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. Brink, James L. M. Ferrara and Pavan Reddy ()
Additional contact information
Hideaki Fujiwara: University of Michigan Comprehensive Cancer Center
Melissa D. Docampo: Memorial Sloan Kettering Cancer Center
Mary Riwes: University of Michigan Comprehensive Cancer Center
Daniel Peltier: University of Michigan
Tomomi Toubai: University of Michigan Comprehensive Cancer Center
Israel Henig: University of Michigan Comprehensive Cancer Center
S. Julia Wu: University of Michigan Comprehensive Cancer Center
Stephanie Kim: University of Michigan Comprehensive Cancer Center
Austin Taylor: University of Michigan Comprehensive Cancer Center
Stuart Brabbs: University of Michigan Comprehensive Cancer Center
Chen Liu: Rutgers-Robert Wood Johnson Medical School
Cynthia Zajac: University of Michigan Comprehensive Cancer Center
Katherine Oravecz-Wilson: University of Michigan Comprehensive Cancer Center
Yaping Sun: University of Michigan Comprehensive Cancer Center
Gabriel Núñez: University of Michigan Medical School
John E. Levine: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai
Marcel R.M. Brink: Memorial Sloan Kettering Cancer Center
James L. M. Ferrara: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai
Pavan Reddy: University of Michigan Comprehensive Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06048-w

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