*4.5. Short Chain Fatty Acids*

SCFAs are products of polysaccharides which could not be properly digested by the human digestive system, and thus, are broken down by microbial fermentation. Bacteria, such as *Bacteroides* spp. and *Clostridiae* spp., are two of the most important microbes for the production of SCFAs [21]. SCFAs represent not only a major energy source for microorganisms, but also show neuroactive and anti-inflammatory effects on the host [170,171]. A study by MacFabe et al. demonstrated that when SCFAs, such as propionic acid are intracebreoventriculary (ICV), administered to rodents, they show biochemical alterations similar to individuals who from autism [172]. Besides, the same authors found that high levels of the SCFA worsened symptoms of autistic individuals [172].

As ADHD, similar to autism, is a neurodevelopmental disease, it seems likely that SCFAs may affect the development of ADHD. Research shows that SCFAs influence the immune system, and as discussed earlier, this can influence the CNS [50]. An animal study using mice showed that the microbiome could influence the levels of the brain-derived neurotrophic factor (BDNF) via SCFA production [173]. The neurotrophin BDNF is important for neurogenesis and has a positive effect on the survival of neurons meaning that the microbiome can indirectly influence neural functions via SCFA s modulating effect on the BDNF production. The same study showed that GF mice whose BDNF levels had been decreased displayed problems with their working memory [173]. Confirmatory data were generated by Corominas-Roso et al. who showed in a human study that adults with ADHD have lower levels of BDNF compared to healthy controls [174]. Similarly, Akay et al. tested the effects of methylphenidate on BDNF levels on 50 drug-naïve ADHD boys and detected significantly increased BDNF levels in the serum and improved ADHD symptoms after eight weeks of methylphenidate treatment [175]. The same findings were found by an older study by Amiri et al. [176]. This is a direct confirmation of a potential link between the dopaminergic system, BDNF function, and ADHD. In contrast, another study enrolling 41 untreated ADHD and 107 control patients concluded that drug-naïve ADHD children had higher levels of BDNF in their plasma and that these levels are positively associated with the severity of inattentiveness [177].

Besides hypothesizing a compensatory mechanism in ADHD children, a potential reason for these differing results could be varying methodology as Akay et al. measured BDNF levels in the serum, known to have a higher BDNF concertation in comparison to the plasma [178].

In conclusion, SCFAs most probably affect the development of ADHD indirectly by influencing the production of BDNF.
