effector cells for immune signalling to the central nervous system. The presence of a complex microbiota community, was shown to be essential for proper microglia maturation and function [1].

The main products of microbial fermentation in the gut are; acetate, propionate and butyrate, collectively known as short chain fatty acids(SCFA’s). Their beneficial role in human physiology have been well described, and recently evidence suggests that these molecules are able to cross blood brain barrier [2]. Moreover, gut microbiota have been associated with the brain barrier integrity. Mice raised in absence of bacteria are reported to have reduced brain barrier integrity. Once colonized with either a butyrate or an acetate/propionate producing bacteria, significant improvements were reported in the barrier [3]. Notably the integrity of the blood-brain barrier from the germ free mice was able to be restored through the oral administration of butyrate.

Gut_Microbes and Mental HealthSCFA’s are among the molecules having the privilege to cross the blood brain barrier and access the brain directly, their role should be studied in detail.

Recent studies also demonstrate that gut microbes regulate levels of intestinal neurotransmitters. The enteric nervous system interacts with a plethora of neurotransmitters (more than 30 have been identified so far.) Actually, the bulk of serotonin production ~90%, a neurotransmitter associated with mood and appetite is located in the gut. Specialized cells known as enterochromaffin cells are the main serotonin producers in the gut. In the absence of intestinal microbiota gastrointestinal serotonin levels are depleted. However, they can be restored by the addition of a specific spore forming consortium of intestinal bacteria. Specific bacterial metabolites have been reported to mediate this effect [4].

Other intestinal microbiota have been reported also to regulate the levels of the GABA neurotransmitter. Reduced levels of GABA have been associated with anxiety, panic disorder and depression. Bacterial GABA producers have been known to exist for years but it was not until 2016 that a gut bacteria was identified as GABA consumer [5]. For example, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings. Intervention with the lactic acid bacteria Lactobacillus rhamnosus (JB-1) in healthy mice reduced anxiety related symptoms (accompanied by a reduction in the mRNA expression of GABA receptors in the Central Nervous System.) Lactic acid producing bacteria have also been reported to produce GABA in several food products such as kimchi, fermented fish and cheese [6].

Collectively, our gut microbiota encodes for ~100 times more genes than the human genome. The potential for some of these microbial genes to produce compounds able to interact with the nervous system and regulate critical pathways implicated in the gut brain axis is realistic and worth being explored.

Authors Prokopis Konstanti, MSc and Clara Belzer, PhD are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.

Footnotes

  1. Erny, D., et al., Host microbiota constantly control maturation and function of microglia in the CNS. Nature neuroscience, 2015. 18(7): p. 965-977.
  2. Joseph, J., et al., Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Frontiers in Neuroscience, 2017. 11(155).
  3. Braniste, V., et al., The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 2014. 6(263): p. 263ra158-263ra158.
  4. Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015. 161(2): p. 264-276.
  5. P. Strandwitz, K.K., D. Dietrich, D. McDonald, T. Ramadhar, E. J. Stewart, R. Knight, J. Clardy, K. Lewis; , Gaba Modulating Bacteria of the Human Gut Microbiome. 2016.
  6. Dhakal, R., V.K. Bajpai, and K.-H. Baek, Production of gaba (γ – Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology, 2012. 43(4): p. 1230-1241.

 

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The reason why I look at impulsive behavior is because mental disorders are the single largest contributors to disease burden in Europe. Impulsivity and compulsivity increase the risk of psychiatric disorders, especially Attention Deficit Hyperactivity Disorder, alcohol and drug abuse disorders, conduct disorder and antisocial disorders (including aggression). The urgency of addressing impulsivity and compulsivity is additionally strongly supported by the fact that these problems increase the risk for mortality.

My name is Yvonne Willemsen and I have started my PhD track at Radboud University in the Netherlands in October 2017. For my project I will assess the association between nutrition, gut microbiota composition and impulsive behavior in toddlers and young adolescents. In the following paragraphs, I will explain the first study that I am currently conducting.

