Table 1.
Pro- and anti-inflammatory effect of SCFA depending on the SCFA molecule, concentration, and activated pathways
| Molecule | Concentration | Pathway | Mediators | Effectors | Reference |
|---|---|---|---|---|---|
| A) Pro-inflammatory effects | |||||
|
Butyrate (C4) Propionate (C3) |
C4, 2.5–5 mmol/l C3: not specified |
GPR43 (FFAR2) | Protein kinase p38α, MAPK phosphorylation, TACE (ADAM17) | ICAM-1↑, E-selectin↑, CINC-2αβ↑ (cytokine-induced neutrophil chemoattractant-2αβ)↑, L-selectin shedding↑ | [102, 207] |
| SCFA unspecified | Not specified | HDAC inhibition | STAT3, NF-κB, and RUNX1 | IL-6↑, CXCL1 ↑, and CXCL2 ↑ | [99, 208] |
|
Acetate (C2) Propionate (C3) Butyrate (C4) |
Not specified |
C3/C4: GPR41 (FFAR3); C2/C3: GPR43 (FFAR2) |
GPR41 (Gq) -> PLC/Ca+ ↑ or PI3K ↑ -> rac/ras -> ERK1/2 or JNK1/3 or p38αMAPK GPR43 (Gi), adenyl cyclase↓, cAMP ↓ -> Ras/Rac ↑ -> ERK1/2 or JNK1/3 or p38α MAPK pathways↑; rapamycin (mTOR) activation of PI3K |
IL-6 ↑, CXCL1↑, and CXCL2↑, and interferon gamma (INFγ)↑ | [99, 105, 209, 210] |
| B) Anti-inflammatory effects | |||||
| Butyrate (C4) > propionate (C3) > acetate (C2) |
C4, 46μmol/l C3, 120μmol/l C2, 1–2.4mmol/l |
HDAC 1-3 inhibition | MKP-1 acetylation -> dephosphorylation of MAPK, ERK, JNK and p38 MAPK => LPS-induced phosphorylation of p38↓, NF-κB activity↓, eicosanoid production (LOX activation), Mi-2β↑(transcriptional repressor recruited to the IL-6 and TNF promoter); sodium-coupled monocarboxylate transporter 1 (SMCT-1 ) - direct interaction with NF-kB corepressor p65 and p50, deacetylation of p65, enhanced binding of inhibiting molecule IκBα to NF-κB | LPS-induced TNF-α secretion↓ and iNOS expression↓ IL-1β↓, NF-κB activity↓ IL-12 ↓ IL-8↓ CCL2↓, VCAM1↓, MMP2↓, oxLDL uptake↓ CD36↓ | [105, 155, 158–161, 170, 172, 176, 211–214] |
| SCFA unspecified (C3>C4>others) | 0.03–5mM | Aryl hydrocarbon receptor (AhR), GPR41 (FFAR3) | Histone deacetylase (HDAC 7, 9, 11) inhibitory activity of the of the Foxp3 promoter; ERK, JNK, and p38 MAPK activation; CTLA-4 | adenyl cyclase↓, cAMP ↓; LPS-induced TNFα↓, IL-6↓ and iNOS expression↓; Foxp3↑, Regulatory B cell upregulation => secretion of interleukin-10 (IL-10)↑, IL-35↑, IL-4 ↑ and transforming growth factor-beta (TGF-β)↑, IL 12↓ | [103, 104, 171, 172, 215–223] |
|
Acetate (C2) Proprionate (C3) Butyrate (C4) |
10mM | GPR43 (FFAR2) | BAX–BAK1–BCL2L1 cluster and the PRKCA–PTPN6–LCK clusters | Induce apoptosis of neutrophils by caspase-8 and caspase-9 pathways | [224, 225] |
| SCFA unspecified (C2, C3>others) | Not specified | GPR43 (FFAR2) (Gi) heterodimerization and internalization of C5aR and CXCR2, ChemR23 | C5a or fMLP (N-formyl peptide f-Met-Leu-Phe); beta-arrestin-2 -> inhibit proteasomal degradation via of IκBα via β-arrestin | Inhibit human neutrophil migration toward C5a or fMLP; cAMP ↓, PLC↑, Ca2+↑ | [155, 225] |
|
Butyrate (C4) Propionate (C3) |
C4, >0.4 mmol/l C3, >4 mmol/l |
HDAC activity, GPR43(FFAR2) | Ca2+ mobilization↑, NF-κB↓ | TNF-α↓ and CINC-2αβ↓ | [155] |
| Butyrate (C4) | C4, 0.5–10 mmol/l | Nuclear translocation of the p65 subunit↓ NF-κB b↓, peroxisome proliferator-activated receptor–PPAR expression | TNF-α–induced expression of VCAM-1 and ICAM-1 | [176, 226] | |
|
Propionate (C3) Butyrate (C4) |
C3, 12 mmol/l C4, 1.6 mmol/l |
GPR109A (Gi) | cAMP↑, NADPH oxidase ↓, reduced phosphorylation of the regulatory subunit NADPH oxidase subunits (p47phox and p22phox); MPO↓ | ROS↓ NO↓ superoxide ↓ hydrogen peroxide ↓ and hypochlorous↓ | [207, 225, 227] |
|
Acetate (C2) > propionate (C3) Butyrate (C4) |
Not specified | GPCR | NALP3 inflammasome activation↑, AMPK activation, MUC2 mRNA expression↑ | L-18 production↑, K+ efflux↓, Ca2+ influx↑, MUC2 secretion, assembly of tight junction proteins ZO-1 and occludin | [228, 229] |
| SCFA unspecified (C4>others) | Not specified | GPR109A (Gi) | β arrestin-2 -> inhibits proteasomal degradation of IκBα -> NFIB↓, HDAC5, TLR4-; cAMP ↓, PLC↑, Ca2+ ↑ | TNF-α↓, IL-6↓, and MCP-1↓ | [177, 178, 230–232] |
GPR G protein-coupled receptor, FFAR free fatty acid receptor, HDAC histone deacetylase, ADAM a disintegrin and metalloprotease, TACE tumor necrosis factor-α-converting enzyme, PLC phospholipase C, LPS lipopolysaccharides, TNFa tumor necrosis factor a, cAMP cyclic adenosine monophosphate, PKA protein kinase A, PI3K phosphoinostide 3-kinase, MAPK mitogen-activated protein kinase, MEK mitogen-activated protein kinase kinase, aMKP acetylated mitogen-activated protein kinase phosphatase, ERK extracellular signal-regulated kinases, JNK jun N-terminal kinase, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, I-κB inhibitor of nuclear factor kappa B, LOX lipoxygenase, MCP-1 monocyte chemoattractant protein-1, ICAM intercellular adhesion molecule, VCAM vascular adhesion molecule, iNOS inducible nitric oxide synthase, fMLP N-formylmethionyl-leucyl-phenylalanine, CXCL chemokine ligand, AMPK AMP-activated protein kinase, NALP nucleotide-binding oligomerization domain, leucine-rich repeat and Pyrin domain containing, MMP matrix metalloproteinase, TLR toll-like receptor, ZO zonula occludens, MUC mucin