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Главная » Статьи » Биополитика и микробиология

PROBIOTIC MICROORGANISMS: THE ROLE OF NEUROMEDIATORS IN THE HOST-MICROBIOTA DIALOGUE

Symbiotic microorganisms inhabit various niches of the human organism. They are present on the skin, the eye conjunctiva, and the mucosa of the upper airway and the uro-genital tract. However, they are particularly abundant and multifarious in the gastro-intestinal (GI) tract. In the large intestine, the concentration of microbial cells can be as high as 1012 / cm3, and their total number is at least 1014 cells, i.e. ten times the number of the human cells. Up to 10,000 microbial species can be detected in the GI tract of an adult human individual. Only 700—1000 species are culturable. The total weight of the microbial biomass is over 1.5 kg. Among the 160—300 microbial species that dominate the microbiota, only 18 are detected in all tested individuals, 57 in 90%, and 75 in 50% of the tested subjects.

In the human (animal) organism, the microbiota represents a peculiar “microbial organ” [1, 2] that is directly or indirectly involved in a wide variety of metabolic, behavioral, and communicative activities of the host macroorganism. Some of the main physiological functions of the microbiota include [3-7]: (1) protecting the GI tract against colonization by pathogenic microorganisms, which implies the production of antimicrobial substances and competition for nutrients with them; (2) preventing the penetration of pathogenic microorganisms into host tissues by helping the intestinal epithelium perform its barrier  function and by inducing the synthesis of secretory immunoglobulin A; (3) facilitating the digestion of nutritional ingredients (by utilizing the components that are not metabolized by intestinal cells) and enriching the nutrients with microbial products; (4) promoting the ontogenetic development and the operation of the immune system by releasing a number of various signal molecules that help “attune” the immune system to its potential targets.    

This review article is focused on probiotic microorganisms. “Probiotics is a term of microorganisms that have beneficial properties for the host. Products are derived from foods, especially, cultured milk products” [8]. Probiotics were officially defined by FAO/WHO [9] as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host”. A large number of probiotic microorganisms belong to the genera Lactobacillus and Bifidobacterium. Besides, representatives of other genera, e.g., Bacteroides [5] and symbiotic (non-pathogenic) strains of Escherichia coli (exemplified by the Nissle-1917 strain that was used to develop the probiotic Mutaflor®) and Clostridium butyricum conform with the aforementioned definition. Undoubtedly, all the microbiota functions listed above are efficiently performed by most probiotics.

For instance, while stress results in increasing the intestinal epithelium’s permeability, its barrier function is restored under the influence of the probiotic Lactobacillus farciminis. It prevents the penetration of microbial endotoxins into the bloodstream, which manifests itself in suppressing the stress-induced activation of the hypothalamus-pitiutary-adrenal axis [4].

Probiotics also perform the function of promoting the development of the immune system at the local and the systemic level. Suffice it to mention that the cytokine profile of the immune system changes under the influence of the probiotic Bifidobacterium infantis. Instead of pro-inflammatory factors, the immune system tends to predominantly produce anti-inflammatory factors in its presence [4].

Apart from its direct involvement in performing the main functions of the GI microbiota, probiotics ameliorate the pre-existing intestinal microbiota, according to the data available in the literature [7].

Probiotics include a subgroup that is referred to as psychobiotics, i.e.,  “live organisms that, when ingested in adequate amounts, produce a health benefit in patients suffering from psychiatric illness” [10]. A large number of probiotic strains, e.g., the Lactobacillus helveticus R0052 + Bifidobacterium longum R0175 combination, mitigates depression and anxiety. The antidepressive effect of Lactobacillus rhamnosus on mice is associated with a decrease in the corticosterone level in the host organism; this effect seems to depend on the vagus nerve. In contrast to probiotics, opportunistic pathogens such as Citrobacter rodentium enhance the anxious behavior of mice, which is mitigated by the subsequent addition of a probiotic cocktail [4].

