*3.1. Microbiome*

The influence of the microbiome on the ADHD pathophysiology is being intensively researched. The microbiota consists of the different microorganisms [18], and the microbiome describes the entire genome of the microbiota [18]. The primary functions of the microbiota include: (i) Protecting the host organism against pathogens by increasing the mucine production, and thus, stabilizing the gut-blood barrier; (ii) support of the immune system [19]; (iii) the production of vitamins [20]; and (iv) short-chain fatty acids (SCFAs), whereby the latter are products of microbial catabolism of indigestible carbohydrates [21]. Throughout the GI-tract, the composition and density of microbes changes, increasing from 102 cells per gram of content in the stomach to 108 cells per gram in the cecum [22]. Additionally, up to 1000 different bacterial species have been found to inhabit the GI-tract of humans [23]. Thereby the composition in species of the microbiome can be influenced by genetics [24], geography [25], disease, medication [26], and age [27].

The GI-microbiota goes through a physiological change from its prenatal period until the age of three [27]. For a long time, it has been thought that the intrauterine environment is sterile and that the first bacterial colonization of the newborn happens during delivery [28]. However, numerous studies have shown that bacteria exist in the placenta, amniotic fluid [29–31], and meconium [32] indicating that the unique microbial composition in utero may already influence the development of the microbiome of the fetus before birth. Research demonstrates that the microbiome of the placenta is low in richness and diversity and is predominantly colonized by the phyla Proteobacteria and Bacteroidetes. The former is mostly represented by the spp. *Escherichia coli* and *Neisseria lactamica*, while Bacteroidetes is dominated by *Bacteroides* spp. [31]. Other important phyla include Firmicutes, Fusobacteria and Tenericutes [31], whereby the latter includes genera, such as *Mycoplasma* and *Ureaplasma* [33].

The colonization of the gut in the postnatal period is sensitive to environmental factors. Nonetheless, the normal composition of the microbiome in a newborn is low in diversity and shows dominance in Proteobacteria and Actinobacteria [34]. More specifically, Proteobacteria shows its peak at birth, whereas Actinobacteria increases and dominates at the age of four months [35]. At this point, Proteobacteria is still mostly represented by *Escherichia coli* and Actinobacteria by the genus *Bifidobacterium longum* [35]. As seen in Figure 1, at the age of three and onwards, the microbiome stabilizes to four major phyla: Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, which normally cover more than 90% of the total bacterial population in a human body [36].

**Figure 1.** The most prevalent bacterial phyla in utero and in the GI-tract of humans. This figure represents the dynamic and development of the composition of the microbiome from fetuses in utero until the age of three years, at which point the microbiome gains its stability and consists of mostly four phyla: Proteobacteria, Actinobacteria, Firmicutes, and Bacteroides.
