A role for the gut microbiota and the metabolite sensing receptor GPR43 in a murine model of gout
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.
|Authors||Vieira, A. T. ; Macia, L. ; Galvao, I. ; Martins, F. S. ; Canesso, M. C. ; Amaral, F. A. ; Garcia, C. C. ; Maslowski, K. M. ; De Leon, E. ; Shim, D. ; Nicoli, J. R. ; Harper, J. L. ; Teixeira, M. M. ; Mackay, C. R.;|
|Publisher Name||Arthritis & Rheumatology|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25914377|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13340|