Table 2.

Effects of metabolites on immune cells

Immune cell	Molecular mechanism(s)	Immunomodulatory metabolite	Effects on immune function	Key references
Interactions with innate immune cells
Intestinal epithelial cells (IECs)	Inhibition of histone deacetylase. Activation of the NLRP3 inflammasome (butyrate only)	Short-chain fatty acids (acetate, propionate, butyrate)	Provides energy. Induces goblet cell differentiation and mucus expression. Strengthens tight junctions. Promotes production of IL-18	[121, 124–127]
	Activation of the NLRP6 inflammasome	Taurine	Enhances epithelial barrier function and production of IL-18	[128]
	Activation of FXR	Secondary bile acids	Promotes epithelial barrier function	[129, 130]
	Activation of PXR	Indole	Reinforces tight junctions	[131]
	Unclear. Inhibition of pro-inflammatory cytokines expression	Polyamines	Increases production of occludin, zonula occludens 1 and E-cadherin	[132]
Innate lymphoid cells (ILCs)	Activation of AhR	Indole and indole derivatives	Promotes expression of IL-22, increasing production of antimicrobial peptides and strengthening intestinal mucosa integrity. Protects against colitis	[133–136]
Dendritic cells (DCs)	Inhibition of histone deacetylase. Binding to the transporter Slc5a8 (propionate and butyrate only)	Short-chain fatty acids (acetate, propionate, butyrate)	Inhibits expression of pro-inflammatory cytokines (TNF-α, IL-12 and IFN-γ) and promote production of anti-inflammatory cytokines (IL-10). Inhibits differentiation from bone-marrow precursors and expression of co-stimulatory proteins	[84, 137–139]
	Activation of H2R	Histamine	Protects against colitis. Inhibits expression of pro-inflammatory cytokines and the MAPK pathway	[140]
	Activation of GPBAR1 and FXR	Secondary bile acids	Inhibits NF-κB-dependent transcription of proinflammatory genes	[141]
Neutrophils	Activation of GPR43. Inhibition of histone deacetylase	Short-chain fatty acids (acetate, propionate, butyrate)	Promotes chemotaxis. Suppresses activation of NF-κB and expression of NO. Regulates production of ROS	[142–145]
Interactions with adaptive immune cells
T helper (Th) cells	Activation of AhR	Indole-3-lactic acid	Inhibits polarization of Th17 cells	[146]
	Activation of H2R or H1R	Histamine	Suppresses or promotes Th1 and Th2 polarization	[147]
Regulatory T (Treg) cells	Activation of GPR43 and GPR41. Inhibition of histone deacetylase	Short-chain fatty acids (acetate, propionate, butyrate)	Stimulates proliferation. Regulates the mTOR pathway for generation of IL-10	[148–150]
	Activation of RAR and RXR heterodimer	Retinoic acid	Activates the TGFβ–SMAD pathway. Increases expression of gut-homing markers	[151, 152]
	Increase expression of the antiapoptotic factor BCL-2	Folic acid	Promotes cell survival	[153, 154]
	Activation of GPR35, GPR109A and AhR	Tryptophan metabolites	Induces differentiation	[155, 156]
B cells	Inhibition of histone deacetylase	Short-chain fatty acids (acetate, propionate, butyrate)	Enhances oxidative phosphorylation, glycolysis and fatty acid synthesis. Promotes antibody production	[157, 158]
	Unclear	Retinoic acid	Facilitates IgA class-switch recombination and IgA production	[159]