Table 2.
Health benefits and molecular mechanisms of SCFAs from preclinical studies.
| SCFAs Species | Study Type | Subjects | Doses | Effects and Mechanisms | Ref. |
|---|---|---|---|---|---|
| Anti-inflammation | |||||
| Acetate | In vivo | C57BL/6 mice and C57BL6 GFP Het | 150 mM in drinking water | Induce caspase-dependent apoptosis of neutrophils; Decrease the activity of NF-κB; Enhance production of IL-10, TGF-β, and annexin A1. |
[22] |
| Propionate | In vitro | HPMECs | 0.6 mM | Accelerate Nrf2 nuclear translocation; Protect cells and promote angiogenesis; Reduce inflammatory response via NF-κB pathway. |
[23] |
| Propionate | In vivo | C57BL/6J and Nrf2−/− mice | 1.2 mg/g i.p. | Reduce pulmonary inflammation and oxidative stress. | [23] |
| Propionate | In vivo | BALB/c and C57BL/6 mice | 150 mM in drinking water | Interfere with the production and migration of inflammatory mediators. | [24] |
| Butyrate | In vivo | ICR mice | 200 mg/kg i.p. | Up-regulate the IL-10 in septic shock. | [21] |
| Butyrate | In vitro | RAW 264.7 cells | 100 μM | Down-regulate the IL-6 and IL-1β; Increase the IL-10. |
[21] |
| Propionate; Butyrate | In vitro | THP-1 cells | 10 µM | Inhibit the expressions of IL-4, IL-6, and ROS; Enhance the expressions of IL-10 and IFN-γ. |
[20] |
| Immunoregulation | |||||
| Butyrate | In vivo | C57BL/6J mice | 200 mM in drinking water | Promote IL-22 production by CD4+ T cells and ILCs. | [28] |
| Acetate; Propionate; Butyrate | In vitro | CD4+ T cells | 10 mM acetate; 0.5 mM propionate; 0.5 mM butyrate | Promote CD4+ T cell and ILC production of IL-22 through GPR41 and HDAC inhibition. | [28] |
| Acetate; Propionate; Butyrate | In vitro | Synovial fibroblasts | 250 µM propionate or the mixture (300 µM acetate, 100 µM propionate, 100 µM butyrate) | Interfere with arthritogenic properties of synovial fibroblasts; Induce cellular senescence. |
[24] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6J and C.129-IL4tm1Lky/J (4get) mice | 40 mM butyrate, 67.5 mM acetate and 25.9 mM propionate in drinking water | Regulate T cells and DC activities; Reduce the production of IL4-producing CD4+ T cells; Decrease circulating IgE level. |
[27] |
| Acetate; Propionate; Butyrate; Pentanoate | In vitro | Splenic B cells isolated from C57BL/6J mice | 0.5 mM of NaAc, NaPr, NaBu or NaPe | Promote B10 cell generation; Enhance B10 cell function. |
[29] |
| Acetate; Propionate; Butyrate; Pentanoate | In vivo | C57BL/6J mice | 150 mM acetate, propionate, butyrate or pentanoate in drinking water | Promote B10 cell generation via activation of GPCR. | [29] |
| Anti-obesity | |||||
| Propionate | In vitro | YAMC cells | 5 mM | Repress the TG accumulation via modulating the expression levels of PPARα-responsive genes. | [36] |
| Acetate; Propionate; Butyrate | In vitro | 3T3-L1 cells | 6.4 mM acetic acid; 3.2 mM propionic acid or 0.4 mM butyric acid | Accelerate the 3T3-L1 adipocyte differentiation; Promote lipid accumulation via modulation of the expression of LPL, adipocyte FABP4, FATP4, and FAS. |
[115] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6J mice | 5% acetate, propionate, or butyrate in the diet | Protect against high-fat diet-induced obesity; Suppress hepatic weight and lipid synthesis. |
[37] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6 mice | 6 mmol/kg acetate; 6 mmol/kg propionate; 1–6 mmol/kg butyrate, 10 mL/kg i.p. | Activate vagal afferent neurons. | [32] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6J mice | 5% sodium acetate; 5% sodium propionate or 5% sodium butyrate in a high-fat diet | Reduce appetite and fat accumulation via modulating relevant genes and hormones; Regulate the expressions of several mRNA. |
[34] |
