Microbiome, gut-brain axis and ADHD
Recent findings suggest that gut microbiota may play a critical role in the pathophysiology of ADHD. 5, 30 The gut microbiota is recognised for its role in influencing brain function and behaviour through a bidirectional communication system, known as the microbiota-gut-brain axis. 5, 30, 31 This axis affects brain function and behaviour via neural, immune, and endocrine pathways. 5 In children and adolescents diagnosed with ADHD, the microbiomegut-brain axis plays a significant role in the pathophysiological processes of neuroinflammation and oxidative stress, which contribute not only to underpinning the primary symptoms of ADHD but also to related comorbid conditions. 31 A multitude of studies have demonstrated that changes in microbial abundance, richness, and diversity correlate with various conditions, such as ADHD, anxiety, depression, and autism spectrum disorder. 5 Evidence indicates that individuals with ADHD frequently display a lower diversity of gut microbiota in comparison to healthy individuals, implying a connection between diminished microbial diversity and ADHD. 5 A study found notable differences in gut microbiota composition and short-chain fatty acid( SCFA) profiles between children aged 6 to 18 years with ADHD and healthy control subjects. In particular, individuals with ADHD showed reduced alpha diversity and lower concentrations of essential SCFAs, including acetic, propionic, isobutyric, isovaleric, and valeric acids. These changes in gut microbiota and SCFA concentrations indicate a unique microbial and metabolic profile associated with individuals diagnosed with ADHD. 5 The impact of SCFAs on ADHD may also involve the regulation of neurotransmitters, particularly serotonin( 5-HT), which is primarily generated in the gastrointestinal tract. Roughly 90 % of serotonin is produced within the intestinal epithelium, and this process is influenced by metabolites derived from gut microbiota. 5
Lead exposure and ADHD
Lead exposure through water, soil, and other sources remains a global health concern. 32 Exposure to lead has been linked to ADHD. 10, 11 Blood lead levels exceeding 10 μg / dL have consistently been associated with ADHD and associated behaviours. Furthermore, lead exposure, even at lower concentrations(< 10 μg / dL), has been linked to decreased cognitive abilities. 32 A population survey conducted in the United States found that children with blood lead levels over 2 μg / dL were more likely to exhibit ADHD symptoms than those with blood lead levels below 0.7 μg / dL. 3 The study found a significant dose – response relationship between lead exposure and ADHD, with the highest quintile of blood lead concentration showing a significantly higher risk of ADHD. 3
Tobacco smoke, alcohol, and ADHD
Prenatal exposure to tobacco 12-14 and alcohol 14, 15 are common risk factors linked to ADHD in both human and animal models. 14 Numerous studies have identified a significant correlation between exposure to environmental tobacco smoke during the prenatal period and the occurrence of ADHD or behaviours associated with ADHD. 3 Prenatal tobacco exposure was significantly associated with ADHD( OR = 2.5; 95 % CI, 1.2-5.2). 3 One study examined the combined effects of genetic factors and prenatal substance exposure on various ADHD subtypes. 14 Significant interactions were identified between prenatal smoking exposure and genetic variations at the Dopamine Transporter 1( DAT1) gene and dopamine D4 receptor gene( DRD4) loci in children diagnosed with either the DSM-IV combined subtype or the populationdefined ADHD combined subtypes. The likelihood of receiving a DSM-IV combined subtype diagnosis was 2.9 times higher in twins who inherited the DAT1 440 allele and were exposed to prenatal smoking, than in their unexposed peers without the risk allele. For the population-defined subtype the odds ratio was 2.6. Moreover, the odds ratios for the DRD4 seven-repeat allele were reported as 3.0 for the populationdefined subtype and 2.8 for the DSM-IV combined ADHD subtypes. In children exposed to both alleles, the odds ratio was 9.0( with a 95 % CI of 2.0-41.5) for the population-defined combined subtypes. 14
A retrospective, hospital-based, casecontrol study was conducted involving 280 ADHD cases and 242 non-ADHD controls across both genders. 33 The ADHD cases showed a 2.1-fold increase( 95 % confidence interval = 1.1-4.1; P = 0.02) in the likelihood of having been exposed to cigarette smoke, and a 2.5- fold increase( 95 % confidence interval = 1.1-5.5; P = 0.03) in the likelihood of having been exposed to alcohol in utero compared to the non-ADHD control subjects. 33
An Australian study investigated how maternal alcohol use disorder influences the prevalence of ADHD in offspring, using a children-of-twins methodology. 34 The analysis utilised diagnostic telephone interview data from high-risk families, specifically female monozygotic and dizygotic twins who were either concordant or discordant for alcohol use disorder as parents, alongside control families selected from a large Australian twin cohort. Logistic regression models were applied to the data. The results showed that children of twins with a history of alcohol use disorder, as well as those from non-alcohol use disorder monozygotic twins whose co-twin had alcohol use disorder, had a significantly higher likelihood of developing ADHD than children from control families. 34 Additionally, people with foetal alcohol spectrum disorder are at greater risk of ADHD. 20
Other risk factors for ADHD
Other risk factors for ADHD have been noted in the literature, including preterm birth, 16 extremely preterm birth, 20 extremely low birth weight, 20 and people with foetal alcohol spectrum disorder, 20 family adversity, 17 and children in outof-home care 20 to be associated with an increased risk of ADHD. Additionally,
208 | vol31 | no4 | AJNM