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A Role for Gut Microbiota and the Metabolite‐Sensing Receptor GPR43 in a Murine Model of Gout
Author(s) -
Vieira Angélica T.,
Macia Laurence,
Galvão Izabela,
Martins Flaviano S.,
Canesso Maria Cecília C.,
Amaral Flávio A.,
Garcia Cristiana C.,
Maslowski Kendle M.,
De Leon Ellen,
Shim Doris,
Nicoli Jacques R.,
Harper Jacquie L.,
Teixeira Mauro M.,
Mackay Charles R.
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39107
Subject(s) - inflammasome , inflammation , chemistry , reactive oxygen species , lipopolysaccharide , immunology , biology , biochemistry
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‐1β (IL‐1β) 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‐1β 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‐1β 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.