Exploring synbiotic treatment in ADHD, and immune-mediated prenatal risks for neurodevelopmental disorders

The etiologies of neurodevelopmental disorders (NDDs) and psychiatric disorders are considered to be multifactorial, with both genetic and environmental factors. NDDs are associated with early atypical brain development and a significant genetic origin. Nonetheless, the genes behind the heritability are still not completely identified, and environmental factors are not fully mapped. Attention deficit hyperactivity disorder (ADHD) and Autism spectrum disorders (ASD) belong to the NDD family. Over the past twenty years, a growing body of evidence indicates an interaction between the gut microbiota and the central nervous system affecting behavior and ASD-like pathophysiology. This interaction is suggested to be mediated in part through the immune system and the bacterial fermentation products, the short-chain fatty acids (SCFAs). In animal studies, prenatal exposure to inflammation or a disturbed maternal gut microbiome has caused the offspring to display changes in CNS and behavior. Epidemiological studies have suggested that prenatal exposure to certain maternal immune mediated disorders such as autoimmune disorders (ADs) increases the risk for offspring ASD. Immune activity upregulation has been shown in NDDs, primarily ASD, and some psychiatric disorders e.g. depression and there is an overrepresentation of co-occurrence of immune-mediated and/or autoimmune disorders (e.g., asthma and eczema) with ADHD specifically, and NDDs in general. Further, there is a high comorbidity between gastro-intestinal symptoms and NDDs, both ADHD and ASD in particular, which has been suggested to co-vary in symptom burden episodes. A few studies, mainly focusing on ASD, have suggested that treatment with oral probiotics can reduce core ASD symptoms. There is a high comorbidity between ASD and ADHD. However, the possible implication for adjuvant treatment through targeting the gut-brain axis has been investigated to a lesser extent in ADHD. In addition, a comprehensive range of prenatal AD exposures in relation to a wide spectrum of offspring NDDs or psychiatric disorders has been investigated to a lesser extent. The aims of this thesis were to investigate (i) treatment effects with a synbiotic in ADHD on clinical and biological aspects, and (ii) effects on child psychopathology of prenatal exposure to maternal immune mediated disorders.

1. Investigate treatment effects of Synbiotic2000 on (i) ADHD symptoms, ASD symptoms, daily function and emotion regulation, N=248 participants included, 182 completers (study I) and (ii) plasma immune activity markers and SCFAs, N=156 participant completers with blood samples (study II) in children and adults through a randomized controlled trail (RCT) with a nine week intervention.

2. Investigate prenatal exposure to (i) maternal Crohn’s disease (CD), N = 1 105 997 (study III) and (ii) a wide range of maternal ADs, N= 1 107 802 (study IV) on offspring NDDs and psychiatric diagnoses through registry cohort studies.

In the RCT there was a reduction in (i) ASD symptoms in children and (ii) emotion regulation difficulties in adults after intervention with Synbiotic2000 compared to placebo. The symptom improvement was most pronounced in the ADHD cohort with higher inflammatory, sVCAM-1, at baseline (study I). At baseline, adults with ADHD had lower levels of SCFAs and higher levels sICAM-1 and sVCAM-1 compared to controls. Children with ADHD had lower level of SCFAs, and higher levels of proinflammatory sICAM-1, sVCAM-1, IL-12/IL-23p40 and IL-2Rα, than adults with ADHD. In the child cohort, Synbiotic2000 significantly reduced IL-12/IL-23p40 and suggestively increased propionic acid. Synbiotic2000 suggestively decreased several additional proinflammatory markers in the child or adult cohorts (study II). In the epidemiological studies, children exposed to maternal CD prenatally had an increased risk of sleeping disorder, feeding disorder and incontinence compared to children without exposure. These associations were not explained by perinatal risk factors nor child inflammatory bowel disorder (IBD), (study III). In study IV, we assessed in utero exposure to several maternal ADs, and show that maternal AD overall was associated with a modestly increased risk for offspring mental disorders combined. Certain specific ADs contributed to a doubled risk for offspring diagnosis, these associations were (i) Systemic Involvement of Connective tissue (SIC) with sleeping disorder, (ii) autoimmune thyroiditis with ASD and (iii) pernicious anemia with other behavioral or emotional disorders (F98). Assessing several maternal ADs and a comprehensive range of offspring diagnoses enables comparisons between different exposures and outcomes.

In conclusion, this thesis demonstrates (i) a potentially significant role for Synbiotic2000 in managing symptoms closely associated with ADHD, (ii) higher baseline levels of certain immune activity markers in ADHD, and (iii) modest-to-moderate risk estimates for offspring NDDs and psychiatric disorders, typically manifesting in early childhood, after several prenatal AD exposures. Further studies are needed for confirmation of the findings.

List of scientific papers

I. Skott, E., Yang, L. L., Stiernborg, M., Söderström, Å., Rȕegg, J., Schalling, M., Forsell, Y., Giacobini, M., & Lavebratt, C. (2020). Effects of a synbiotic on symptoms, and daily functioning in attention deficit hyperactivity disorder – A double-blind randomized controlled trial. Brain, Behavior, and Immunity. 89, 9–19.
https://doi.org/10.1016/j.bbi.2020.05.056

II. Yang, L. L., Stiernborg, M., Skott, E., Xu, J., Wu, Y., Landberg, R., & Arefin, S. (2023). Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial. Nutrients. 15(5).
https://doi.org/10.3390/nu15051293

III. Skott, E., Söderberg, G., Giacobini, MB., Chen, X., Lindqvist, D., Gissler, M., Sjöberg, K., Lavebratt, C. Offspring exposed to Crohn’s disease during pregnancy and association with psychiatric regulatory disturbances in childhood - a nationwide cohort study. [Manuscript]

IV. Skott, E., Nivins, S., Stiernborg, M., Fogdell-Hahn, A., Giacobini, MB., Gissler, M., Lavebratt, C. Associations of prenatal exposure to maternal autoimmune disorders with a wide spectrum of psychiatric and neurodevelopmental disorders in offspring – a nationwide cohort study. [Manuscript]