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Microbial metabolite sensor GPR43 controls severity of experimental GVHD.

ABSTRACT: Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versus-host disease (GVHD), but the molecular mechanisms remain unknown. Here we show the metabolite sensor G-protein-coupled receptor 43 (GPR43) is important for attenuation of gastrointestinal GVHD in multiple clinically relevant murine models. GPR43 is critical for the protective effects of short-chain fatty acids (SCFAs), butyrate and propionate. Increased severity of GVHD in the absence of GPR43 is not due to baseline differences in the endogenous microbiota of the hosts. We confirm the ability of microbiome-derived metabolites to reduce GVHD by several methods, including co-housing, antibiotic treatment, and administration of exogenous SCFAs. The GVHD protective effect of SCFAs requires GPR43-mediated ERK phosphorylation and activation of the NLRP3 inflammasome in non-hematopoietic target tissues of the host. These data provide insight into mechanisms of microbial metabolite-mediated protection of target tissues from the damage caused allogeneic T cells.

SUBMITTER: Fujiwara H

PROVIDER: S-EPMC6131147 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Microbial metabolite sensor GPR43 controls severity of experimental GVHD.

Fujiwara Hideaki H Docampo Melissa D MD Riwes Mary M Peltier Daniel D Toubai Tomomi T Henig Israel I Wu S Julia SJ Kim Stephanie S Taylor Austin A Brabbs Stuart S Liu Chen C Zajac Cynthia C Oravecz-Wilson Katherine K Sun Yaping Y Núñez Gabriel G Levine John E JE van den Brink Marcel R M MRM Ferrara James L M JLM Reddy Pavan P

Nature communications 20180910 1

Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versus-host disease (GVHD), but the molecular mechanisms remain unknown. Here we show the metabolite sensor G-protein-coupled receptor 43 (GPR43) is important for attenuation of gastrointestinal GVHD in multiple clinically relevant murine models. GPR43 is critical for the protective effects of short-chain fatty acids (SCFAs), butyrate and propionate. Increased severity of GVHD in the absence of GPR43 is not due to ...[more]

PMID: 30201970

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Dataset Information

Microbial metabolite sensor GPR43 controls severity of experimental GVHD.

Publications

Microbial metabolite sensor GPR43 controls severity of experimental GVHD.

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