| Acetate; Propionate; Butyrate | In vivo | Barrows (Duroc × Landrace × Yorkshire) | 0.1% acetate; 0.1% propionate; 0.1% butyrate; 0.1% mixed SCFAs (3:1:1) in diet supplement | Increase the concentrations of the serum GLP-1, PYY and leptin to regulate the appetite; Down-regulate of the mRNA expressions of FAS, ACC, and SREBP-1C to participate the de novo synthesis of fatty acids; Enhance the mRNA expressions of LIPE and CPT-1α to participate in fatty acids oxidation. |
[33] |
| Acetate; Propionate; Butyrate | In vivo | Long–Evans rats | MNaAc:MNaPr:MNaBu = 60:20:20, dissolve in 0.1 M PBS, 500 mg/kg i.p. | Suppress the de novo lipogenesis by reducing mRNA expression of hepatic Acc1. | [35] |
| Cardiovascular protection | |||||
| Acetate | In vivo | SD rats | 200 mmol/L magnesium acetate in drinking water | Up-regulate SCFAs receptors Olfr78, GPR41, and GPR43 to keep the balance of vasoconstriction and vasodilation shifts. | [47] |
| Propionate | In vivo | NMRI and ApoE−/− mice | 200 mmol/L in drinking water | Reduce blood pressure; Attenuate cardiac hypertrophy, fibrosis, and vascular dysfunction. |
[48] |
| Propionate | In vivo | ApoE−/− mice | 200 mg/kg i.g. | Reduce intestinal cholesterol absorption and aortic atherosclerotic lesion area; Increase levels of regulatory T-cell numbers and IL-10; Reduce the levels of NPC1l1. |
[44] |
| Butyrate | In vitro | Caco-2 cells | 0, 0.1, 1 and 10 mmol/L | Inhibit cholesterol absorption; Reduce the levels of NPC1l1; Increase the levels of ABCG5 and ABCG8. |
[43] |
| Butyrate | In vivo | SD rats | 200 mmol/L in drinking water | Improves myocardial I/R injury via gut-brain neural circuit. | [49] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6J mice | 100 mmol/L in drinking water | Reduce blood pressure. | [46] |
| Acetate; Propionate; Butyrate; valerate | In vivo | Golden Syrian hamsters | 0.5 mol/kg sodium acetate, sodium propionate, sodium butyrate, and valeric acid in high-cholesterol diet | Enhance fecal excretion of bile acids; Up-regulate the gene expressions of SREBP2, LDLR, and CYP7A1 in the liver. |
[45] |
| Hepatoprotection | |||||
| Acetate | In vivo | C57BL/6 mice | 200µL LITA-Rhd i.p. | Decrease lipid accumulation; Improve hepatic function; Increase mitochondrial efficiency. |
[39] |
| Propionate | In vitro | HepG2 cells | 0.2, 0.4, 0.8 mM | Enhance hepatic function; Alleviate ethanol-induced hepatic steatosis. |
[56] |
| Propionate | In vivo | C57BL/6J mice | 100 or 200 mM in the diet | Prevent ethanol-induced loss of hepatic function; Alleviate ethanol-induced hepatic steatosis. |
[56] |
| Acetate; Propionate; Butyrate | In vitro | BRL 3A cell | 10 mM NaAc, 5 mM NaPr, 2.5 Mm NaBu or 10 mM mixture (MNaAc:MNaPr:MNaBu = 3:1:1) | Reduce the production of ROS and MDA; Activate AMPK and PPAR signaling pathways; Down-regulate the expression of genes related to lipid synthesis. |
[59] |
| Acetate; Propionate; Butyrate | In vitro | human-iPSC-derived liver organoids | 1 μM acetate; 1 μM propionate; 1 μM butyrate | Increase the expression of CYP3A4 and ALB. | [63] |
| Anti-diabetes | |||||
| Propionate | In vitro | HepG2 cells | 0, 0.25, 0.5 mM | Suppress gluconeogenesis by down-regulation of gluconeogenic enzymes; Suppress hepatic gluconeogenesis by activating AMPK; Activate AMPK via Ca2+/CaMKKβ pathway. |
[70] |
| Acetate; Propionate | In vivo | C3H/HeOuJ mice | 5% SCFA (Ac:Pr, 2.5:1 or Ac:Pr, 1:2.5) in the diet | Attenuate high-fat diet-induced insulin resistance. | [38] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6 WT and IL22 KO mice | 67.5 mM acetate, 40 mM butyrate and 25.9 mM propionate in drinking water | Prevent type 1 diabetes; Promote development of regulatory T cells. |
