Microbiome signatures correlate with diet-mediated ADHD symptom reduction

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood neuropsychiatric conditions. Both (epi)genetic and environmental factors are suggested to contribute to the etiology of ADHD. In the last decade, nutrition has received considerable attention as a potential environmental factor triggering ADHD behavior, particularly applying a few-foods diet (FFD) has been shown to elicit considerable behavioral improvements. These studies are observational rather than investigating underlying molecular mechanisms. The present study included 79 children (boys aged 8-10) with ADHD following a progressive, i.e., increasingly restrictive, FFD diet for 5 weeks. Minimally invasive samples (feces, urine, blood, and buccal swabs) were collected before and after the intervention to obtain a multi-omics perspective of the dietary responses in the participating children. For 63% of the participating children, a more than 40% behavior score improvement was observed, with an average improvement of 73%. The strength of diet-induced changes in ADHD symptoms among children was significantly associated with the gut microbiome composition, particularly when analyzing species-stratified abundance profiles of previously characterized gut-brain modules in the fecal metagenomic data. While integrative multi-omics analysis did not identify composite signatures linked to symptom changes, the strongest multi-omics signal confirmed compliance with the dietary intervention. Our findings implicate a role of the gut microbiome and its metabolic capacity to communicate with the central nervous system in children with food-associated ADHD.