Some probiotics produce a pronounced analgetic effect, particularly with respect to abdominal pain. The analgetic effect seems to be due to the capacity of lactobacilli, e.g., Lactobacillus acidophila, to induce the expression of m-opioid (“morphine”) and cannabioid receptors in the intestinal epithelium [4]. The neuropsychological impact of probiotics apparently are “the tip of the iceberg” that also includes their somatic effects. For example, “intraduodenal injection of live Lactobacillus johnsonii reduced blood pressure within minutes by changing autonomic neurotransmission via central histaminergic nerves through H3 receptors and involving the suprachiasmatic nuclei” [3].  

Currently, increasing attention is paid to the liaison between the functioning of the brain and the activities of the symbiotic microbiota. Since bacteria are capable of both recognizing and synthesizing neuroactive substances, we should agree with Wenner [11] that “if you mess around with the gut microbes, you mess around with brain chemistry in major ways”. Interactivity involving intestinal microbiota and the nervous system of the GI tract as well as the brain is in the focus of attention of a relatively large number of recent works [12-15].

 

Influence of Neuromediators on Microbiota Including Probiotics

 

An important aspect of the neurochemical effects of microorganisms including probiotics is their capacity to modulate the concentrations of neuromediators, i.e., substances that transmit impulses between nervous cells (neurons) or between neurons and the cells of an endocrine gland or a muscle. Microorganisms can indirectly modulate neuromediator concentrations in the central nervous system and in the whole host organism by releasing factors that influence the synthesis, transport, and utilization of neuromediators. For instance, the probiotic strain B. infantis 3562 increases the pool of tryptophan, the precursor of the neuromediator serotonin, in the blood plasma [16].

Microorgansims can also directly modulate neuromediator concentrations in the macroorganism, and this subject will be discussed in a large section within this work (see below). However, the neuromediator-based communication channel between the host and microbiota is bidirectional, i.e., microorganisms not only produce their own neuromediators (which influence the host organism) but also respond  to the neuromediators released by the host. Neuromediators are subdivided into several groups. In this review, the following neuromediator groups will be considered: (1) biogenic amines (catecholamines, serotonin, and histamine); (2) neuroactive amino acids (glutamic, aspartic, and gamma-aminobutyric acid, glycine, and taurine); and (3) gasotransmitters such as nitric oxide, carbon monoxide, sulfur hydrogen, methane, ammonia, and others.

  1. Catecholamines (dopamine, noperipephrine, and epinephrine) are hydroxylated derivatives of tyrosine.   Dopamine and norepinephrine function as both neuromediators and hormones (norepinephrine is an adrenal hormone; dopamine is a hypothalamic hormone inviolved in regulating lactation in females; epinephrine is an adrenal hormone performing no neuromediator function).

Stress (physical or psychic trauma, infection, environmental pollution, etc.) results in releasing catecholamines (norepinephrine, epinephrine, and–to a lesser extent—dopamine) into the  bloodstream. Catecholamines are released by the neurons of the enteric nervous system into the intestinal lumen [17]. What effects do these catecholamines produce on the microbiota of the human organism?

In the literature, there is much evidence that catecholamines exert a stimulatory influence on the growth of various microorganisms  [1, 2, 17, 18]. A direct stimulatory effect of catecholamines  was revealed in in vitro studies with a wide variety of pathogenic, opportunistic, and saprotrophic bacteria, including Yersinia enterocolitica, several enterotoxic and enterohaemorrhagic strains of E. coli, Shigella spp, Salmonella spp, Pseudomonas aeruginosa [17], Bordetella pertussis, B. bronchiseptica [19], Aeromonas hydrophila [20], Helicobacter pylori, Haemophilus influenza, Klebsiella pneumonia [21], Listeria monocytogenes [22], Campylobacter jejunii [23].

The list of catcholamines-stimulated microorganisms also includes a number of potential probiotics. They are exemplified by the symbiotic strain E. coli MC4100, in which dopamine at a concentration of 100 mM stimulated colony-forming unit (CFU) formation and biomass accumulation (estimated from optical density values). Norepinephrine was less efficient in this system [24]. It should be re-emphasized that many symbiotic E. coli strains are envisaged as probiotics that are used in the commercial preparations Mutaflor®, Vitaflor®, and others.

