TABLE 4.

Studies investigating the effects of indole metabolites on depressive-like behavior.

Treatment	Species or strain	Model	Behavioral outcomes	Molecular mechanisms	Reference
Isatin (15 mg/kg i.p. in mice and 20 mg/kg i.p. in rats); yohimbine (2 mg/kg i.p. in mice and 2.5 mg/kg i.p. in rats)	Male Charles Foster rats and Wistar mice	-	↑anxiety in the OFT and EPM in mice, and the SIT in rats, comparable to yohimbine. ↓anxiolytic effects of diazepam in the OFT	-	[150]
Isatin (0–160 mg/kg i.p.)	Male Sprague-Dawley rats (90-100 days)	-	↑immobility in the OFT and FST	-	[151]
Oxindole or isatin (50 or 100 mg/kg, i.p.) or indole (500 mg/kg intra-cecal administration); inoculation with 1 mL of BW25113 or JW3686 bacterial cultures	F344 male rats (2–2.5 months)	Conventional, SPF and GF	Acute intra-cecal administration of indole induced ↓motor activity and ↑ concentrations of oxindole and isatin in the brain. Chronic overproduction of indole by colonization with E. coli caused no change in motor activity and no detectable oxindole or isatin in the brain but ↑ helplessness in the TST and ↑anxiety in the novelty test, EPM and OFT.	↑eye blinking frequency and ↑c-Fos protein expression in the dorsal vagal complex	[154]
Tryptophan-depleted diet with or without tryptophan supplementation; I3S, IPA, IAld or indole supplementation	female C57BL/6J mice (WT and GFAP AhR-deficient)	EAE	-	↑Ccl2 and Nos2 expression in astrocytes in tryptophan depleted group, reverted by supplementation; administration of I3S, IPA, IAld activates AhR and ↓Ccl2 and Nos2 expression	[153]

AhR: Aryl Hydrocarbon Receptor; Ccl2: C-C Motif Chemokine Ligand 2; EAE: Experimental Autoimmune Encephalomyelitis; EPM: Elevated Plus Maze; FST: Forced Swim Test; GF: Germ Free; GFAP: Glial Fibrillary Acidic Protein; I3S: Indoxyl-3-sulfate; IAld: Indole-3-aldehyde; IPA: Indole-3-propionic acid; Nos2: Nitric Oxide Synthase 2; OFT: Open Field Test; SIT: Social Interaction Test; SPF: Specific Pathogen Free; WT: Wild Type.