TABLE 1.

Studies investigating the effect of a lack of microbiota on neurotransmitter systems.

Model	Species or strain	Behavioral outcomes	Molecular mechanisms	Reference
GF	Adult male BALB/c mice (7–9 weeks)	-	Biologically inactive and conjugated form of colonic norepinephrine and dopamine in GF mice (compared to the biologically active, free form in conventional mice); reduced intestinal norepinephrine and dopamine rescued by microbiota recolonisation	[45]
GF	Male Swiss Webster mice (8–10 weeks)	-	altered blood concentrations of indole derivatives (including ↑ tryptophan and ↓5-HT), phenyl derivatives (including ↑ tyrosine) and other metabolites in GF compared to conventional mice	[32]
GF	Male BALB/c mice (7 weeks)	-	Altered cerebral metabolome (including ↓ tryptophan and tyrosine, but ↑ dopamine and N-acetylaspartatic acid) of germ-free mice compared to Ex-GF mice, which were inoculated with suspension of feces from SPF mice; reduced GABA in faeces and blood (but not in brain) rescued by microbiota recolonisation	[46]
GF	Male and female Swiss Webster mice	↑ anxiety phenotype normalised by conventionalisation	↓ immune response and ↑ HPA axis reactivity in GF mice; ↓ BDNF expression in hippocampus; ↑ hippocampal 5-HT and 5-HIAA in males only; ↑ plasma tryptophan availability and ↓ kynurenine:tryptophan ratio in males (restored by colonisation); ↑ hippocampal 5-HT and 5-HIAA not normalised by conventionalisation	[49]
GF	Male mice (8-10 week)	↓ anxiety-like behavior	↑norepinephrine, Dopamine, and 5-HT turnover in the Striatum; Altered Expression of Synaptic Plasticity-Related Genes; Colonization of GF Mice Reduces Protein Expression of Synaptophysin and PSD-95 in Striatum	[2]
GF	C57Bl/6J mice	-	↓ circulatory and faecal (colonic ECs) 5-HT in GF compared to SPF mice; colonisation of GF mice with SPF microbiota restores serotonergic abnormalities, elevates TPH1 expression and decreases SLC6A4 expression.	[48]
GF	BALB/c mice	-	Altered intestinal concentration of several metabolites (including ↓ GABA in GF compared to colonised mice)	[53]
GF	Male Swiss Webster mice (12–14 weeks)	-	Altered levels of microbial metabolites in serum of GF compared to conventional mice, including ↓serum concentrations of dopamine and tyramine and of trans - 2-aminomethylcyclopropanecarboxylic acid, a cyclopropane analog of GABA	[52]

5-HIAA: 5-Hydroxyindoleacetic Acid; 5-HT: 5-Hydroxytryptamine; BDNF: Brain-Derived Neurotrophic Factor; GABA: Gamma-Aminobutyric Acid; GF: Germ-Free; HPA: Hypothalamic-Pituitary-Adrenal; PSD-95: Postsynaptic Density Protein 95; SLC6A4: Serotonin Transporter; SPF: Specific Pathogen Free; TPH-1: Tryptophan Hydroxylase 1.