Journal Article

Microbial metabolite sensor GPR43 controls severity of experimental GVHD

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

2018

Overview

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. The microbial metabolite sensor GPR43 has been previously shown to be a crucial modulator of immune responses. Here the authors show GPR43 is required for controlling disease pathology severity in the context of experimental models of GVHD.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/21 / 13/31 / 631/250/1854 / 631/250/1904 / 631/250/249/1529 / 631/250/2520 / 64/60 / 82/1 / 96/1 / 96/106 / 96/31 / Animal models / Animals / Antibiotics / Attenuation / Bone Marrow Transplantation / Butyrates - metabolism / Extracellular Signal-Regulated MAP Kinases - metabolism / Fatty acids / Fatty Acids, Volatile - metabolism / Female / G protein-coupled receptors / Gastrointestinal Microbiome / Gene Expression Profiling / Gene Expression Regulation / Graft vs Host Disease - genetics / Graft vs Host Disease - metabolism / Graft-versus-host reaction / Homeostasis / Housing / Humanities and Social Sciences / Immunophenotyping / Inflammasomes / Inflammasomes - metabolism / Intestine / Intestines - microbiology / Lymphocyte Culture Test, Mixed / Lymphocytes / Lymphocytes T / Metabolites / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Microbiomes / Microbiota / Microorganisms / Molecular modelling / multidisciplinary / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Phosphorylation / Propionic acid / Proteins / Receptors, G-Protein-Coupled - metabolism / RNA, Ribosomal, 16S - metabolism / Science / Science (multidisciplinary) / T-Lymphocytes - immunology