Table 1.

Immunomodulatory metabolites that are produced by intestinal bacteria.

Metabolite	Molecular Mechanism(s) of Action	Origin	Effects on Immune System	Key References
Metabolites that are produced by bacteria from dietary components
Short-chain fatty acids (primarily acetate, propionate, butyrate)	Extracellular: activation of FFAR2 (GPR43), FFAR3 (GPR41), HCAR2 (GPR109A, butyrate only). Intracellular: inhibition of histone deacetylases and activation of histone acetyl transferases (butyrate and propionate only). Can also activate extracellular OR51E2 and intracellular PPAR-γ (butyrate only), but no relevance for immune system demonstrated yet.	Fermentation of polysaccharides by colonic microbiota. Bacteroidetes: acetate and propionate. Firmicutes: butyrate.	Generally anti-inflammatory, protect against colitis. Promote integrity and function of the intestinal epithelium. Inhibit production of pro-inflammatory cytokines by innate immune cells. Promote function of microglia. Inhibit maturation of dendritic cells. Promote antibody production by B cells. Promote de novo differentiation and expansion of Tregs.	(Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; M. Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009b; 2009a)
Indole derivatives	Activation of AhR and NR1I2.	Derived from dietary tryptophan by different intestinal bacteria.	AhR activation promotes maintenance of ILC3 cells, which strengthen integrity of intestinal mucosa by secreting IL-22. NR1I2 activation also enhances epithelial barrier function.	(Kiss et al., 2011; Lee et al., 2011; Y. Li et al., 2011; J. Qiu et al., 2012; Venkatesh et al., 2014; Zelante et al., 2013)
Polyamines (primarily putrescine, spermidine, spermine)	Unclear. Inhibit expression of pro-inflammatory cytokines in conjunction with AHSG. Also inhibit activation of NLRP6 inflammasome.	Derived from arginine by host and bacteria.	Enhance development and maintenance of intestinal mucosa and resident immune cells. Inhibit expression of pro-inflammatory cytokines by LPS-stimulated monocytes and macrophages.	(Dufour et al., 1988; Levy et al., 2015; Pérez-Cano et al., 2010; H. Wang et al., 1997; M. Zhang et al., 1999)
Metabolites that are produced by the host and biochemically modified by gut bacteria
Secondary bile acids	Extracellular: activation of GPBAR1. Intracellular: activation of BAR.	Derived from host-produced primary bile acids by intestinal microbiota.	Inhibit NF-κB-dependent transcription of pro-inflammatory genes in monocytes, macrophages, dendritic cells. Inhibit production of pro-inflammatory cytokine osteopontin by NKT cells.	(Cipriani et al., 2011; C. Guo et al., 2015; Kawamata et al., 2003; Mencarelli et al., 2009; Sayin et al., 2013; Vavassori et al., 2009; Y.-D. Wang et al., 2011)
Taurine	Enhancement of NLRP6 inflammasome activation.	Derived from host-produced primary bile salts by intestinal microbiota.	Enhances epithelial barrier function and maintenance by promoting epithelial production of IL-18.	(Levy et al., 2015)
Metabolites that are synthesized de novo by gut microbes
ATP	Activation of P2X and P2Y receptors.	Actively secreted by subset of intestinal bacteria.	Limits numbers of Tfh cells in Peyer's patches, thus reducing secretion of bacteria-specific IgA by B cells across intestinal epithelium. Promotes differentiation of TH17 cells in intestinal mucosa. May promote epithelial barrier function by activating NLRP3 inflammasome and subsequent IL-18 secretion by macrophages.	(Atarashi et al., 2008; Kusu et al., 2013; Mariathasan et al., 2006; Nuttle and Dubyak, 1994; Perruzza et al., 2017; Sutterwala et al., 2006)
Polysaccharide A (PSA)	Activation of TLR2 on DCs and Tregs. Presentation of PSA fragments with MHC-II to CD4+ T cells.	Bacteroides fragilis (required for colonization).	Potent anti-inflammatory effects: induces secretion of IL-10 from CD4+ T cells, directly and indirectly. Skews TH1:TH2 ratio towards TH1 cells.	(Cobb et al., 2004; Dasgupta et al., 2014; Johnson et al., 2015; Mazmanian et al., 2008; Round et al., 2011)