Table 1 Pro- and anti-inflammatory effect of SCFA depending on the SCFA molecule, concentration, and activated pathways

 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]

 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, 158,159,160,161, 170, 172, 176, 211,212,213,214]

 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, 215,216,217,218,219,220,221,222,223]

 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, 230,231,232]