Exploring the gut microbiome in ADHD and schizophrenia spectrum disorder

Emerging research indicates a complex relationship between the gut bacterial microbiome and psychiatric disorders, though findings are not always consistent. The gut-brain axis, involving gut microbiota, plays a crucial role in the connection between the gut and the brain. Research, mainly in animal models, has begun to unravel how this communication influences behavior, with limited but growing evidence in humans. However, many of the studies in humans have been performed in small cohorts with little information about confounding variables, such as diet, antibiotic drug medication and stool consistency, and lack of proper use of statistical methods suited for this type of data. As for now, replicating findings and determining causation is challenging, highlighting the need for more research in well-characterized large cohorts.

This thesis aims to investigate the gut microbiome and related biological markers in patients with Attention Deficit Hyperactivity Disorder (ADHD) and in young patients with Schizophrenia Spectrum Disorder (SSD). Through five studies, we analyzed: 1. Plasma levels of vascular inflammatory markers, n= 154, (study I) and the bacterial metabolites, short-chain fatty acids (SCFAs), n= 233, (study II) in children and adults with ADHD. 2. The fecal bacterial microbiome, n=147, (study III), and the impact of a placebocontrolled synbiotic intervention in children and adults with ADHD, ncompleters=101, (study IV). 3. The fecal microbiome of young SSD patients, n=52, (study V).

The results indicated higher vascular inflammation and lower SCFAs plasma levels associated with ADHD diagnosis in adults and medication use in children with ADHD. A difference in microbiome diversity was found across ADHD diagnosis in adults and medication use in children with ADHD. Specifically, adult ADHD patients had different enzyme and strain β- diversity, along with differently abundant bacterial species and genes. Furthermore, we found the genus Prevotella to be more abundant, and bacterial genes encoding vitamin B12 synthesis to be less abundant in children on psychostimulant medication (vs not). Daily intake of an antiinflammatory multispecies probiotic and associated dietary fibers (Synbiotic 2000), previously reported to improve psychiatric symptoms, resulted in changes to the fecal microbiome, also impacting bacterial species beyond those included in the Synbiotic 2000. Results suggest that the synbiotic-bacteria stayed in the large intestine for at least 2 weeks. In SSD patients, differences in bacterial microbiome diversity and bacterial enzyme function were observed, with oral-origin species and amino-acid synthesis pathways being more abundant, while butyrate synthesis and acetate degradation pathways were less abundant in SSD. Our findings continue to support the presence of gut microbiome changes in these disorders, while also revealing associations between psychostimulant medication usage and biological markers, as well as with the microbiome. Further research that elucidates the causality between the microbiome and pathophysiology of these disorders is warranted.

List of scientific papers

I. Yang, L. L., Stiernborg, M., Skott, E., Söderström, Å., Giacobini, M., & Lavebratt, C. (2020, Dec). Proinflammatory mediators and their associations with medication and comorbid traits in children and adults with ADHD. Eur Neuropsychopharmacol. 41, 118-131.
https://doi.org/10.1016/j.euroneuro.2020.10.005

II. Yang, L. L., Stiernborg, M., Skott, E., Gillberg, T., Landberg, R., Giacobini, M., & Lavebratt, C. (2022, Dec). Lower plasma concentrations of short-chain fatty acids (SCFAs) in patients with ADHD. J Psychiatr Res. 156, 36-43.
https://doi.org/10.1016/j.jpsychires.2022.09.042

III. Stiernborg, M., Debelius, J. W., Yang, L. L., Skott, E., Millischer, V., Giacobini, M., Melas, P. A., Boulund, F., & Lavebratt, C. (2023, May). Bacterial gut microbiome differences in adults with ADHD and in children with ADHD on psychostimulant medication. Brain, Behavior, and Immunity. 110, 310-321.
https://doi.org/10.1016/j.bbi.2023.03.012

IV. Stiernborg, M., Debelius, J. W., Yang, L. L., Skott, E., Giacobini, M., Melas, P. A., Lavebratt, C. Exploring the gut microbiome in ADHD patients and the longitudinal effects of a synbiotic treatment. [Manuscript]

V. Stiernborg, M., Prast-Nielsen, S., Melas, P. A., Skott, M., Millischer, V., Boulund, F., Forsell, Y., & Lavebratt, C. (2024, March). Differences in the Gut Microbiome of Young Adults with Schizophrenia Spectrum Disorder: Using Machine Learning to Distinguish Cases from Controls. Brain, Behavior, and Immunity. 117, 298-309.
https://doi.org/10.1016/j.bbi.2024.01.218