TABLE 3.
Studies investigating the effects of SCFAs on depressive-like behavior.
| Treatment | Species or strain | Model | Behavioral outcomes | Molecular mechanisms | Reference |
|---|---|---|---|---|---|
| Sodium butyrate (100 mg/kg or 1.2 g/kg; ip; 1 or 21 days) | 129SvEv x C57BI/6 mice (F1 crosses) | - | ↑ immobility time and ↑ latency to consume peanut butter chips in the novel environment after acute treatment with SB100; no effect of chronic treatment | ↑ acH4/H3 and acH3/H3 protein in HP after acute SB 100 and/or 1.2 treatment, respectively;↓ acH4/H3 (no changes in acH3/H3) in HP after chronic SB100 administration | [95] |
| Sodium butyrate (1.2 g/kg ip; 1 or 7 days) | Sprague-Dawley rats | - | ↓ immobility time in rats after repeated (but not acute) SB administration; no changes in OFT | ↑ Ttr and ↓ Slc8a3, Casr, Htr2a, Tcf12 and no changes in Sin3a, Gnrhr, Crhr2, Bdnf, Slc8a2 gene expression in hippocampus after repeated SB treatment; ↑ levels of acH4-associated DNA at the Ttr promotor region in HP of rats repeated treated with SB; ↑ Ttr and no changes in acH3/H3, acH4/H4 protein level in HP after repeated SB administration | [97] |
| Sodium butyrate (0.3 g/kg ot 0.6 g/kg) | ICR mice | CRS | ↓ anhedonia, time spent in dark and immobility time after SB0.6 administration in CRS-treated mice | SB0.6 reverses CRS-induced decrease in acH3 level in HP | [96] |
| Fluoxetine (10 mg/kg; oral) + Sodium butyrate (300 mg/kg; ip) for 21 days | Sprague-Dawley rats (2 months) | - | ↓ time spent in social grooming and frequency of pouncing and ↑ immobility time and immobility events in PNFlx rats; ↑ latency to approach center and ↓ time spent in the center and path length in the center in PNFlx animals; postnatal treatment with SB and adult fluoxetine (AFlx) treatment prevented the PNFlx-evoked behavioral changes | ↑ Hdac4, Ppp2r2b, Gal, Dcx, Kcnh2, Grm8, ElkI and ↓mTOR, Gnai1, Prkcc, HcnI, Notch3 and Avpr2 mRNA levels in HP of PNFlx rats;co-administration of SB prevented the PNFlx-evoked dysregulation of Hdac4 and mTOR, but not Gnai1, Prkcc and HcnI in HP; AFlx administration did no alter hippocampal expression of Hdac4, mTOR, Gnai1, HcnIand Prkcc; ↑ acetylation of H3 and H4 at the Hdac4 promoter and ↑ HDAC4 enrichment in Gnai1 and mTOR promoter in HP of PNFlx rats and normalization after adult fluoxetine treatment; ↓ mTOR protein level in HP of PNFlx rats and no changes after AFlx treatment | [98] |
| Sodium butyrate (0.4 g/kg; ip) twice a day for 23 days | Male FRL and FSL rats (3 months) | - | chronic NaB-treatment rescued the FSL depression-like phenotype; ↓ immobility time | The FSL-NaB group exhibited ↑ Tet1 mRNA (and protein); ↓ Dnmt1 mRNA (but not protein) levels in the FSL-NaB group; ↓ 5hmC levels at the Bdnf P4 locus; hypermethylation of Bdnf P4 compared to FRL-Veh; the NaB-dependent increase in 5hmC levels in Bdnf P4 of FSL was associated with DNA hypomethylation at the same locus; NaB-dependent increase in TET1 and 5hmC levels in the FSL group was associated with a Bdnf P4 overexpression | [91] |
