4. Discussion
autistic traits, IBD, ADHD
PATHOLOGY, INFLAMMATORY BOWEL DISEASE
This study is the first to report the effects of a synbiotic intervention on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. We previously reported that this intervention in an RCT design reduced autistic traits in children and improved emotion regulation in adults with ADHD [IL-12 and IL-23 are heterodimers and share the p40 subunit called IL-12/IL-23p40. IL-12 and IL-23 promote Th1 and Th17 expansion, respectively, and are reported to be involved in the pathology of inflammatory bowel disease (IBD). The p40 subunit is a therapeutic target in IBD [Notably, the pattern of correlations between levels of immune activity markers and SCFAs detected in ADHD patients was not found in controls, suggesting that the associations between immune activity analytes and SCFAs are not generalizable beyond ADHD but depend on a complex regulation at physiological conditions (To our knowledge, we are the first to report plasma levels of fractalkine, GRO-α, IL-12/IL-23p40, IL-18, IL-2Rα, TGF-β1, TGF-β2, TGF-β3, TRAIL, and VEFG-A in individuals with ADHD. The adult ADHD patients displayed at baseline different levels only of pro-inflammatory sICAM-1 and sVCAM-1 compared to the whole control group. Compared to the adults with ADHD, the children with ADHD had different baseline levels of eight of the immune activity markers and were hence analyzed separately. Most of these differences in marker levels between children and adults are not previously reported, neither in ADHD patients nor healthy individuals. Levels at baseline of eotaxin-1, fractalkine, MCP-1, TGF-β3, and TRAIL were higher in healthy family members of the ADHD patients than among healthy unrelated controls. Both genetic and environmental underpinnings may explain this, although there is no report showing that these markers are higher in persons with ADHD. The plasma SCFA concentrations at baseline of the patients and family controls of this study were previously reported to show lower levels of plasma formic and propionic acid in adults with ADHD compared to family controls after controlling for antibiotic drug exposure and other potential influencing factors [The sample size of our RCT was relatively large, including 182 children and adults. An additional main strength is that the conducted in vitro experiments of SCFAs possible anti-inflammatory effect was at physiological SCFA levels. There are limitations to this study. First, there were only four healthy controls for children, and hence, we could not analyze this group. Therefore, we were unable to adequately relate the analyte levels in children with ADHD to reference values. Second, our data on medications with anti-inflammatory effects (melatonin, antidepressants, antipsychotics, anxiolytics, sleeping pills, proton-pump inhibitors, and statins) or medications with gut microbiome effects (melatonin, antipsychotics, or antidepressants) (