3.3. Focus on Bacterial Metabolites and Gut-Brain Axis
As we discussed, it is known that certain bacteria are able to produce different essential neurotransmitters and specific neuromodulators. Indeed, several neurotransmitters such as gamma-aminobutyric acid (GABA), serotonin, catecholamines and acetylcholine are produced by bacteria, some of which are inhabitants of the human gut. Indeed, researchers report that
Lactobacillus spp. and
Bifidobacterium spp. produce GABA [
169];
Escherichia spp.,
Bacillus spp. and
Saccharomyces spp. produce noradrenalin;
Candida spp.,
Streptococcus spp.,
Escherichia spp. and
Enterococcus spp. produce serotonin;
Bacillus spp. produce dopamine; and
Lactobacillus spp. produce acetylcholine [
172]. Neurotransmitters secreted from gut bacteria may induce cells to release molecules that have the ability to modulate neural signaling within the enteric nervous system and subsequently control brain function and behavior, trough the microbiome-gut-brain axis. Significant deviations in the bacterial metabolites present in faeces and urine of children with ASD were seen [
173]. Two possible pathways we hypothesize may be principally involved which are reviewed below.
3.4 Short-Chain Fatty Acids (SCFAs) and Gut-Microbial Metabolites
Short-chain fatty acids (SCFAs) as acetic acid (AA), propionic acid (PPA), and butyric acid (BA), are the fermatation end-products of non-digested carbohydrates in the colon and have been suggested to have various health benefits to the host related to weight control, lipid profiles, and colon health [174]. However, the accumulation of SCFAs, and specifically of propionate, has also been shown to have broad effects on the nervous system physiology, and it is associated to the pathogenesis of ASD [175,176]. In fact, higher levels of AA and PPA that is used as a preservative in the food industry and can also induce autistic-like behaviors in rodents have been reported in ASD children [177,178]. At the same time, lower levels of BA, that can positively modulates neurotransmitter gene expression and can rescue behavioural abnormalities in mouse model, have been reported in ASD [179]. Moreover, ASD patients seem to be characterized by both elevated levels of SCFA concentrations in stool and serum, and increased level of SCFA-producing bacteria (e.g., Clostridia, Desulfovibrio, and Bacteroides) [29,36,180]. Thereby, translocation through the blood–brain barrier by transporters or by passive diffusion could cause potential effects on the brain and lead to development of some ASD symptoms [181]. The precise mechanisms of how SCFAs alter behavior in ASD are unknown, but effects on mitochondrial function (e.g., Krebs cycle) or epigenetic alterations may be involved [182]. In addition to direct effects on the brain, propionate has been shown to modulate 5-hydroxytryptamine (5’-HT) secretion in the gut and deplete 5’-HT and dopamine levels in the brain, which could potentially contribute to the hyperserotonemia observed in children with ASD [182–184]. Another metabolite that we could considered is p-cresol and its co-metabolite p-cresyl sulfate, which are phenolic compounds that are produced by bacteria such as C. difficile and Bifidobacterium [185–187]. It has been demonstrated that an early exposure to p-cresol may contribute to the severity of behavioral symptoms and cognitive impairment in ASD [185]. Furthermore, ASD patients have high level of free amino acids (FAAs) [186], which are derived from hydrolysis of proteins and peptides, like glutamate that may be involved in the etiopathogenesis of neurodevelopmental disorders [187]. This picture shows how there is a bidirectional influence between microbiota and diet, through the production of metabolites, which can be characterized through metabolomics and can help todelineate new therapeutical strategies in autistic patients.
