TY - JOUR
T1 - Microbial metabolite sensor GPR43 controls severity of experimental GVHD
AU - Fujiwara, Hideaki
AU - Docampo, Melissa D.
AU - Riwes, Mary
AU - Peltier, Daniel
AU - Toubai, Tomomi
AU - Henig, Israel
AU - Wu, S. Julia
AU - Kim, Stephanie
AU - Taylor, Austin
AU - Brabbs, Stuart
AU - Liu, Chen
AU - Zajac, Cynthia
AU - Oravecz-Wilson, Katherine
AU - Sun, Yaping
AU - Núñez, Gabriel
AU - Levine, John E.
AU - van den Brink, Marcel R.M.
AU - Ferrara, James L.M.
AU - Reddy, Pavan
N1 - Funding Information:
This work was supported by the US National Institutes of Health grants HL090775, CA173878, CA203542 (P.R.), CA-039542 (J.L.M.F.) and JSPS Postdoctoral Fellowships for Research Abroad (H.F.) and The YASUDA Medical Foundation Grants for Research Abroad (H.F.). We acknowledge use of the Microscopy & Image-analysis Laboratory (MIL) of the University of Michigan’s Biomedical Research Core Facilities for preparation of samples and images. Support for the MIL core is provided by the University of Michigan Cancer Center (NIH grant CA46592). This research was supported by work performed by The University of Michigan Microbial Systems Molecular Biology Laboratory.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06048-w
DO - 10.1038/s41467-018-06048-w
M3 - Article
C2 - 30201970
AN - SCOPUS:85053208491
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3674
ER -