Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis

Bifidobacterium and Lactobacillus are essential microbes for normal intestinal function.

“Bifidobacterium and Lactobacillus are essential microbes for normal intestinal function.”

These micro-organisms ferment indigestible foods and produce metabolites that promote gut motility, such as short-chain fatty acids and serotonin.

“These micro-organisms ferment indigestible foods and produce metabolites that promote gut motility, such as short-chain fatty acids and serotonin.46 47”

Enterochromaffin cells can bind several microbial products and secrete serotonin into the lamina propria, increasing colonic and blood concentrations of 5-HT.

“Possible signal transducers involved in the communication of the microbiota with the CNS include enterochromaffin cells, which can bind several microbial products and secrete serotonin into the lamina propria, increasing colonic and blood concentrations of 5-HT (55, 56).”

Short-chain fatty acids regulate the expression levels of tryptophan 5-hydroxylase 1 and tyrosine hydroxylase, producing an effect on brain neurochemistry.

“these SCFAs regulate the expression levels of tryptophan 5-hydroxylase 1, the enzyme involved in synthesis of serotonin, and tyrosine hydroxylase, which is involved in a rate-limiting step in the biosynthesis of dopamine, noradrenaline and adrenaline; therefore, producing an effect on brain neurochemistry (21, 55, 56, 116, 117).”

Short-chain fatty acids may modulate the levels of neurotransmitters and neurotrophic factors.

“It was described that SCFAs may modulate the levels of neurotransmitters and neurotrophic factors.”

Specific gut bacterial strains, such as spore-forming clostridia taxa, can up-regulate expression of colonic TPH1, boosting 5-HT biosynthesis in the gut, and increasing intestinal transit in the host.

“specific gut bacterial strains, such as the spore-forming clostridia taxa, can up-regulate the expression of colonic TPH1 (the rate-limiting enzyme in the production of 5-HT), boosting 5-HT biosynthesis in the gut, and increasing intestinal transit in the host (Reigstad et al., 2015;Yano et al., 2015).”

C. perfringens modulates host colonic 5-HT synthesis via host TPH-1.

“It was recently demonstrated that C. perfringens modulates host colonic 5-HT synthesis via host TPH-1 (Yano et al., 2015).”

A single intrarectal injection of deoxycholic acid (a secondary bile acid produced by clostridia) could partially replicate the effects of the bacteria.

“a single intrarectal injection of deoxycholic acid (a secondary bile acid produced by clostridia) could partially replicate the effects of the bacteria (Yano et al., 2015).”

Gut microbiota is capable of producing or stimulating the production of neurotransmitters, including serotonin, dopamine, and γ-aminobutyric acid (GABA).

“Studies have shown that gut microbiota is capable of producing or stimulating the production of neurotransmitters, including serotonin,33–35 dopamine,36 and γ-aminobutyric acid (GABA).37”

Serotonin levels are restored with reconstitution of the gut microbiome in GF mice.

“5-HT (serotonin) levels in blood from Germ-free (GF) mice are decreased compared to mice with normal gut microbiota; where serotonin levels are restored with reconstitution of the gut microbiome [579].”

5-HT (serotonin) levels in blood from germ-free (GF) mice are decreased compared to mice with normal gut microbiota.

“5-HT (serotonin) levels in blood from Germ-free (GF) mice are decreased compared to mice with normal gut microbiota; where serotonin levels are restored with reconstitution of the gut microbiome [579].”

Circulation of microbe-derived neurotransmitters, including acetylcholine (Lactobacillus), GABA (Bifidobacteria and Lactobacillus), and serotonin (Enterococcus and Streptococcus), can potentially influence microglial activation through direct and indirect means.

“Circulation of microbe-derived neurotransmitters, including acetylcholine (Lactobacillus), GABA (Bifidobacteria and Lactobacillus), and serotonin (Enterococcus and Streptococcus), can potentially influence microglial activation through direct and indirect means (Komatsuzaki et al., 2005; Yano et al., 2015; Pokusaeva et al., 2017).”

Non-canonical functions of nervous systems may include roles in regeneration, development of innervated tissues, tissue homeostasis, and bidirectional communication with the commensal microbiota.

“Non-canonical functions may include a role in regeneration, development of innervated tissues, and tissue homeostasis [113,114] as well as bidirectional communication with the commensal microbiota [115–120].”

The spectrum of functions performed by nervous systems is broader than communication and information exchange between the central nervous system, the rest of the body and the environment.

“However, the spectrum of functions performed by nervous systems is much broader.”

Gut-produced serotonin cannot cross the blood-brain barrier but influences mood and social behavior through peripheral systems.

“While gut-produced serotonin cannot cross the blood–brain barrier, it influences mood and social behavior through peripheral systems [136,137,138,139,140].”

Indigenous spore-forming bacteria, including Clostridiales, promote serotonin biosynthesis from colonic enterochromaffin cells.

