A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout

Angelica T Vieira, Laurence Macia, Izabela Galvao, Flaviano S Martins, Maria C C Canesso, Flavio A Amaral, Cristiana C O Garcia, Kendle M Maslowski, Ellen De Leon, Doris S C Shim, Jacques R Nicoli, Jacquie L Harper, Mauro M Teixeira, Charles R Mackay

    Research output: Contribution to journalArticleResearchpeer-review

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    Abstract

    OBJECTIVE: Host-microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin-1beta (IL-1beta) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite-sensing receptor GPR43 in regulating inflammation in a murine model of gout. METHODS: Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). RESULTS: Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL-1beta and CXCL1. These parameters were greatly decreased in germ-free mice, mice treated with antibiotics, and GPR-43-deficient mice. Recolonization or administration of acetate to germ-free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ-free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR-43-deficient mice. Treatment of germ-free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. CONCLUSION: In the absence of microbiota, there is decreased production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1beta production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host s ability to respond to an inflammasome-dependent acute inflammatory stimulus outside the gut.
    Original languageEnglish
    Pages (from-to)1646 - 1656
    Number of pages11
    JournalArthritis and Rheumatology
    Volume67
    Issue number6
    DOIs
    Publication statusPublished - 2015

    Cite this

    Vieira, A. T., Macia, L., Galvao, I., Martins, F. S., Canesso, M. C. C., Amaral, F. A., ... Mackay, C. R. (2015). A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis and Rheumatology, 67(6), 1646 - 1656. https://doi.org/10.1002/art.39107
    Vieira, Angelica T ; Macia, Laurence ; Galvao, Izabela ; Martins, Flaviano S ; Canesso, Maria C C ; Amaral, Flavio A ; Garcia, Cristiana C O ; Maslowski, Kendle M ; De Leon, Ellen ; Shim, Doris S C ; Nicoli, Jacques R ; Harper, Jacquie L ; Teixeira, Mauro M ; Mackay, Charles R. / A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. In: Arthritis and Rheumatology. 2015 ; Vol. 67, No. 6. pp. 1646 - 1656.
    @article{830281d88c2f40c48ec76bb8ef0efe71,
    title = "A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout",
    abstract = "OBJECTIVE: Host-microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin-1beta (IL-1beta) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite-sensing receptor GPR43 in regulating inflammation in a murine model of gout. METHODS: Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). RESULTS: Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL-1beta and CXCL1. These parameters were greatly decreased in germ-free mice, mice treated with antibiotics, and GPR-43-deficient mice. Recolonization or administration of acetate to germ-free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ-free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR-43-deficient mice. Treatment of germ-free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. CONCLUSION: In the absence of microbiota, there is decreased production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1beta production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host s ability to respond to an inflammasome-dependent acute inflammatory stimulus outside the gut.",
    author = "Vieira, {Angelica T} and Laurence Macia and Izabela Galvao and Martins, {Flaviano S} and Canesso, {Maria C C} and Amaral, {Flavio A} and Garcia, {Cristiana C O} and Maslowski, {Kendle M} and {De Leon}, Ellen and Shim, {Doris S C} and Nicoli, {Jacques R} and Harper, {Jacquie L} and Teixeira, {Mauro M} and Mackay, {Charles R}",
    year = "2015",
    doi = "10.1002/art.39107",
    language = "English",
    volume = "67",
    pages = "1646 -- 1656",
    journal = "Arthritis and Rheumatology",
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    Vieira, AT, Macia, L, Galvao, I, Martins, FS, Canesso, MCC, Amaral, FA, Garcia, CCO, Maslowski, KM, De Leon, E, Shim, DSC, Nicoli, JR, Harper, JL, Teixeira, MM & Mackay, CR 2015, 'A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout', Arthritis and Rheumatology, vol. 67, no. 6, pp. 1646 - 1656. https://doi.org/10.1002/art.39107

    A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. / Vieira, Angelica T; Macia, Laurence; Galvao, Izabela; Martins, Flaviano S; Canesso, Maria C C; Amaral, Flavio A; Garcia, Cristiana C O; Maslowski, Kendle M; De Leon, Ellen; Shim, Doris S C; Nicoli, Jacques R; Harper, Jacquie L; Teixeira, Mauro M; Mackay, Charles R.

    In: Arthritis and Rheumatology, Vol. 67, No. 6, 2015, p. 1646 - 1656.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout

    AU - Vieira, Angelica T

    AU - Macia, Laurence

    AU - Galvao, Izabela

    AU - Martins, Flaviano S

    AU - Canesso, Maria C C

    AU - Amaral, Flavio A

    AU - Garcia, Cristiana C O

    AU - Maslowski, Kendle M

    AU - De Leon, Ellen

    AU - Shim, Doris S C

    AU - Nicoli, Jacques R

    AU - Harper, Jacquie L

    AU - Teixeira, Mauro M

    AU - Mackay, Charles R

    PY - 2015

    Y1 - 2015

    N2 - OBJECTIVE: Host-microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin-1beta (IL-1beta) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite-sensing receptor GPR43 in regulating inflammation in a murine model of gout. METHODS: Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). RESULTS: Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL-1beta and CXCL1. These parameters were greatly decreased in germ-free mice, mice treated with antibiotics, and GPR-43-deficient mice. Recolonization or administration of acetate to germ-free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ-free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR-43-deficient mice. Treatment of germ-free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. CONCLUSION: In the absence of microbiota, there is decreased production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1beta production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host s ability to respond to an inflammasome-dependent acute inflammatory stimulus outside the gut.

    AB - OBJECTIVE: Host-microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin-1beta (IL-1beta) production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite-sensing receptor GPR43 in regulating inflammation in a murine model of gout. METHODS: Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS). RESULTS: Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL-1beta and CXCL1. These parameters were greatly decreased in germ-free mice, mice treated with antibiotics, and GPR-43-deficient mice. Recolonization or administration of acetate to germ-free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ-free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR-43-deficient mice. Treatment of germ-free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals. CONCLUSION: In the absence of microbiota, there is decreased production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1beta production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host s ability to respond to an inflammasome-dependent acute inflammatory stimulus outside the gut.

    UR - http://onlinelibrary.wiley.com/doi/10.1002/art.39107/epdf

    U2 - 10.1002/art.39107

    DO - 10.1002/art.39107

    M3 - Article

    VL - 67

    SP - 1646

    EP - 1656

    JO - Arthritis and Rheumatology

    JF - Arthritis and Rheumatology

    SN - 2326-5191

    IS - 6

    ER -