Many previous studies have examined the association between nutrition and executive functions. Executive functions are cognitive processes in the brain that contribute to regulating thoughts and behaviors. Executive functions can be roughly divided into three core functions, namely: inhibitory control, working memory, and cognitive flexibility. Inhibitory control, which can be interpreted as the opposite of impulsivity, is necessary to suppress impulses. It is also an important core function of executive functions, as it supports working memory and cognitive flexibility.  To date, studies have examined the association between nutrition and executive functions in general (1). Whether nutrition is related to inhibitory control specifically (in toddlers and young adolescents) is something that still needs to be investigated.

The next step of my study is to understand how nutrition is associated with inhibitory control. To explain a possible mechanism, we will look at the gut microbiota. The reason why the gut microbiota is a point of interest is because gut microbiota can secrete molecules that may influence brain function, and thus may influence inhibitory control (2). This connection between the gut and the brain is also known as the gut-brain axis. Gut microbiota composition can change according to nutritional intake, and can therefore play a role in the gut brain axis (3). To assess the association between nutrition, gut microbiota and behavior in toddlers and young adolescents, we will use questionnaires and different behavioural measures.

  1. Cohen, J. F. W., Gorski, M. T., Gruber, S. A., Kurdziel, L. B. F. & Rimm, E. B. The effect of healthy dietary consumption on executive cognitive functioning in children and adolescents: a systematic review. Br. J. Nutr. 116, 989–1000 (2016). Link
  2. Rogers, G. B. et al. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol. Psychiatry 21, 738–748 (2016). Link
  3. Oriach, C. S., Robertson, R. C., Stanton, C., Cryan, J. F. & Dinan, T. G. Food for thought: The role of nutrition in the microbiota-gut–brain axis. Clin. Nutr. Exp. 6, 25–38 (2016). Link
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The human gut is colonized by microorganisms in a similar number as the cells of the human body.

“Microbiota” refers to these microorganisms, and it maintains a symbiotic relationship with the host, contributing to essential functions such as food digestion, energy harvest and storage, the function of the intestinal barrier, and the immune system and protection against pathogenic organisms. Prenatal and postnatal factors can alter the composition of the microbiota, such as stress and diet or the use of antibiotics (see image).

Prenatal and Postnatal factors influence gut-brain axis and mental healthFor instance, stress during pregnancy can alter the composition of vaginal microbiota, which affects the composition of the microbiota of the newborn and is related to gastrointestinal (GI) symptoms and allergic reactions. Interestingly, there is a bidirectional communication between the GI tract and the central nervous system (the gut-brain axis) that involves neuronal and metabolic pathways, immune and endocrine mechanisms. Changes in the composition of the microbiota can lead to altered development of the brain and increased risk of psychiatric and neurodevelopmental disorders, such as anxiety, depression and autism (see image).

Depression is one of the most recurrent stress-related disorders that highly impacts the quality of life. Fecal samples of patients with depression have a decreased microbial richness and diversity than controls. The use of probiotics have been shown to help with sad mood and negative thoughts, which may be a potential preventive strategy for depression.

Autism is characterized by impaired communication, poor social engagement and repetitive behaviours, with frequent GI symptoms. We know that the bacteria composition is more diverse in autistic individuals than in unaffected subjects.

For other psychiatric disorders, such as Attention deficit/hyperactivity disorder (ADHD) and Schizophrenia, there is indirect evidence for a role of the microbiota, but more studies are needed.

This connection between the gut and brain is two way communication, and is known as “The Gut-Brain Axis.”

Our knowledge of the impact of gut microbiota on brain function is growing fast, which may pave the way to possible applications for the treatment of psychiatric and neurodevelopmental disorders.

Authors Judit Cabana, Bru Cormand, and Noelia Fernandez Castillo are in the Department of Genetics, Microbiology & Statistics, University of Barcelona, Catalonia, Spain

More information can be found in: Felice VD, O’Mahony SM. The microbiome and disorders of the central nervous system. (2017) Pharmacol Biochem Behav. Sep;160:1-13.
https://www.ncbi.nlm.nih.gov/pubmed/28666895

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