[116] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6 mice | Acetate (5% w/w of diet), propionate (10% w/w of diet), butyrate (10% w/w of diet), acetate + propionate (5% + 10% w/w of diet) | Improve insulin sensitivity. | [67] |
| Prevention and management of inflammatory bowel disease | |||||
| Propionate | In vivo | WT C57BL / 6 mice | 200 mM in drinking water | Promote intestinal epithelial cell migration; Increase cell speed and persistence. |
[74] |
| Butyrate | In vivo | WT C57BL/6J mice | 200 mM in drinking water | promote IL-22; Protect the intestines from Citrobacter rodentium infection. |
[28] |
| Butyrate | In vitro | ICR mice crypt | 100μM | Elicit α-defensin secretion by Paneth cells; Improve enteric innate immunity through potent microbicidal activities. |
[79] |
| Acetate; Propionate; Butyrate | In vitro | Sheep ruminal tissue | 60 mM NaAc, 30 mM NaPr and 10 mM NaBu | Release protons; Induce subacute ruminal acidosis. |
[117] |
| Acetate; Propionate; Butyrate | In vitro | Caco-2 cells | acetate (12.5, 25, and 50 mM), butyrate (5, 10, and 20 mM) and propionate (5, 10, and 20 mM) | Increase the level of Hspa1a expression. Up-regulate HSP70; phosphorylate HSP1. |
[76] |
| Acetate; Propionate; Butyrate | In vitro | Caco-2 and T84 cells | Acetate: 0–20 mM, propionate: 0–10 mM, butyrate: 0–2.5 mM | Reduce IL-8 and IL-6 expression levels; Reduce the activation of NF-κB, ERK, p38 MAPK, JNK, and Syk. |
[81] |
| Acetate; Propionate; Butyrate | In vitro | MODE-K and MC38 cell lines | A mixture of 0.5 mM acetate, 0.01 mM propionate, and 0.01 mM butyrate | Inhibit DUSP6 by up-regulating miR-145 through decreasing the CEBPB expression. | [82] |
| Acetate; Propionate; Butyrate | In vitro | Caco-2 cells | 0.5 mM acetate, 0.01 mM butyrate, 0.01 mM propionate | Increase TER; Improve the formation of tight junction; Inhibit the activation of NLRP3 inflammasome and autophagy induced by LPS. |
[78] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6J mice | 200 mM propionate, 200 mM acetate or 100 mM butyrate in the drinking water | Repress IL-17- and IL-22-producing γδ T cells; Reduce IL-17 production by γδ T cells by inhibiting HDAC. |
[80] |
| Acetate; Propionate; Butyrate | In vivo | C57BL/6J mice | 25 mM propionate, 40 mM butyrate and 67.5 mM acetate in drinking water | Inhibit DUSP6 via up-regulating miR-145 by suppressing CEBPB; Improve DAI. |
[82] |
| Prevention and management of constipation | |||||
| Butyrate | In vitro | ICCs | 0, 0.00005, 0.0005, 0.005, 0.05 and 0.5 mmol/L | Promote mouse ICC proliferation by activating AKT/NF-κB signaling. | [88] |
| Butyrate | In vivo | Kunming mice | 1.1% in the drinking water | Promote defecation; Improve intestinal mobility; Activate the AKT-NF-κB signaling pathway. |
[88] |
| Acetate; Propionate; Butyrate | In vivo | BALB/c mice | Diets supplemented with 150 g/kg of either acetylated starch, propylated starch, butylated starch | Acetylated starch and butylated starch relieve constipation; Acetic acid increases WCF and SITR; Butyric acid decreases the transit time through the gut. |
[86] |
| Neuroprotection | |||||
| Acetate | In vitro | BV2 cells | 1200 μM | Improve cognitive impairment; Decrease the CD11b level; Suppress neuroinflammation. |
[93] |
| Acetate | In vivo | APP/PS1 transgenic and matched WT mice | 1.5 g/kg i.g. | Inhibit the phosphorylation of NF-κB p65, ERK, and JNK; Decrease COX-2 and IL-1β levels; Increase GPR41 level. |
[93] |
| Propionate | In vivo | Western albino rats | 75 mg/kg or 250 mg/kg i.g. | Increase the levels of IFN-γ and caspase-3; Decrease levels of nor-adrenaline, dopamine, and 5-HT. |
[118] |
| Propionate | In vivo | Western albino rats | 75 mg/kg or 250 mg/kg i.g. | Increase the levels of glutamate and the glutamate/glutamine ratio; Decrease GABA, glutamine, and the GABA/glutamate ratio. |
[119] |
| Anticancer | |||||
