Microbial metabolite sensor GPR43 controls severity of experimental GVHD

Hideaki Fujiwara, Melissa D. Docampo, Mary Riwes, Daniel Peltier, Tomomi Toubai, Israel Henig, S. Julia Wu, Stephanie Kim, Austin Taylor, Stuart Brabbs, Chen Liu, Cynthia Zajac, Katherine Oravecz-Wilson, Yaping Sun, Gabriel Núñez, John E. Levine, Marcel R.M. van den Brink, James L.M. Ferrara, Pavan Reddy

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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.

Original languageEnglish
Article number3674
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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