TABLE 1.

Studies investigating the biological link of microbial metabolites on depressive-like behavior.

Family	Microbial metabolite	Host behavior outcomes	Molecular mechanisms	Strains	Stimulation	Model	References
Neurotransmitter	5-HT	↑Turotransmitt ↓depressive-like behaviors	↓5-HT in the colonic; ↑5-HT in the frontal cortex and hippocampus	Lactobacillus rhamnosus	CUMS	Mice	Li H. et al., 2019
		↓Anxiety and depressive-like behavior	↑5-HT in the hippocampus, PFC, and striatum	Lactobacillus paracasei PS23 (live)	Corticosterone-induced	Mice	Wei et al., 2019
	DA	↓Anxiety and depressive-like behavior; altered the GM structure	↑ DA and 5-HT in the striatum	Lactobacillus plantarum	GF	Mice	Liu W.-H. et al., 2016; Dhaliwal et al., 2018
		↓Depressive-like behaviors; restoration of the GM structure	Restored abnormal variations in DA, corticosterone, and BDNF	Akkermansia muciniphila	CRS	Mice	Ding et al., 2021
		↓Stress response of the HPA axis; ↓IFN-γ; ↓reversed gut dysbiosis; depressive-like behaviors	↓DA in the hypothalamus	Bifidobacterium CECT 7765	MS	Mice	Moya-Pérez et al., 2017
	γ-GABA	↓Depressive-like behavior	↑GABA	Lactobacillus plantarum 90sk; Bifidobacterium adolescentis 150	FST	Mice	Yunes et al., 2020
		↓Corticosterone; ↓anxiety and depressive-like behavior	↓GABA (Aα2) mRNA expression in the PFC and amygdala	Lactobacillus rhamnosus	Stress-induced	Mice	Bravo et al., 2011
	NE	Normalization of the immune response; reversal of behavioral deficits	↑NE in the brainstem; ↓IL-6	Bifidobacterium infantis	FST	Mice	Desbonnet et al., 2010
	Glu	↓Anxiety and depressive-like behavior	Differential regulation of Glu receptors and MicroRNA124a/132	Lactobacillus paracasei	SSE	Mice	Karen et al., 2021
SCFAs	Sodium butyrate	↓Hippocampal microglial activation; ↓depressive-like behavior	Recovery of the microglial gene profiles	L. plantarum, B. infantis, Clostridium butyricum and F. prausnitzii	LPS-induced	Mice	Yamawaki et al., 2018
		↓Behavioral deficits; recovery of BBB impairments	↑5-HT; ↑TJs protein levels; ↑BDNF expression in the hippocampus		CUMS	Mice	Sun et al., 2016
		↓Neuroinflammatory; ↓depressive-like behavior	↓IL-1β; ↓ IL-6; ↓TNF-α		LPS-induced	Mice	Qiu et al., 2020
	Sodium Propionate	↓Depressive-like behavior	Reduction of catabolism of NE, tryptophan, and DA	Phascolarctobacterium succinatutens; Veillonella spp.; Megasphaera elsdenii	CUMS	Mice	Louis and Flint, 2017; Li et al., 2018
Tryptophan metabolites	Indoles	↓Motor activity; vagus nerve activation; ↑helplessness; ↑anxiety and mood disorders	↑c-Fos protein expression in the dorsal vagal	Escherichia coli	GF	Mice	Jaglin et al., 2018
	Indole derivatives	Positive association with recurrent depressive symptoms	↑3-indoxyl sulfate	gut dysbiosis		Human cases	Philippe et al., 2021
Other metabolites	Lactate	↓Immobility time in the open space; ↓depressive-like behavior	↓GSK3α/β in the hippocampus; ↓COX-2 mRNA in the hippocampus; ↓expression of PDE4D and NOS1	L. lactis, L. gasseri, L. reuteri, Bifidobacteria, and Proteobacteria (Louis and Flint, 2017)	Corticosterone-induced	Mice	Carrard et al., 2018
		↑Social avoidance; ↓anxiety and depressive-like behavior	Hippocampal class II HDAC5 deactivation		CSDS	Mice	Karnib et al., 2019
	Bile acids	↓Depressive-like behavior	↑BDNF expression in hippocampal	Lactobacilli, bifidobacteria, Clostridium and Bacteroides (Wahlström et al., 2016)	CUMS	Mice	Chen et al., 2018
		↓Neuroinflammation; ↓oxido-nitrosative; ↓depressive-like behavior	↓TNF-α and IL-6 in the hippocampus and PFC		CUS	Mice	Lu et al., 2018
	Choline metabolites	↓Depressive-like behavior	↑DNA methylation; ↑expression of the insulin receptor	The order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae (Wang et al., 2015)	MS	Mice	Paternain et al., 2016
	Vitamins (folate)	↓Cardiovascular measures; anxiety and depressive-like behavior	↓DNA methylation in the hippocampus; ↑brain methionine levels	Lactobacillus and Bifidobacterium (Gu and Li, 2016)	MS	Mice	McCoy et al., 2016

5-HT, 5-Hydroxytryptamine; PFC, prefrontal cortex; DA, dopamine; γ-GABA, Gamma-aminobutyric acid; NE, Norepinephrine; Glu, Glutamate; GM, gut microbiota; CUMS, chronic unpredictable mild stress; GF, germ-free; BDNF, brain-derived neurotrophic factor; CRS, chronic restraint stress; HPA, hypothalamic-pituitary-adrenal; IFN-γ, interferon-gamma; MS, maternal separation; FST, Forced-Swim Test; IL-6, interleukin-6; SSE, stressful social experience; LPS, lipopolysaccharides; BBB, blood-brain barrier; TNF-α, tumor necrosis factor-α; GSK3α/β, Glycogen synthase kinase 3 alpha/beta; COX-2, Cyclooxygenase 2; PDE4D, Camp-Specific 3′,5′-Cyclic Phosphodiesterase 4D; NOS1, Nitric Oxide Synthase 1; HDAC5, Histone Deacetylase 5; CSDS, Chronic Social Defeat Stress; CUS, Chronic Unpredictable Stress; ↑, upregulated; ↓, downregulated.