**2.3 Trimethylamines**

*Human Microbiome*

[16, 17], we believe that special attention should be paid to further confirmation of the involvement of *C. sporogenes* and studying the pathophysiological role of its

The essential amino acid tryptophan is the only amino acid that contains the structure of an indole-bicyclic compound consisting of a six-membered benzene ring connected to a five-membered N-containing pyrrole ring, according to the Human Metabolome Database. Tryptophan is absorbed in the small intestine and metabolized to kynurenine, serotonin, and melatonin via the host's endogenous pathways. Manipulating heavily depleted tryptophan by way of diet has helped to identify patients who are prone to depression or other mood-lowering symptoms associated with dysfunctional monoaminergic systems, which can be attributed to serotonin deficiency [18]. The part of tryptophan that reaches the colon can be catabolized by the gut bacteria resulting in a variety of indole derivatives, such as indole, tryptamine, indoleethanol, indolepropionic acid (IPA), indolelactic acid (ILA), indoleacetic acid (IAA), skatole, indolealdehyde (IAld), and indoleacrylic acid [18, 19]. It is known that some products of bacterial biodegradation of tryptophan can be toxic, for example, indole, as well as indoxyl sulfate (IS), which is produced in the liver from indole and has a cytotoxic effect in high concentrations [19]. However, research shows that microbial tryptophan metabolites may also have a positive impact on host physiology. Tryptophan metabolites can modulate both the function of intestinal immune cells and astrocytes in the CNS via the aryl hydrocarbon receptor (AHR) [19, 20]. In experimental autoimmune encephalomyelitis, the effect of limiting inflammation of the CNS by affecting astrocytes in mice treated with antibiotics was shown by adding microbial metabolites of tryptophan from the gut microbiota (indole, indoxyl-3-sulfate, IPA, IAld) or the bacterial

Several studies have noted that IPA and IAA have anti-oxidative and antiinflammatory effects. A comparison of the varying data on the blood concentrations of IPA and IAA in patients with different diseases suggests that levels of both indole metabolites (IPA and IAA) are reduced in cancer [21]. Unfortunately, no studies to date have analyzed the behavior of these metabolites in patients with

There is information about the bacteria of the gut microbiota that is associated with the production of specific metabolites of indole. Interestingly, many species of anaerobes from different families are able to carry out biotransformation of tryptophan in vitro with the formation of IAA (nine species of *Clostridium*, four of *Bacteroides*, three of *Bifidobacterium*, and one of *Peptostreptococcus*). However, the ability to produce IPA was found only in three *species* of *Clostridiaceae*, and one of *Peptostreptococcus* [16, 21]. At the same time, the results obtained in vivo are more modest. In an experimental study of germ-free (GF) mice, production of IPA was

The severity of stroke outcome in patients is associated with a stroke-induced inflammatory response, which in turn is linked with an increase in tryptophan catabolism [23, 24]. In Parkinson disease (PD) patients, CSF levels of tryptophan and kynurenic acid have been found to be significantly lower compared to healthy controls [25]. Future investigations are required to decipher how tryptophan metabolites derived from microbes are linked to inflammation in brain disorders [5]. The search and modification of methods for accurate measurement of microbial tryptophan metabolites continues. The availability of methods for determining

completely dependent on gut colonization only by *C. sporogenes* [22].

metabolites in the process of neurorehabilitation.

enzyme tryptophanase as AHR agonists [20].

brain tumors, which could be extremely interesting.

*2.2.2 Indolic metabolites of tryptophan*

**30**

The formation of trimethylamine (TMA) occurs in the intestine via biotransformation of dietary lecithin, choline, or L-carnitine found in certain animal products (red meat, egg yolks) and is associated with bacteria of the genera *Anaerococcus*, *Clostridium*, *Escherichia*, *Proteus*, *Providencia*, and *Edwardsiella*. It is known that TMA is absorbed into the blood and oxidized in the liver by the flavin monooxygenase enzyme to form trimethylamine N-oxide (TMAO) [27]. TMAO is found in CSF, indicating its ability to penetrate the blood–brain barrier [28].

The role of TMAO in neurodegenerative diseases, including AD, has been investigated extensively in the last five years. A study by Xu et al. [29] analyzed 20 metabolites that are significantly associated with cognitive decline in patients with AD. Potential genetic pathways underlying the strong association between TMAO and AD have been investigated. Employing an integrated computational approach, researchers identified nine main pathways and found that AD is closely related to TMAO. Thus, common genetic pathways underlying known biomarkers of AD were identified, with TMAO identified as the top-ranked microbial metabolite [29].

Researchers studied TMAO as a biomarker of AD by comparing three groups of patients: those with AD clinical syndrome, those with mild cognitive impairment (MCI), and cognitively unimpaired individuals. All patient groups had undergone lumbar puncture with CSF collection (n = 410), as well as TMAO and other biomarkers of AD quantification. Metabolites of microbiota TMAO were significantly elevated in CSF and associated with other biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein), which confirms gut microbial involvement in AD [30].
