The role of the gut microbiota in patients with Kleefstra syndrome.

Kleefstra Syndrome (KS) is a rare monogenetic syndrome, caused by haploinsufficiency of the euchromatic histone methyl transferase 1 (EHMT1) gene, an important regulator of neurodevelopment. The clinical features of KS include intellectual disability, autistic behavior and gastrointestinal problems. The gut microbiota, an important modifier of the gut-brain-axis, may constitute an unexplored mechanism underlying clinical KS variation. We investigated the gut microbiota composition of 23 individuals with KS (patients) and 40 of their family members, to test whether (1) variation in the gut microbiota associates with KS diagnosis and (2) variation within the gut microbiota relates with KS syndrome symptoms. Both alpha and beta diversity of patients were different from their family members. Genus Coprococcus 3 was lower in abundance in patients compared to family members. Moreover, abundance of genus Merdibacter was lower in patients versus family members, but only in participants reporting intestinal complaints. Within the patient group, behavioral problems explained 7% of beta diversity variance. Also, within this group, we detected higher levels of Atopobiaceae - uncultured and Ruminococcaceae Subdoligranulum associated with higher symptom severity. These significant signatures in the gut microbiota composition in patients with KS suggest that microbiota differences are part of the KS phenotype.

The Role of Diet and the Gut Microbiota in Reactive Aggression and Adult ADHD-An Exploratory Analysis.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition, of-ten persistent into adulthood and accompanied by reactive aggression. Associations of diet and the gut-microbiome with ADHD as well as emotional behaviors suggest potential clinical rele-vance of both. However, studies on diet and the gut-microbiome in human reactive aggression are lacking, and should investigate the interaction between diet and the gut-microbiome leading to behavioral changes to assess their potential clinical relevance. In this study, we investigated the interaction of diet and gut-microbiota with adult ADHD and reactive aggression in 77 adults with ADHD and 76 neurotypical individuals. We studied the relationships of ADHD and reactive ag-gression with dietary patterns, bacterial community and taxonomic differences of 16S-sequenced fecal microbiome samples, and potential mediating effects of bacterial genus abundance on signifi-cant diet-behavior associations. The key findings include: (1) An association of high-energy intake with reactive aggeression scores (pFDR = 4.01 × 10-02); (2) Significant associations of several genera with either reactive aggression or ADHD diagnosis with no overlap; and (3) No significant mediation effects of the selected genera on the association of reactive aggression with the high-energy diet. Our results suggest that diet and the microbiome are linked to reactive aggression and/or ADHD individually, and highlight the need to further study the way diet and the gut-microbiome inter-act.

Serotonin Transporter (SERT) Expression Modulates the Composition of the Western-Diet-Induced Microbiota in Aged Female Mice.

Background. The serotonin transporter (SERT), highly expressed in the gut and brain, is implicated in metabolic processes. A genetic variant of the upstream regulatory region of the SLC6A4 gene encoding SERT, the so-called short (s) allele, in comparison with the long (l) allele, results in the decreased function of this transporter, altered serotonergic regulation, an increased risk of psychiatric pathology and type-2 diabetes and obesity, especially in older women. Aged female mice with the complete (Sert-/-: KO) or partial (Sert+/-: HET) loss of SERT exhibit more pronounced negative effects following their exposure to a Western diet in comparison to wild-type (Sert+/+: WT) animals. Aims. We hypothesized that these effects might be mediated by an altered gut microbiota, which has been shown to influence serotonin metabolism. We performed V4 16S rRNA sequencing of the gut microbiota in 12-month-old WT, KO and HET female mice that were housed on a control or Western diet for three weeks. Results. The relative abundance of 11 genera was increased, and the abundance of 6 genera was decreased in the Western-diet-housed mice compared to the controls. There were correlations between the abundance of Streptococcus and Ruminococcaceae_UCG-014 and the expression of the pro-inflammatory marker Toll-like-Receptor 4 (Tlr4) in the dorsal raphe, as well as the expression of the mitochondrial activity marker perixome-proliferator-activated-receptor-cofactor-1b (Ppargc1b) in the prefrontal cortex. Although there was no significant impact of genotype on the microbiota in animals fed with the Control diet, there were significant interactions between diet and genotype. Following FDR correction, the Western diet increased the relative abundance of Intestinimonas and Atopostipes in the KO animals, which was not observed in the other groups. Erysipelatoclostridium abundance was increased by the Western diet in the WT group but not in HET or KO animals. Conclusions. The enhanced effects of a challenge with a Western diet in SERT-deficient mice include the altered representation of several gut genera, such as Intestinimonas, Atopostipes and Erysipelatoclostridium, which are also implicated in serotonergic and lipid metabolism. The manipulation of these genera may prove useful in individuals with the short SERT allele.