Microorganisms form cell aggregates, or microcolonies, that develop into biofilms [25]. Catecholamines produced different effects on the ratio between the numbers of solitary cells and their compact aggregates in an E. coli culture on an agar medium supplemented with catecholamines upon inoculation. Compared to the catecholamine-free control system, this ratio increased in the presence of dopamine and, conversely, decreased with norepinephrine [24].

Apart from prokaryotes, catecholamines also stimulate the growth of the yeast Saccharomyces cerevisiae [26, 27] that is considered a promising probiotic [28]. In particular, 1 mM dopamine caused an approximately 8-fold stimulation of  cell proliferation in S. cerevisiae  [26].

We have recently demonstrated that catecholamines stimulates the growth of the probiotic strain Lactobacillus acidophila NK-1 that was estimated from CFU number and optical density data.  Norepinephrine, the main stress-associated neurochemical, drastically (~4-fold) increases the CFU number at concentrations as low as 1 nM; however, CFU formation is inhibited at very high norepinephrine concentrations (> 10 mM). Dopamine and epinephrine strimulate CFU formation less efficiently and at relatively high concentrations [29]. These findings seem to suggest an ambivalent influence of stress that should increase the growth of both beneficial and detrimental [1, 18] bacteria in the GI tract and, therefore, presumably intensify their antagonism.

The effects of catecholamines on microorganisms can be interpreted in terms of the currently popular concept of quorum sensing systems [30, 31]. It seems likely that catecholamines behave in microbial systems as analogs of a quorum-sensing autoinducer, an aromatic compound called AI-3. Similar to it, they bind to receptors such as the hidstidine kinases QseC and QseE that are, therefore, to be considered as functional analogs of the adrenergic receptors of eukaryotes, even though they structurally differ from the eukaryotic G proteins [30, 32].

 

2. Serotonin (5-Hydroxytryptamine), a derivative of the amino acid tryptophan, functions both as a neuromediator and a histohormone. In addition to its role in the central nervous system, serotonin regulates blood pressure, immune responses, and trombocyte aggregation; it is also involved in the operation of a number of visceral systems. Serotonin is implicated in the functioning of the microbiota-gut-brain axis; in the GI tract, it regulates secretion, peristalsis, blood vessel tone, and pain perception.

Serotonin insignificantly stimulated the growth of the pathogen Aeromonas hydrophila [20] and statistically significantly increased the growth rate of a potentially probiotic E. coli strain [24, 33] and of the yeast Candida guillermondii [34] and S. cerevisiae [26, 27].

At a concentration of ~ 1 mM, serotonin stimulated cell aggregation and microcolony formation in E. coli K-12 [24, 33], Rhodospirillum rubrum, and the myxobacterium Polyangium sp. [33]. Conversely. at higher concentrations (25—100 mM and above), serotonin caused the dissipation of cell aggregates in these bacteria, inhibited the formation of the extracellular matrix, and decelerated their growth [33]. Unlike catecholamines (see above), serotonin only insignificantly (by ~25%) stimulates CFU formation in the probiotic L. acidophilus NK-1 [29].   

Presumably, the stimulatory effect of serotonin on the growth of pro- and eukaryotic microorganisms can be due to its binding to hypothetic receptors on their cells, which may also bind chemically similar compounds, e.g., indole.

 

3. Histamine, a derivative of the amino acid histidine, also combines the functions of a neuromediator and a histohorome (a local inflammation factor). It is an efficient stimulator of cell proliferation and biomass accumulation in the potentially probiotic strain E. coli K-12; its maximum stimulatory effect is attained at a concentration of 0.1 mM (causing an approximately twofold increase in CFU formation in E. coli). Similar to serotonin, histamine increased cell aggregation and microcolony formation E. coli [24]. Like serotonin, histamine did not stimulate cell aggregation at concentrations over 1 mM. Histamine also stimulated cell proliferation in the yeast S. cerevisiae; its effect in this system was comparable to that of serotonin (both amines increased growth rate by ~70% at a concentration of 1 mM [26, 27]. Histamine increased the CFU number in the probiotic strain L. acidophila NK-1 2.5-3-fold at a concentration of 1 mM [29].