| Valerate | In vitro | Hep3B, SNU-449, HepG2, THLE-3, MCF-7, MDA-MB-231, MCF-10A, A549, U-87 and A172, HeLa, DU145, and HL-60 cells | 0.5, 1, 2, 4, 8 mM | Suppress colony formation, migration, and invasion of liver cancer cells; Suppresses 3D spheroid formation of liver cancer cells. |
[100] |
| Valerate | In vivo | Athymic nude mice | 100 mg/kg tail injection | Suppress HCC development; Improve the survival rate. |
[100] |
| Butyrate; Propionate | In vivo | C57BL/6 mice | 300 mg/kg acetate, 150 mg/kg propionate or 88 mg/kg butyrate i.p. | Increase the expression of CCL20; Reduce the recruitment of Th17 cells; Inhibit the lung metastasis of melanoma cells. |
[99] |
| Acetate; Butyrate; Propionate | In vivo | BALB/c mice | 67.5 mM acetate, 40 mM butyrate and 25.9 mM propionate in drinking water | Decrease cell proliferation. | [98] |
| Acetate; Propionate; Butyrate Pentanoate | In vivo | CD45.1 WT; CD45.2 WT; CD45.1 OT-I; CD45.2 Ffar2−/− Ffar3−/− mice; CD45.2 FIR × tiger; Rag1−/− mice |
0.5, 1.0, 2.5 mM | Increase the anticancer activity of cytotoxic T lymphocytes and chimeric antigen receptor T cells via metabolic and epigenetic reprogramming. | [101] |
| Prevention and management of arthritis | |||||
| Acetate; Propionate; Butyrate | In vivo | WT C57BL/6J mice and DBA/1J mice | 150 mM acetate, propionate or butyrate in drinking water | Increase systemic bone mass via inducing the reprogramming of osteoclasts metabolism, enhancing glycolysis, and down-regulating TRAF6 and NFATc1; Prevent bone loss after menopause; Alleviate arthritis. |
[112] |
| Acetate; Propionate; Butyrate | In vivo | DBA/1JGpt, Ffar2fl/fl and Ffar2fl/fl/CD19-Cre mice | 150 mM acetate, propionate or butyrate in drinking water | Synergistic treatment of CIA; Regulate B cell differentiation via FFA2 receptors; Suppress the inflammatory response. |
[113] |
Abbreviation: ABCG5, ATP-binding cassette transporters G5; ABCG8, ATP-binding cassette transporters G8; Ac, Acetate; Acc1, acetyl-CoA carboxylase-1; CaMKKβ, Ca2+-calmodulin-dependent protein kinase β; CCL20, chemokine (C-C motif) ligand 20; CEBPB, CCAAT enhancer-binding protein beta; CIA, collagen-induced arthritis; COX-2, cyclooxygenase-2; CPT-1α, carnitine palmitoyltransferase-1α; CYP7A1, cholesterol 7 alpha-hydroxylase; DAI, disease activity index; DC, dendritic cells; DUSP6, dual-specificity phosphatase 6; ERK, extracellular signal-regulated kinase; FABP4, fatty acid binding protein 4; FATP4, fatty acid transporter protein 4; FAS, fatty acid synthase; GABA, gamma amino butyric acid; GPR41, G-protein-coupled receptor 41; HAMS, High-amylose maize starch; HCC, hepatocellular carcinoma; HPMECs, human primary pulmonary microvascular endothelial cells; HSP, heat shock protein; ICCs, interstitial cells of Cajal; IFN-γ, Interferon-γ; Ig, immunoglobulin; i.g., intragastric administration; IL, interleukin; i.p., intraperitoneal injection; iPSC, induced pluripotent stem cell; I/R, ischemia/reperfusion; JNK, c-Jun N-terminal kinase; LDLR, low-density lipoprotein receptor; LIPE, lipase hormone sensitive; LPL, lipoprotein lipase; LPS, lipopolysaccharide; LITA, liposome-encapsulated acetate; MAPK, mitogen-activated protein kinase; miR, microRNA-145; NF-κB, nuclear factor-kappa B; NGNs, nodose ganglion neurons; NPC1l1, Niemann-Pick C1-like 1; NTS, nucleus tractus solitaries; OCFA, odd-chain fatty acids; Pr, Propionate; ROS, reactive oxygen species; SD, Sprague–Dawley; SITR, small intestinal transit rate; SREBP2, sterol-regulatory-element-binding protein 2; Syk, spleen tyrosine kinase; TER, transepithelial electrical resistance; TG, triglyceride; TGF-β, transforming growth factor-β; Th17, T helper 17; TNF, tumor necrosis factor; WCF, water content of feces; WT, wide type; YAMC, young adult mouse colon.