3.5 Neurotransmitters
In the last few years a role of the serotonin pathway in ASD, especially in the gut-brain axis, is emerging in the literature. Although most serotonin, or 5'-HT, is produced in the GI tract and can also be metabolized directly by the gut microbiota, it modulates neurodevelopment and might be important in social function and repetitive behavior [188]. High levels of 5'-HT may be caused by a gastrointestinal 5'-HT hypersecretion, produced by the enterochromaffin cells in the gut and it is involved in functions such as motility and secretion [189]. Furthermore, a study show the role of the 5'-HT as the link for the gut-brain-axis in ASD [190]. However, hyposerotonemia and lower synthesis of 5'-HT in the brain in ASD children has been reported [191]. Some bacterial species that are known to influence 5'-HT metabolism (e.g., Clostridium spp, Lactobacillus spp) were observed to be increased in stool samples from ASD children. In patients with ASD, altered function and metabolism of neurotransmitters, such as 5'-HT and catecholamines, and dysfunction of the serotonergic system have been reported to contribute to symptomatology [188,192–196]. 5'-HT is elevated in whole blood and platelets in approximately 30% of children with ASD, making it a potential candidate as a biomarker for ASD [193]. Interestingly, administration of Bacteroides fragilis normalized plasma levels of 5'-HT in an animal model of ASD [197,198]. These data indicate that the gut microbiota could be involved in higher 5'-HT production, thus identifying 5'-HT as a potential pathway through which the gut microbiota and brain communicate in ASD. In ASD, abnormal intestinal permeability could allow 5'-HT to translocate into the systemic circulation, leading to elevated levels of blood 5'-HT [34,35,127,193]. Increased 5'-HT production by some species of the gut microbiota in ASD could deplete peripheral tryptophan availability. This corresponds to data showing decreased capacity for 5'-HT synthesis in children with ASD as well as to reports showing a worsening in repetitive behaviors in individuals with ASD after tryptophan depletion [191,199]. Lastly, higher levels of 5'-HT in children with ASD can be linked to intestinal inflammation and play an important role in intestinal inflammatory responses [200], so there is a connection between enteric serotonin production and dysbiosis. On the other hand, dysbiosis can decrease the number of amino acids that are absorbed from the diet and reduce the availability of tryptophan [201], that is a precursor for a number of metabolites as serotonin, thus creating a vicious cycle. Indeed, a lower level of tryptophan may influence the synthesis of serotonin in the brain, playing a role on the mood and cognitive impairment which characterize ASD children [202]. Thus, it can be proposed that the intestinal inflammatory response in children with ASD, which is exacerbated by gut microbiota, can lead to a further increase in 5'-HT levels and, ultimately, to upstream behavioral effects on the brain.
3.6 Conclusions
It has been observed that ASD children are characterized by a strong food selectivity that consequently deeply influences their gut microbiota composition. Indeed, an increase in SCFA and 5'-HT-producing bacteria was observed in several studies on ASD patients. Increased levels of 5'-HT result in a different modulation of 5'-HT metabolism in the host, leading to tryptophan depletion and hyperserotoninemia, which may affect GI symptoms. Moreover, some ASDs are even characterized by higher levels of intestinal permeability which allow passive diffusion of bacteria-derived lipopolysaccharides (LPS) and metabolites
through the intestinal barrier. As a consequence, an increase in pro-inflammatory cytokines (e.g., IL-1B, IL-6, IL-8, and IL-12p40) was observed, which are associated with impaired social communication and neurodevelopmental disorders. At the same time, gut-brain cross-talk through the vagus nerve and the
hypothalamus-pituitary-adrenal (HPA) glands, influences vagal chemo- and mechanoreceptors on the mucosal villi and systemic cortisol levels, leading to an exacerbation of GI symptoms and inflammatory status (Figure 3). Further studies are needed to assess the effect of different dietary interventions (such as
the Mediterranean diet) on GI symptoms and, as a consequence, how they may affect behavioral patterns
associated to ASD conditions.
Figure 3. Role of the gut-brain axis in the etiology of ASD. (1,2) Food that escapes digestion can be used by the gut microbiota bacteria to produce metabolites (e.g., SCFAs and/or 5'-HT) that can be used by the host. Among metabolites (3) 5'-HT is produced particularly by Lactobacillus, Streptococcus, and Lactococcus species, while SCFAs (e.g., propionate) are produced by Clostridia, Bacteroidetes, and Desulfovibrio species. (4) Increased 5'-HT production by the microbiota acts on the metabolism of 5’-HT, leading to tryptophan depletion and contributing to hyperserotonemia, which is associated with GI Symptoms. (5) Intestinal permeability in children with ASD could allow passive diffusion of metabolites, and cause neurodevelopment disorders, such as behavioral and chemical changes (e.g.mood, cognitive state and emotion). (6,7) Moreover, higher intestinal permeability allow the increase in circulating bacteria-derived lipopolysaccharide (LPS), thus stimulating systemic pro-inflammatory cytokines production (e.g., IL-1B, IL-6, IL-8, and IL-12p40), which is associated with impaired social communication. (8) The vagal-mediated signaling from the gut microbiota to the brain can be transmitted through vagal chemoreceptors on mucosal villi that are activated by bacterial metabolites (e.g., 5'-HT, SCFAs) or by vagal mechanoreceptors that sense motility changes induced by bacterial species. (9) Gut microbiota influences the activity of Hypothalamus-Pituitary-Adrenal glands (HPA) axis that increased levels of cortisol in the systemic system. As a consequence, higher levels of cortisol may affect cytokines response and exacerbate GI symptoms.
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