 

4. Neuroactive amino acids activate (glutamic and aspartic acid) or inhibit (gamma-aminobutyric acid, glycin) the activity of the nervous system; they also produce multifarious effects on the functioning of the whole organism. It should be noted that microorganisms use amino acids, including those that serve as neuromediators, as nutrient substrates.

However, some amino acids have been established to perform specific regulatory functions. For instance, glutamic acid (along with lysine, methionine, and succinic acid), stimulate, whereas aspartic acid (like lactic and formic acid) inhibits the growth of the probiotic strain E. coli M-17. Interestingly, aspartic acid stimulates the growth of another E. coli strain (BL) [35, 36]. Overall, the effects of these regulators vary  [35, 36] depending on their dose, the tested strain, culture growth stage, and medium composition.

The neuromediator gamma-aminobutyric acid (GABA), apart from decelerating the spreading of impulses in the brain and regulating the functioning of the enteric nervous system, can suppress the release of pro-inflammatory cytokines and immune cell proliferation [37]. Despite this apparently anti-inflammatory effect, GABA stimulates the expression of virulence-related genes in the pathogenic yeast Candida albicans. This manifests itself in enhancing the synthesis of the mRNA  that codes for phospholipase B1, stimulating germ tube formation and subsequent hypha growth, which promotes the development of the infection [38]. Of considerable interest would be further research on the regulatory effects of GABA and other neuroactive amino acids on microbiota, including probiotics.

 

5. Nitric oxide (NO) is a gasotransmitter that displays a variety of neuromediator and regulatory activities. In the human (animal) organism, NO regulates gene transcription and posttranscriptional modification, cell proliferation and differentiation, and apoptosis. NO dilates blood vessels, lowers blood pressure, stimulates peristalsis and penal erection, and promotes the embryonic development of the retina. As a neuromediator, nitric oxide is involved in memorizing and learning activities.

Similar to eukaryotes, prokaryotes use NO as a regulatory agent. NO inhibited biofilm formation in Pseudomonas aeruginosa [39, 40], Staphylococcus aureus (Schlag et al., 2007), and Nitrosomonas europea [42]; it stimulated flagellar motility in P. aeruginosa [39]. Conversely, NO stimulated biofilm formation in some other bacteria including the pathogen Neisseria gonorrhoeae [42], and the nitrifiers Nitrosomonas europaea, Nitrosolobus multiformis, and Nitrospira briensis [43]. Apparently, the regulatory effects of NO can vary depending on the taxonomic group of the microorganisms involved and the conditions to which they are adapted.        

 

Biosynthesis of Neuromediators by Probiotic Microorganisms

 

Data on the synthesis of neuromediators by representatives of symbiotic intestinal microbiota that were available by the end of the 20th century were generalized in a monograph by B.A. Shenderov (1998); a large number of the microbial strains described therein are currently used as probiotics, for the purpose of preventing and treating dysbiosis-related diseases. Over the course of the last decades, the use of new preparative techniques for purifying and identifying low molecular weight compounds enabled researchers to conduct a large number of studies concerning the microbial synthesis of various neuromediators.

 

1. Microbial catecholamines. Using high-performance liquid chromatography (HPLC) with amperometric detection, Tsavkelova et al. [45] determined the content of catecholamines in the cultures of a large number of pro- and eukaryotic microorganisms. For instance, norepinephrine was present, at concentrations of 0.2—2 mM, in the biomass of B. mycoides, B.subtilis P. vulgaris, and S. marcescens; dopamine (0.5—2 mM) in most tested prokaryotes. These concentrations were significantly higher than those in the human blood that contains 0.1—0.5 nM dopamine (unbound) and 1-2 nM norepinephrine [46]. Some researchers believe that dopamine is ubiquitous in the world of pro- and eukaryotic microorganisms [47]. In the eukaryotes S. cerevisiae and Penicillium chrysogenum, sufficiently high norepinephrine concentrations (0.21 and 21.1 mM, respectively) were detected [45]. In Bacillus subtilis, norepinephrine and dopamine were predominantly present in the extracellular matrix fraction; therefore, they might be involved in cell-cell communication not only in animals (where they transmit impulses between neurons) but also in microorganisms.

