Table 2.

Gut Microbiota-derived Molecules Modulating Pathogenesis of Disorders for Gut-Brain Interactions

Metabolites	Targeting cell types	Pathophysiological mechanisms	Key findings
Butyrate and acetate	EC cells	Altered gut motility	These metabolites increase 5-HT biosynthesis from EC cells through stimulatory activities.75
SCFAs	EC cells and 5-HT3R+ vagal nerves	Altered gut motility	Release of 5-HT from EC cells in response to SCFAs stimulates 5-HT3R located on the vagal sensory fibers. The sensory information is transferred to the vagal efferent and stimulates the release of acetylcholine from the colonic myenteric plexus, resulting in muscle contraction.142
Butyrate	EC cells and TRPV1+ cells	Visceral hypersensitivity	Repetitive stimulation of TRPV1 receptor via butyrate-induced 5-HT release desensitize TRPV1+ neurons resulting in less pain sensation.143
Butyrate	Enterocytes and immune cells	Altered gut immune function and impaired barrier function	Butyrate regulates neutrophil function and migration, inhibits inflammatory cytokine induced expression of vascular cell adhesion molecule-1, increases expression of tight junction proteins in colon epithelia, and exhibits anti-inflammatory effects by reducing cytokine and chemokine release from immune cells. Butyrate or specific species of butyrate producing gut bacteria may be a new target for restoring host immune function and barrier integrity.144
Acetate	Enterocytes and EC cells	Abnormal secretion	Gut microbiota alters 5-HT-evoked intestinal secretion in a 5-HT3R-dependent mechanism. Acetate alters 5-HT3R expression in colonoids.145
BAs	EC cells	Altered gut motility	TGR5 receptor on EC cells mediates the effects of BAs on colonic motility.
			Deficiency of TGR5 causes constipation in mice.73
Tryptamine	Enterocytes	Altered gut motility and secretion	Tryptamine accelerates gut transit and increases colonic secretion by activating epithelial 5-HT4R. Genetically engineered bacteria Bacteroides thetaiotaomicron produce tryptamine.84
Methane	EC cells and nitrergic neurons	Altered gut motility	Methane derived from Methanobravibacter smithii in the colon depletes gut 5-HT resulting in slowed gut transit and constipation.146
		Visceral hypersensitivity
Isovalerate	EC cells	Altered gut motility	Isovalerate evoked 5-HT release from EC cells through voltage-gated Ca2+ channel and modulated 5-HT3R neurons in visceral sensation and gut motility.12
		Visceral hypersensitivity
Indole	EC cells	Altered gut motility	Edwardsiella tarda metabolized tryptophan to produce indoles that activate TRPA1 on EC cells to produce 5-HT that stimulates enteric neurons and induces gut motility.51

EC, enterochromaffin; 5-HT, 5-hydroxytryptamine; SCFA, short chain fatty acid; 5-HTR, 5-hydroxytryptamine receptor; TRPA1, transient receptor potential ankyrin 1 channel; BAs, bile acids; TGR5, Takeda G protein-coupled receptor 5; TRPV1, transient receptor potential vanilloid 1.