“Indigenous spore-forming bacteria, including Clostridiales, promote serotonin biosynthesis from colonic enterochromaffin cells”

In mice, indigenous spore-forming microbes directly stimulated intestinal serotonin synthesis and release.

“For instance, a study led by Yano et al. [92] has demonstrated in mice that indigenous spore-forming microbes directly stimulated intestinal serotonin synthesis and release.”

Germ-free mice exhibit reduced colonic serotonin production and decreased blood serotonin, which normalize with microbial colonization.

“Germ-free mice exhibit reduced colonic serotonin production and decreased levels in the blood, which normalize with microbial colonization (164, 223).”

The GM regulates serotonin availability by signaling enterochromaffin cells to produce serotonin via TPH expression, and by altering SCFAs and BAs.

“The GM can further regulate serotonin availability by signaling enterochromaffin cells to produce serotonin via expression of tryptophan hydroxylase, and by altering levels of SCFAs and BAs which can influence serotonin production (46, 164, 221–223).”

SCFAs modulate neurotransmitter and neurotrophic factor levels and regulate expression of tryptophan 5-hydroxylase and tyrosine hydroxylase.

“SCFAs can modulate the levels of neurotransmitters and neurotrophic factors and regulate the expression of tryptophan 5-hydroxylase, the enzyme involved in the synthesis of serotonin, and tyrosine hydroxylase, the enzyme involved in the rate-limiting step in dopamine, noradrenaline, and adrenaline synthesis (18, 132, 164, 222).”

Evidence for release of stress-induced serotonin from enterochromaffin cells into the gut lumen has been reported, with some microbes exhibiting a serotonin transporter in their cell membranes.

“Evidence for a similar release of stress-induced serotonin from enterochromaffin cells into the gut lumen has been reported, with some microbes exhibiting a serotonin transporter in their cell membranes [19].”

Specific gut microbiota play a critical role in the modulation of Trp into various metabolites including kynurenine, indoles, and tryptamine.

“Specific gut microbiota play a critical role in the modulation of Trp into various metabolites, which include but are not limited to kynurenine, indoles, and tryptamine [19, 27, 28].”

Microbial metabolites (SCFAs and BAs) stimulate the production and release of serotonin by ECCs.

“Microbial metabolites (SCFAs and BAs) have been shown to stimulate the production and release of serotonin by ECCs [19].”

Stimulation of ECCs by microbes or intestinal contents moving through the gastrointestinal tract triggers secretion of serotonin onto vagal sensory nerve endings and into the circulation and gut lumen.

“Stimulation of ECCs by microbes or intestinal contents moving through the gastrointestinal tract trigger the secretion of serotonin onto vagal sensory nerve endings and into the circulation and gut lumen [19].”

Neurotransmitters such as acetylcholine, GABA, and serotonin produced by bacteria belonging to Lactobacillus, Bifidobacteria, Enterococcus, and Streptococcus species can influence brain cell physiology directly and indirectly.

“Neurotransmitters, such as acetylcholine, GABA, and serotonin, produced by bacteria belonging to Lactobacillus, Bifidobacteria, Enterococcus, and Streptococcus species, can influence brain cell physiology directly and indirectly (11, 85, 86).”

Clostridiales are emerging as major microbial regulators of gut-derived T-cell immune and serotonergic signals that may be associated with ASD.

“the Clostridiales are emerging as major microbial regulators of gut-derived T-cell immune and serotonergic signals that may be associated with ASD.30, 31, 32, 33, 35”

Gut microbes, in particular spore-forming clostridia, have been shown to regulate 5-HT metabolism in the GI tract.

“Gut microbes, in particular spore-forming clostridia, have been shown to regulate 5-HT metabolism in the GI tract (Yano et al., 2015).”

Blautia bacteria belong to the Clostridiales order, representatives of which modulate 5-HT metabolism by increasing Tph1 expression, activating 5-HT synthesis and accelerating GI motility.

“Indeed, Blautia bacteria belong to the Clostridiales order, representatives of which have been shown to modulate 5-HT metabolism in the host by increasing the expression of Tph1 in the gut, activating 5-HT synthesis and accelerating GI motility (Yano et al., 2015).”

The gut microbiota and its metabolites are potent stimulators of the production of serotonin by enterochromaffin cells.

“The gut microbiota and its metabolites are potent stimulators of the production of serotonin by enterochromaffin cells52.”

Administration of Bacteroides fragilis normalized plasma levels of 5-HT in an animal model of ASD.

“Interestingly, administration of Bacteroides fragilis normalized plasma levels of 5′-HT in an animal model of ASD [197,198].”

Fecal metabolites produced by spore-forming bacteria, particularly Clostridial species, increase 5-HT levels in EC cell cultures and in the colon and blood of germ-free mice.

“fecal metabolites produced by spore-forming bacteria, and particularly Clostridial species, have been shown to increase 5-HT levels in EC cell cultures as well as in the colon and blood of germ-free mice [62].”