The biomass of E. coli, S. cerevisiae, and lactobacilli was found to contain DOPA (dihyroxyphenylalanine) that represents the catecholamine precursor in animal cells, as well as the products of oxidative deamination of catecholamines (dihydroxyphenylacetic acid, DHPA, and homovanilic acid) [48].

The culture fluid of E. coli grown on a neuromediator-free synthetic medium (M-9) was analyzed, and nanomolar concentrations of extracellular dopamine, norepinephrine, and also serotonin were detected at the later growth stages of the culture [48]. These concentrations are sufficient for these amines to bind to the specific receptors of the GI tract. Of considerable interest is the fact that the culture fluid of the E. coli culture contained micromolar concentrations of DOPA.

Unlike E. coli, the yeast S. cerevisiae accumulated neuromediators (dopamine, norepinephrine, and serotonin), the products of their metabolism (homovanillinic acid and DHPA), and the catecholamine precursor DOPA only inside the cells but not in the culture fluid fraction. All these substances were contained at micromolar concentrations in the biomass if the yeast was grown on a neuromediator-free synthetic medium. If the nutrient-rich Saboureaud’s  medium was used, the concentrations of the aforementioned compounds decreased during cultivation, indicative of their active uptake from the medium by the growing yeast culture [26, 27, 49].

Of paramount importance in the context of this work on probiotics is the detection of catecholamines in dairy products fermented by probiotic bacteria. For instance, several kinds of yogurts were found to contain 1-10 mM dopamine and 0.1—2 mM norepinephrine, whereas unfermented milk lacked dopamine and maximally contained 0.09 mM norepinephrine. DOPA was present in the yogurts at concentrations of 80—250 mM, while its maximum concentration in milk was 57 mM [50].

Starter cultures of lactobacilli (Lactobacillus helveticus 100ash, L. helveticus NK-1, L. casei K3III24, and L. delbrueckii subsp. bulgaricus) differed in terms of the amounts of catecolamines they produced. On the milk- or milk hydrolysate-containing mnedia, dopamine was only synthesized by L. helveticus NK-1 and L. delbrueckii subsp. bulgaricus; all tested strains, except L. casei К3III24, enriched the media in norepinephrine. All the strains formed DOPA, and its maximum concentration (over 5 mM) was attained using the NK-1 strain [51, 52]. Since DOPA passes the gut-blood and the blood-brain barriers and is used for treating patients with Parkinson’s disease, these results open up new horizons in terms of applying DOPA in the form of dairy items fermented by DOPA superproducers.

In the model of germ-free mice intragastrically treated with a mixture of 46 Clostridium species (belonging to the coccoides and leptum groups), it was established that the content of dopamine and norepinephrine in the coecal lumen was increased by the treatment. In the intestine of the control mice, 90% of the dopamine and 40—50% of the norepinephrine pool was in the bound form, whereas 90% of the catecholamine pool of the Clostrifium-treated mice was in the unbound form. From these results, the conclusuion was drawn [12] that the intestinal microbiota plays is of paramount importance for the formation of biologically active catecholamine forms in the gut lumen.

 

2. Serotonin is sufficiently widely spread in the microbial world, incvluding representatives of the symbiotic microbiota of the animal or human organism [44, 53]. Low concentrations of a serotonin-like substance were detected in Rhodospirillum rubrum cells [33]. Serotonin was also present in Bacillus subtilis and Staphylococcus aureus cells; its concentrations (~1 mM) were comparable to those in the blood that normally contains 0.5—1.5 mM serotonin [54]. High concentrations of serotonin were detected in the cultures of Morganella morganii (4.96 mg/L, i.е. 28 mМ serotonin), Klebsiella pneumonia (3.23 mg/L, 18 mМ), and Hafnia alvei (2.69 mg/L, 15 mМ) [55]. 

Serotonin was contained in the culture fluid of E. coli at the late growth stage at low concentrations (10 nM). Yeast did not release serotonin into the medium, although it accumulated it intracellularly [26, 48].

