Abstract
Diet and gut microbial metabolites mediate host immune responses and are central to the maintenance of intestinal health. The metabolite-sensing G-protein coupled receptors (GPCRs) bind metabolites and trigger signals that are important for the host cell function, survival, proliferation and expansion. On the contrary, inadequate signaling of these metabolite-sensing GPCRs most likely participate to the development of diseases including inflammatory bowel diseases (IBD). In the intestine, metabolite-sensing GPCRs are highly expressed by epithelial cells and by specific subsets of immune cells. Such receptors provide an important link between immune system, gut microbiota and metabolic system. Member of these receptors, GPR35, a class A rhodopsin-like GPCR, has been shown to be activated by the metabolites tryptophan-derived kynurenic acid (KYNA), the chemokine CXCL17 and phospholipid derivate lysophosphatidic acid (LPA) species. There have been studies on GPR35 in the context of intestinal diseases since its identification as a risk gene for IBD. In this review, we discuss the pharmacology of GPR35 including its proposed endogenous and synthetic ligands as well as its antagonists. We elaborate on the risk variants of GPR35 implicated in gut-related diseases and the mechanisms by which GPR35 contribute to intestinal homeostasis.
Highlights
The gastrointestinal tract is home to the vast majority of microbiota in the body most of which are colonized in the distal intestine [1]
lysophosphatidic acid (LPA)/ GPR35 axis have been evident across the species, mouse and zebrafish, where LPA led to GPR35-dependent migration of macrophages as well as TNF cytokine induction marked with activation of NF-kB and ERK pathways
GPR35 might prove useful as an intermediate player and a messenger between the microbiota and host via metabolite-sensing
Summary
The gastrointestinal tract is home to the vast majority of microbiota in the body most of which are colonized in the distal intestine [1]. A fiber-rich diet lowers risk of Crohn’s disease whereas a “western” diet containing poly-unsaturated fatty acids, and transfats is associated with IBD [7, 8] In this context, there is increasing evidence that host and/or microbiota-derived metabolites shape the host intestinal immune system by activating signaling cascades in epithelial and immune cells. The ligandGPCR interaction studies are challenged by interspecies variances especially including that of GPR35 Despite this complexity, LPA/ GPR35 axis have been evident across the species, mouse and zebrafish, where LPA led to GPR35-dependent migration of macrophages as well as TNF cytokine induction marked with activation of NF-kB and ERK pathways. 66 mM Not available Not available Not available Not available Not available EC50 (rat) 100 nM 13 nM >100 mM Not available 10 nM 8 mM Not available Not available IC50 (rat) No response No response Not assessed [23, 42, 43] [20, 24] [25] [44] [44, 45] [46]
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