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. Author manuscript; available in PMC: 2020 Aug 22.
Published in final edited form as: Cell. 2019 Aug 22;178(5):1041–1056. doi: 10.1016/j.cell.2019.07.045

Figure 4. Pharmacology of microbial metabolites and host targets.

Figure 4.

Metabolites engage host pathways and elicit diverse signaling outputs. (A) Pleiotropy by paralogs: serotonin (5-HT) has pleiotropic effects on the host due to the fact that there are 14 different 5-HT receptors, each associated with distinct downstream effects in different cell types. (B) Pleiotropy by polypharmacology: kynurenic acid exerts pleiotropic effects on the host by engaging distinct host target proteins with varying affinities. Specifically, kynurenic acid engages aryl hydrocarbon receptor (AhR) and GPR35, thus engaging unique signaling pathways that coordinately regulate immune function (CREB, cAMP response element-binding protein). (C) Antagonism: butyrate can act through GPR43 to antagonize mucus secretion induced by tryptamine signaling through 5-HT4 receptors (AC, adenylate cyclase). (D) Synergistic signaling: heterodimer FxR/RxR transcriptional activity is augmented by concurrent binding to bile acid and retinoic acid derivatives (left panel). Secretion of GLP-1 is dramatically enhanced by concurrent engagement of GPR40 and TGR5 by long-chain fatty acids and bile acids, respectively (right panel) (PLC, phospholipase C; IP3, inositol triphosphate).