There is evidence that serotonin is synthesized by some lactobacilli, including Lactococcus lactis subspecies cremoris MG 1363, L. lactis subspecies lactis IL 1403, and Lactobacillus plantarum NCFB2392 [56]. It was also established that serotonin is present in fermented food items, such as Chinese semi-sweet rice wine that also contains other neuromediator amines (histamine, tyramine, etc.) [57]. Serotonin was detected in the culture fluid of Lactobacillus helveticus 100ash at a concentration of 0.4 mM, but not in that of L. helveticus NK-1, L. casei K3III24, and L. delbrueckii subsp. bulgaricus. 5-Hydroxyindolacetic acid (5-HIAA) was synthesized by L. helveticus 100ash and NK-1 and by L. delbrueckii subsp. bulgaricus [51, 52].

 

3. Histamine, which is produced by microbial decarboxylation of histidine, is present in food items stored for a long time, e.g., in fish (particularly in scombroid fish species), cheese, meat, wine, beer, and sauerkraut [58-62]. The long list of bacterial species that produce histamine includes lactobacilli, such as Lactobacillus buchneri [59, 63]. Apart from functioning as a neuromediator, histamine is involved in inflammation and in allergic responses, and its toxic concentrations (over 75 mg/kg) may be contained in bacterially fermented food [59, 61].

 

4. Neuroactive amino acids (aspartic, glutamic, gamma-aminobutyric acid, glycin, etc.) are synthesized by a wide variety of microorganisms, including human symbionts; they perform, autoregulatory functions in some of them [36, 44, 64, 65].

In the human organism, microbial gamma-aminobutyric acid (GABA) is involved in normalizing the pain sensitivity of the gut and optimizing the operation of the immune system; it mitigates inflammation processes and allergic responses by suppressing the activity of T lymphocytes and promoting the production of anti-inflammatory mediators including interleukine-4 [37]. If the functioning of the GI microbiota is disrupted (dysbiosis), this often results in reducing the concentration of microbial GABA, which increases the risk of the development of inflammatory intestinal diseases including the irritated bowel syndrome [66] (IBS). Among the microbial producers of neuroactive amino acids, an important role is played by lactobacilli and bifidobacteria,  Many of their species represent valuable probiotics and are typical of the microbiota of the GI and uro-genital tract of mammals including the human species. They are also present in fermented dairy products, vegetables, meat, and fish.

The human blood plasma and spinal fluid contain 0.6 and 0.3 mM GABA, respectively [67]. These concentrations are close to those produced by lactobacilli. The L. delbrueckii subsp. bulgaricus synthesized 0.32±0.02 mM GABA on a milk-containing medium [51, 52]. GABA partly penetrates the gut-blood and the blood-brain barrier. Presumably, the effects produced by this amino acid, which improves sleep, concentration, and attention, exerts a relaxing and pacifying influence on the human brain, stimulates metabolic processes in the brain, promotes creative thinking, helps restore speech and locomotive activity after injuries, and functions as an antioxidant, are due to the combined action of the GABA that is contained in food and is produced by the organism per se and its microbiota.

Highly efficient GABA-producing probiotic bacteria (GABA superproducers) that accumulate millimoles of GABA in the medium include Lactobacillus brevis and Lactococcus lactis isolated from Italian cheese [68]; L. lactis subsp. lactis and Lactobacillus rhamnosus GG isolated from Chinese beans  [69], and L. brevis from fermented cod intestines [70]. Apart from GABA, L. brevis BJ20 cultivated in a medium with seaweed enriched the medium in other neuroactive amino acids, such as taurine, glycine, and b-alanine [70] that also positively influence the human brain and psyche.

 

4. Nitric oxide. A large number of microorganisms produce nitric oxide. It is generated via either nitrate reduction [39, 71] or ammonium oxidation [43]. Many representatives of the phyla Firmicutes, Actinobacteria, and Proteobacterium, as well as archaea, e.g., Euryarchaeota, contain an NO synthase that is functionally analogous to the enzyme of eukaryotic cells which catalyzes the synthesis of NO from arginine [43].