| Sodium butyrate (500 mg/kg, i.p.) twice a day for 7 days | Wistar rats (2 months) | maternal deprivation or CMS | ↓depressive-like behavior in FST | ↑ tricarboxylic acid cycle anzyme (succinate dehydrogenase and malate dehydrogenase) and mitochondrial chain complexes (I, II, II-III and IV) activity in the striatum | [103] |
| Propionate | Sprague-Dawley rats | CUMS | Improved performance at the SPT and OFT; short-term antidepressant-like effects. | Restored plasma levels of propionic acid; ↑NE, DA, TRP, 5-HIAA, and 3-HAA in the PFC (no effects on 5-HT and 3-HK) were not; ↓ turnover of TRP to KYN (calculated as KYN/TRP) and ↓turnover of DA to HVA (calculated as HVA/DA); ↑ abundance of DOPAC and 3-MT, but no change in HVA; no effect on turnover of 5-HT to 5-HIAA (calculated as 5-HIAA/5-HT); ↑turnover of KYN to 3-HK | [105] |
| Sodium butyrate (200 mg/kg) or fluoxetine (20 mg/kg) | Male C57BL/B6 mice | CUMS | ↑ sucrose intake in SPT; ↑ locomotor activities in OFT; decreases immobility time in TST and FST | decreases histological abnormalities in hippocampal neurons; ↑ BDNF expression; ↑ Occludin and ZO-1 protein levels | [100] |
| Sodium butyrate (1.2 g/kg or 0.2 g/kg, i.p.); fluoxetine (10 mg/kg, i.p.)+ SB (0.6 mg/kg, i.p.) acutely of chronically (28 days) | male and female C57BL/6J mice (9-22 weeks) | - | improved performance at the TST | ↑ histone acetylation in the brain; ↑ BDNF in mouse frontal cortex | [94] |
3-HAA: 3-Hydroxyanthranilic Acid; 3-HK: 3-Hydroxyanthranilic Acid; 3-MT: 3-Methoxytyramine; 5-HIAA: 5-Hydroxyindoleacetic Acid; 5hmc: 5-Hydroxymethylcytosine; 5-HT: 5-Hydroxytryptamine; Ach4/H3: Acetylated Histone H3/4; Avpr2: Arginine Vasopressin Receptor 2; Casr: Calcium-Sensing Receptor; CMS: Chronic Mild Stress; Crhr2: Corticotropin Releasing Hormone Receptor 2; CRS: Chronic Restraint Stress; CUMS: Chronic Unpredictable Mild Stress; DA: Dopamine; Dcx: Dublecortin; Dnmt1: DNA (Cytosine-5)-Methyltransferase 1; DOPAC: 3,4-Dihydroxyphenylacetic Acid; Elkl: ETS Domain-Containing Protein; FRL: Flinders Sensitive Line; FSL: Flinders Resistant Line; FST: Forced Swim Test; Gal: Galanin; Gnai1: G Protein Subunit Alpha I1; Gnrhr: Gonadotropin Releasing Hormone Receptor; Grm8: Glutamate Metabotropic Receptor 8; Hcnl: Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 1; Hdac4: Histone Deacetylase 4; Htr2a: 5-Hydroxytryptamine Receptor 2A; HVA: Homovanillic Acid; Kcnh2: Potassium Voltage-Gated Channel Subfamily H Member 2; KYN: Kynurenine; Mtor: Mammalian Target of Rapamycin; NE: Norepinephrine; Notch3: Neurogenic Locus Notch Homolog Protein 3; OFT: Open Field Test; PFC: Prefrontal Cortex; Ppp2r2b: Protein Phosphatase 2 Regulatory Subunit Beta; Prkcc: Protein Kinase C Gamma; Sin3a: SIN3 Transcription Regulator Family Member A; Slc8a3: Solute Carrier Family 8 Member A3; SPT: Sucrose Preference Test; Tcf12: Transcription Factor 7-Like 2; TET1: Ten-Eleven Translocation 1; TRP: Tryptophan; TST: Tail Suspention Test; Ttr: Transthyretin; ZO-1: Zonula Occludens-1.