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

From: Bacterial metabolites and cardiovascular risk in children with chronic kidney disease

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, 158,159,160,161, 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]
  1. 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