Microbial metabolite sensor GPR43 controls severity of experimental GVHD

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

doi:10.1038/s41467-018-06048-w

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.

Highlights

Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versushost disease (GVHD), but the molecular mechanisms remain unknown
In this study we show that sensing of the microbiome derived short-chain fatty acids (SCFAs), butyrate, and propionate, by G-protein-coupled receptor 43 (GPR43) on intestinal epithelial cell (IEC) mitigates GVHD by activating NLRP3 inflammasome via extracellular signal-regulated kinase (ERK) phosphorylation
We first examined the expression of known SCFA receptors such as the Gprotein coupled receptors (GPRs) on IECs utilizing a wellcharacterized MHC disparate murine GVHD model (BALB/c → C57BL/6)

Summary

Introduction

Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versushost disease (GVHD), but the molecular mechanisms remain unknown. 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. 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 metabolitemediated protection of target tissues from the damage caused allogeneic T cells. Oral replacement of the SCFA butyrate ameliorated GVHD mortality and was associated with better intestinal epithelial cell (IEC) repair and homeostasis These data suggest that intestinal metabolites such as SCFA butyrate play a protective role in GVHD. In this study we show that sensing of the microbiome derived SCFAs, butyrate, and propionate, by GPR43 on IECs mitigates GVHD by activating NLRP3 inflammasome via ERK phosphorylation

Methods

Results

Conclusion