The gut-microbiome in adult Attention-deficit/hyperactivity disorder - A Meta-analysis.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that persists into adulthood in the majority of individuals. While the gut-microbiome seems to be relevant for ADHD, the few publications on gut-microbial alterations in ADHD are inconsistent, in the investigated phenotypes, sequencing method/region, preprocessing, statistical approaches, and findings. To identify gut-microbiome alterations in adult ADHD, robust across studies and statistical approaches, we harmonized bioinformatic pipelines and analyses of raw 16S rRNA sequencing data from four adult ADHD case-control studies (N ADHD =312, N NoADHD =305). We investigated diversity and differential abundance of selected genera (logistic regression and ANOVA-like Differential Expression tool), corrected for age and sex, and meta-analyzed the study results. Converging results were investigated for association with hyperactive/impulsive and inattentive symptoms across all participants. Beta diversity was associated with ADHD diagnosis but showed significant heterogeneity between cohorts, despite harmonized analyses. Several genera were robustly associated with adult ADHD; e.g., Ruminococcus_torques_group (LogOdds=0.17, p fdr =4.42×10 -2 ), which was more abundant in adults with ADHD, and Eubacterium_xylanophilum_group (LogOdds= -0.12, p fdr =6.9 x 10 -3 ), which was less abundant in ADHD. Ruminococcus_torques_group was further associated with hyperactivity/impulsivity symptoms and Eisenbergiella with inattention and hyperactivity/impulsivity (p fdr <0.05). The literature points towards a role of these genera in inflammatory processes. Irreproducible results in the field of gut-microbiota research, due to between study heterogeneity and small sample sizes, stress the need for meta-analytic approaches and large sample sizes. While we robustly identified genera associated with adult ADHD, that might overall be considered beneficial or risk-conferring, functional studies are needed to shed light on these properties.

Characterizing Creative Thinking and Creative Achievements in Relation to Symptoms of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

Previous research on ADHD and ASD has mainly focused on the deficits associated with these conditions, but there is also evidence for strengths. Unfortunately, our understanding of potential strengths in neurodevelopmental conditions is limited. One particular strength, creativity, has been associated with both ADHD and ASD. However, the distinct presentations of both conditions beg the question whether ADHD and ASD associate with the same or different aspects of creativity. Therefore, the current study investigated the links between ADHD and ASD symptoms, creative thinking abilities, and creative achievements. To investigate the spectrum of ADHD and ASD symptoms, self-reported ADHD and ASD symptoms, convergent (Remote Associations Test) and divergent thinking (Alternative Uses Task) and creative achievements (Creative Achievement Questionnaire) were assessed in a self-reportedly healthy sample of adults (n = 470). We performed correlation analysis to investigate the relation between ADHD/ASD symptoms and creativity measures. In a second phase of analysis, data from an adult ADHD case-control study (n = 151) were added to investigate the association between ADHD symptoms and divergent thinking in individuals with and without a diagnosis of ADHD. Our analysis revealed that having more ADHD symptoms in the general population was associated with higher scores on all the outcome measures for divergent thinking (fluency, flexibility, and originality), but not for convergent thinking. Individuals with an ADHD diagnosis in the case-control sample also scored higher on measures of divergent thinking. Combining data of the population based and case-control studies showed that ADHD symptoms predict divergent thinking up to a certain level of symptoms. No significant associations were found between the total number of ASD symptoms and any of the creativity measures. However, explorative analyses showed interesting links between the ASD subdomains of problems with imagination and symptoms that relate to social difficulties. Our findings showed a link between ADHD symptoms and divergent thinking abilities that plateaus in the clinical spectrum of symptoms. For ASD symptoms, no relation was found with creativity measures. Increasing the knowledge about positive phenotypes associated with neurodevelopmental conditions and their symptom dimensions might aid psychoeducation, decrease stigmatization and improve quality of life of individuals living with such conditions.

Neural Correlates of Reactive Aggression in Adult Attention-Deficit/Hyperactivity Disorder.

Despite not being part of the core diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), emotion dysregulation is a highly prevalent and clinically important component of (adult) ADHD. Emotionally dysregulated behaviors such as reactive aggression have a significant impact on the functional outcome in ADHD. However, little is known about the mechanisms underlying reactive aggression in ADHD. In this study, we aimed to identify the neural correlates of reactive aggression as a measure of emotionally dysregulated behavior in adults with persistent ADHD during implicit emotion regulation processes. We analyzed associations of magnetic resonance imaging-based whole-brain activity during a dynamic facial expression task with levels of reactive aggression in 78 adults with and 78 adults without ADHD, and also investigated relationships of reactive aggression with symptoms and impairments. While participants with ADHD had higher reactive aggression scores than controls, the neural activation patterns of both groups to processing of emotional faces were similar. However, investigating the brain activities associated with reactive aggression in individuals with and without ADHD showed an interaction of diagnosis and reactive aggression scores. We found high levels of activity in the right insula, the hippocampus, and middle and superior frontal areas to be particularly associated with high reactive aggression scores within the ADHD group. Furthermore, the limbic activity was associated with more hyperactivity/impulsivity symptoms. These results suggest a partly differential mechanism associated with reactive aggression in ADHD as compared to controls. Emotional hyper-reactivity in the salience network as well as more effortful top-down regulation from the self-regulation network might contribute to emotionally dysregulated behavior as measured by reactive aggression.