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

doi:10.1038/s41467-018-06048-w

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

University Hospital

Research output: Contribution to journal › Article › peer-review

28 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 language	English
Article number	3674
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06048-w
Publication status	Published - Dec 1 2018

ASJC Scopus subject areas

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

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Fujiwara, H., Docampo, M. D., Riwes, M., Peltier, D., Toubai, T., Henig, I., Wu, S. J., Kim, S., Taylor, A., Brabbs, S., Liu, C., Zajac, C., Oravecz-Wilson, K., Sun, Y., Núñez, G., Levine, J. E., van den Brink, M. R. M., Ferrara, J. L. M., & Reddy, P. (2018). Microbial metabolite sensor GPR43 controls severity of experimental GVHD. Nature communications, 9(1), [3674]. https://doi.org/10.1038/s41467-018-06048-w

Microbial metabolite sensor GPR43 controls severity of experimental GVHD. / Fujiwara, Hideaki; Docampo, Melissa D.; Riwes, Mary; Peltier, Daniel; Toubai, Tomomi; Henig, Israel; Wu, S. Julia; Kim, Stephanie; Taylor, Austin; Brabbs, Stuart; Liu, Chen; Zajac, Cynthia; Oravecz-Wilson, Katherine; Sun, Yaping; Núñez, Gabriel; Levine, John E.; van den Brink, Marcel R.M.; Ferrara, James L.M.; Reddy, Pavan.

In: Nature communications, Vol. 9, No. 1, 3674, 01.12.2018.

Research output: Contribution to journal › Article › peer-review

Fujiwara, H, Docampo, MD, Riwes, M, Peltier, D, Toubai, T, Henig, I, Wu, SJ, Kim, S, Taylor, A, Brabbs, S, Liu, C, Zajac, C, Oravecz-Wilson, K, Sun, Y, Núñez, G, Levine, JE, van den Brink, MRM, Ferrara, JLM & Reddy, P 2018, 'Microbial metabolite sensor GPR43 controls severity of experimental GVHD', Nature communications, vol. 9, no. 1, 3674. https://doi.org/10.1038/s41467-018-06048-w

Fujiwara, Hideaki ; Docampo, Melissa D. ; Riwes, Mary ; Peltier, Daniel ; Toubai, Tomomi ; Henig, Israel ; Wu, S. Julia ; Kim, Stephanie ; Taylor, Austin ; Brabbs, Stuart ; Liu, Chen ; Zajac, Cynthia ; Oravecz-Wilson, Katherine ; Sun, Yaping ; Núñez, Gabriel ; Levine, John E. ; van den Brink, Marcel R.M. ; Ferrara, James L.M. ; Reddy, Pavan. / Microbial metabolite sensor GPR43 controls severity of experimental GVHD. In: Nature communications. 2018 ; Vol. 9, No. 1.

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title = "Microbial metabolite sensor GPR43 controls severity of experimental GVHD",

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.",

author = "Hideaki Fujiwara and Docampo, {Melissa D.} and Mary Riwes and Daniel Peltier and Tomomi Toubai and Israel Henig and Wu, {S. Julia} and Stephanie Kim and Austin Taylor and Stuart Brabbs and Chen Liu and Cynthia Zajac and Katherine Oravecz-Wilson and Yaping Sun and Gabriel N{\'u}{\~n}ez and Levine, {John E.} and {van den Brink}, {Marcel R.M.} and Ferrara, {James L.M.} and Pavan Reddy",

note = "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{\textquoteright}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.",

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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.

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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.

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