Dietary intake, gut microbiome, and neurometabolite profiles in adolescents with attention-deficit/hyperactivity disorder

Naomi Lewis

doi:10.25907/01103

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition emerging in childhood and often persisting into adulthood, affecting academic, social, and mental health outcomes. In addition to neurotransmitter and structural/functional brain alterations, converging evidence implicates immune dysregulation, neuroinflammation, oxidative stress, and gut microbiome disturbances in its pathophysiology. Although diet is a key modulator of these processes, diet, microbiome, and neurobiological factors have typically been examined in isolation in ADHD, with limited integration within a gut-brain axis framework. Moreover, adolescents are underrepresented in the literature despite adolescence being a critical neurodevelopmental period; leaving gaps in the understanding of diet-microbiome- brain processes underlying adolescent ADHD. This thesis had two overarching aims: first, to provide a critical overview of nutrition and the gut microbiome in ADHD, including identifying key gaps; and second, to address these gaps and explore potential biological pathways in ADHD during adolescence through empirical investigation of nutritional, gut microbiome, and neurochemical domains. To achieve this, two narrative reviews (Chapters 2 and 4), and three empirical studies (Chapters 3, 5, and 6) and a short communication (Chapter 7) derived from a case-control study of adolescents (N = 39, 13-18 years; ADHD: n = 18, controls: n = 21), were conducted. Chapter 2 reviewed the role of individual nutrients and dietary patterns in ADHD, including links to diet-regulated biological pathways. Evidence highlighted omega-3 fatty acids, key micronutrients, and harmful dietary components, alongside broader Western and Mediterranean dietary (MedDiet) patterns. Poor diet quality was consistently associated with symptom severity, whereas interventional evidence mostly supported supplementation and whole-diet approaches in ADHD. Limited ADHD-focused research of the MedDiet pattern, and research in non-child populations, was also identified. Chapter 3 examined diet quality, nutrient intakes, nutrient adequacy, and associations with ADHD symptoms and cognitive performance in adolescent ADHD. ADHD and controls, and ADHD subtypes, were compared on MedDiet adherence, energy-adjusted nutrient intakes, and adequacy relative to nutrient reference values. Dietary factors did not significantly differ between groups, however, group x age interactions were observed for MedDiet adherence, and magnesium and iron intakes, and a group x sex interaction for beta-carotene intake. More nutritional targets were met by the combined than the inattentive ADHD subtype. Significant correlations included cognitive outcomes with MedDiet adherence and vitamin B12 (positive), and omega-6:omega-3 (negative); and symptoms with MedDiet adherence (negative). Findings indicate that dietary factors are clinically relevant in ADHD even in the absence of overall intake differences. Chapter 4 reviewed evidence on gut microbiota, inflammation, and neural processes in ADHD. Minimal differences in alpha and beta diversity were observed across studies, however multiple relative abundance differences were reported. Integration with other evidence for gut microbiome differences informed a potential aetiopathogenic model involving gut dysbiosis, neuroinflammation, and neural disturbances in ADHD. The review also identified substantial methodological heterogeneity, inconsistent control for confounders, and a lack of research in adolescents and in regions outside Asia and Europe. Chapter 5 assessed gut microbiota composition using full-length 16S rRNA sequencing in adolescents with ADHD compared to controls, and across ADHD subtypes, including associations with diet and ADHD symptoms. No differences were observed in alpha or beta diversity or the Firmicutes/Bacteroidota ratio. ADHD had nominally higher relative abundance of Peptostreptococcales, Coriobacteriaceae, Collinsella, Gemmiger, and an unclassified Subdoligranulum species, and nominally reduced Eubacterium F/E. xylanophilum. The combined subtype had nominally lower Bacteroides and Parabacteroides species abundance than the inattentive subtype. The strongest associations observed were between Peptostreptococcales and omega-3s (positive). Folate, beta-carotene, vitamin D, magnesium, added sugars, and monounsaturated fat were also nominally associated with ADHD-altered taxa. No taxa-symptom correlations were significant. This exploratory evidence for gut microbiota differences and associations with nutrients highlight the potential relevance of nutrition-microbiome relationships in adolescents with ADHD. Chapter 6 investigated neurometabolite concentrations across adolescents with ADHD and controls using proton magnetic resonance spectroscopy, focusing on markers of neuronal integrity (total N-acetyl-aspartate; tNAA), glial activity (myo-inositol; mI), and oxidative balance (glutathione; GSH) in the prefrontal cortex (PFC), posterior cingulate cortex (PCC), and primary motor cortex (M1). Associations with ADHD symptoms were also examined. No overall concentration differences were observed, however group x age and group x sex interactions occurred for mIPCC, and a group x age interaction for GSHPFC. Nominal associations were observed between inattentive and total symptoms and mIPCC (negative), and between oppositional symptoms and GSHPCC and tNAAPCC (positive), and tNAAPFC (negative). The possible importance of age- and sex-specific effects on neurometabolite differences in adolescent ADHD are discussed. Chapter 7 investigated associations between gut taxa that nominally differed between ADHD and controls and neurometabolites in adolescents with ADHD. Nominal correlations were observed between tNAAPFC and Coriobacteriaceae and Collinsella, mIM1 and Gemmiger and the unclassified Subdoligranulum species, and GSHM1 and Peptostreptococcales. This suggests that taxa with increased relative abundance in adolescents with ADHD may be associated with neurometabolite measures related to neuronal, glial, and oxidative stress processes. This thesis advances the understanding of ADHD as a disorder involving interconnected dietary, gut microbial, and neurobiological factors during adolescence. The integration of narrative reviews and empirical studies emphasises the importance of these domains in ADHD, providing a foundation for future mechanistic and interventional research focusing on nutrition-microbiome-brain pathways.

Dietary intake, gut microbiome, and neurometabolite profiles in adolescents with attention-deficit/hyperactivity disorder

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