3.3.4. Gut Dysbiosis and Immunology

High variability in gut flora prevents the growth of pathogenic bacteria, and thus, stops gut dysbiosis [97]. The term dysbiosis describes a microbial imbalance in which there is a shift from protective to pathogenic microbes in the GI-tract [98]. This can lead to a growing GI-permeability which leads to an increase in migration of pathogenic microbes and translocation of their metabolites into the systemic circulation potentially resulting in systemic inflammation [99]. This can, in turn, decrease the permeability of the BBB, which can lead to inflammation of brain parenchyma [100]. Severe dysbiosis has been associated with chronic inflammatory intestinal disorders and psychiatric illnesses, such as schizophrenia, anxiety, depression [98], and ADHD [90,101]. A systematic review supports the latter findings concluding that patients with ADHD have increased levels of inflammatory cytokines [102]. Similarly, Verlaet et al. also detected increased levels of pro-inflammatory cytokines (IFN gamma and IL-6) in the serum of ADHD patients [101].

An imbalance of pro-inflammatory cytokines can also lead to allergic disease [103], and a positive correlation between ADHD and allergies has been shown in different cohorts [104–106]. Additionally, research has shown an association between an altered gut microbial composition and the tendency to suffer from the allergic disease [107].

An important pro-inflammatory cytokine is interleukin (IL-6). This has been inversely associated with the bacterium *Dialister* spp. [108]. *Dialister* spp. is shown to correlate with an altered temperament and impulsiveness in toddlers positively. These commonly found ADHD symptoms were measured using the Early Childhood Behavior Questionnaire (ECBQ), which measures extroversion, activity levels and feelings of high-intensity pleasure [109]. Furthermore, a review evaluating multiple studies concluded an increase in pro-inflammatory metabolites, such as IL-6 and IL-1 in patients with ADHD [110]. Nonetheless, one study showed that ADHD patients had significantly lower levels of *Dialister* spp. in comparison to healthy controls (HC), hinting towards decreased feelings of activity and lower levels of intense pleasure, and finally higher levels of IL-6 [111].

Although the association between *Dialister* spp. and feelings of pleasure are new findings; and it is important to note that pro-inflammatory interleukin levels are increased in ADHD patients. As high levels of pro-inflammatory interleukins can be linked to neurological inflammation that can lead to a decrease of cortical volume and altered behavior [110,112], reducing the activity of these pro-inflammatory cytokines could represent a vital prophylaxis strategy in ADHD management.

Patients with th2-mediated atopic disorders, such as eczema, asthma and allergic rhinitis have a 30–50% higher chance of developing ADHD [113]. Eczema is an inflammatory skin disease and is the most prevalent chronic condition in early childhood [114]. Children suffering from atopic dermatitis (eczema) have a 50% likelihood of developing asthma and allergic rhinitis, exhibiting airway inflammation and clear nasal discharge, respectively [115]. Th2-cytokines are important for eosinophilic recruitment and the production of IgE by B-lymphocytes. All of these processes are associated with allergies and inflammation of the skin (e.g., eczema) [116,117] as they activate the production of pro-inflammatory cytokines, such as IL-6, IL-1beta, TNF-alpha and IL-8 [103]. Studies have shown that

these atopic diseases are associated with a low level of *Faecalbacteria* spp. In the gut [118]. This species is known to have anti-inflammatory effects on the organisms [119,120]. As explained above, patients with ADHD seem to exhibit higher levels of inflammatory markers which could potentially support the hypothesis that low levels of *Feacalbacteria* spp. Cause an increase of inflammation which affects the development of the brain, and finally the pathogenesis of ADHD.
