TABLE 2.

Tryptophan metabolism and gut microbiota-brain axis

Tryptophan metabolism	Models	Design	Findings	Reference
Serotonin synthesis	GF mice	GF mice were compared with conventional control mice	Anxiety-like behaviors ↑Hippocampal serotonin ↑Circulating tryptophan ↑	Clarke et al., 2013 (15)
	GF mice	GF mice were compared with SPF mice	Depressive-like behaviors ↓mPFC & hippocampal serotonin ↑mPFC & hippocampal tryptophan ↑	Lukic et al., 2019 (11)
	Cecal cannulated piglets	Cecal cannulated piglets were infused with corn starch, whereas the control group received saline	Hypothalamic serotonin ↑Serotonin synthetases ↑Circulating tryptophan ↑	Gao et al., 2019 (10)
	Distal ileal cannulated piglets	Distal ileal cannulated piglets were infused with antibiotic cocktail, whereas the control group received saline	Hypothalamic serotonin ↓Serotonin synthetases ↑Circulating tryptophan ↓	Gao et al., 2018 (12)
	C57BL/B6 mice	Mice with induced stress were treated with sodium butyrate, whereas the control group received vehicle	Stress-induced depressive behaviors ↓Stress-induced blood-brain barrier impairment ↓Hippocampal serotonin ↑Hippocampal BDNF↑	Sun et al., 2016 (72)
	ICR mice	ICR mice were treated or were not treated with LPS	Depressive-like behaviors ↑	Zhu et al., 2015 (73)
			Prefrontal cortex serotonin ↓
	GF mice	Microbiota-colonized GF mice were compared with GF mice	Neuronal serotonin ↑Neuronal 5-HT4receptor ↑Mucosal serotonin ↑Intestinal transit ↑Proliferation of enteric neuronal progenitors ↑	De Vadder et al., 2018 (75)
Kynurenine pathway	AIMD mice	AIMD mice were compared with conventional control mice	Cognitive deficits ↑Anxiety-like behaviors ↓Circulating tryptophan ↑Circulating kynurenine ↓	Desbonnet et al., 2015 (51)
	Sprague-Dawley rats	Rats with microbiota colonization from depressive patients were compared with control rats	Anxiety-like behaviors ↑Circulating kynurenine ↑Circulating kynurenine/tryptophan ratio ↑	Kelly et al., 2016 (7)
	Sprague-Dawley rats	Rats were orally treated or were not treated with probiotic Bifidobacteria infantis	Depressive properties ↓Circulating tryptophan ↑Colonic tryptamine ↑Circulating kynurenic acid ↑	Desbonnet et al., 2008 (60)
	C57BL/6 mice	Mice were infected or were not infected with Toxoplasma gondiido	Central kynurenine ↑Central kynurenic acid ↑Central quinolinic acid ↑	Notarangelo et al., 2014 (79)
	Wistar rats	High fat diet–induced obese rats were treated with anthocyanins, whereas the control group received vehicle	Neuroinflammation ↓Circulating tryptophan ↑Circulating kynurenic acid ↑	Marques et al., 2018 (80)
	GF mice	GF mice were compared with conventional control mice	Hippocampal miR-294–5p ↑Hippocampal Brd2 ↑Hippocampal Slit3kr ↑	Moloney et al., 2017 (82)
	GF mice	Microbiota-colonized GF mice were compared with GF mice	Anxiety-like behaviors ↓Hippocampal IDO activity ↑	Clarke et al., 2013 (15)
	BALB/C & C57BL/6 mice	Mice with induced stress were orally treated or were not treated with Lactobacillus strains	Intestinal IDO1 expression ↓Circulating kynurenine ↓Stress-induced anxiety-like behavior ↓	Marin et al., 2017 (83)
Microbial degradation	F344 rats	Rats received an acute cecal injection of indole, whereas the control group received corn oil	Motor activity ↓Eye blinking frequency ↑Dorsal vagal complex c-Fosprotein expression ↑	Jaglin et al., 2018 (1)
	GF F344 rats	GF rats colonizing with indole-producing bacteria Escherichia coli were compared with GF rats	Anxiety-like behavior ↑Helplessness ↑Despair behaviors ↑Exploration ↓	Jaglin et al., 2018 (1)
	C57BL/6J mice	Mice with induced antibiotics were treated with microbial tryptophan metabolites (indole, indoxyl-3-sulfate, IPA, and IAld), or the bacterial enzyme tryptophanase	Central neuroinflammation ↓	Rothhammer et al., 2016 (14)

AIMD, antibiotic-induced gut microbiota–depleted; BDNF, brain-derived neurotrophic factor; c-Fos, cellular oncogene fos; GF, germ-free; IAld, indole-3-aldehyde; ICR, institute of cancer research; IPA, indole-3-propionic acid; LPS, liposaccharides; mPFC, medial prefrontal cortex; SPF, specific pathogen–free; 5-HT₄, 5-hydroxytryptamine 4.