Microbial NO produces diverse effects on eukaryotic organisms. In the example of the worm Caenorhabditis elegans, it was demonstrated that B. subtilis- and E. coli-synthesized NO behaves as a transcription activator. It induces processes in the worm’s enterocytes that enhance its heat resistance and prolong the lifespan [72]. A similar mechanism may operate in higher animals; it represents an important aspect of the beneficial influence of the intestinal microbiota that may increase the host’s longevity.  

Gram-positive bacteria of the genera Lactobacillus, Streptococcus, and Lactococcus possess NO synthases [73].The NO they release into the GI tract performs cyto-, vaso-, and neuroprotective functions, along with endogenous NO [43]. Apart from the direct synthesis of NO, lactobacilli and bifidobacteria [74] and probiotic strain E. coli Nissle 1917 [75] are capable of stimulating NO production by host cells.

 

Probiotics: Neurochemical Effects and the Implications forHuman Health, Psyche and Social Behavior

 

Microbial consortia that colonize the intestinal mucosa and other niches of the human organism constantly interact with one another as well as with the neural network of the GI tract and the whole nervous and humoral systems of the host organism. The symbiotic microbiota behaves like a pitchfork that is responsive to any changes in the somatic state, stress level, and mood of a human individual that result in neurochemical alterations.

Apart from responding to human neurochemicals, the microbiota, including probiotic species, exerts an influence on human health, psyche, and social behavior. The aforementioned data on the synthesis of extracellular DOPA by symbionts including lactobacilli, provide an important example. Microbial DOPA penetrates into the brain tissue and converts into dopamine and, thereupon, norepinephrine, which influence the locomotive activity, sociability (communicability), and emotionality of a human individual. Optimizing catecolamine concentrations with the help of probiotic microorganisms would help people overcome depression, adynamia, and other consequences of stress. Therefore, of paramount importance are current research and development projects aimed at designing a new generation of probiotics that would produce goal-directed neuropsychological effects exemplified by antidepressant activity.

In addition to DOPA and the catecholamines produced from it in the organism, probiotics (psychobiotics) can also synthesize other neuroactive substances that beneficially influence the brain and the whole human organism. It seems feasible to enhance the therapeutic and preventive neurochemical effects of fermented dairy products. Starter cultures the produce, e.g., sufficient amounts of GABA, can be used for this purpose [2].

In the authors’ opinion, it is also feasible to develop probiotic superproducers of neuromediators. In this context, we should re-emphasize the recent data on the Lactobacillus strains that release millimolar GABA concentrations into the culture fluid [68, 69]. Such superproducer strains can be obtained using both traditional selection methods as well as genetic engineering and the cell fusion technique.

Apart from Lactobacillus-produced substances, humankind has been using, since time immemorial, yeast fermentation products (e.g., beer and wine). To reiterate, yeast synthesizes neuroactive substances that accumulate intracellularly, without releasing them into the culture fluid [26]. Therefore, the consumption of unfiltered drinks that contain yeast cells should enable us to make use of yeast-produced neurochemicals. Large-scale production of unfiltered yeast-containing drinks would enlarge the spectrum of the probiotic effects of yeast that have been described in the literature [28] by adding to them a direct neurochemical influence on the human organism.

Special emphasis should be placed on the potential use of fermented dairy products for the purpose of improving physical and mental health as well as social behavior. A number of starter cultures used in dairy industry and microorganisms that contaminate dairy products synthesize significant amounts of neuroactive compounds [50-52]. Recent data provide evidence that dairy products and their starter cultures (including important probiotics) can exert a significant neurochemical influence on the somatic and mental state of the consumer. These facts provide conceptual foundations for the purposeful development of specialized and personalized functional food items with known neuropsychological effects.

Enlarging the spectrum of tested dairy products whose starter cultures have been analyzed in neurochemical terms can enable us to set up a bank of microbial neurochemical producers and, moreover, to find out how microorganisms used for preparing food items are involved in the evolution of the brain and the enteric nervous system as well as in the development of human  behavioral patterns. Using animals with intentionally modified microbiota, including those inoculated with human intestinal microorganisms [12, 76, 77], and applying modern OMIC technology [78] will provide for the goal-directed production of functional probiotics that can be used as nootropic drugs [14, 79].     

 

 

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