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‐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.

The Pharmacology and Function of Receptors for Short-Chain Fatty Acids

“…C4 inhibits ROS production in neutrophils stimulated with N-formylmethionyl-leucylphenylalanine via cAMP, and a PTX-sensitive release of G protein G bg complex. Conversely, C2 increases ROS production in a PTX-insensitive manner (Vinolo et al, 2009), and macrophages lacking FFA2 do not produce ROS in a model of gouty arthritis (Vieira et al, 2015). This may reflect opposing signaling via FFA2 and Ga q/11 and FFA3 and Ga i/o .…”

Complex Pharmacology of Free Fatty Acid Receptors

“…Once again, the effects of raising the mice GF were reversed by exogenous administration of SCFAs. 278 Finally, GF mice have also been used to link the gut microbiota to the function of FFA2 in adipose tissue, where in one study FFA2 −/− mice were found to be obese compared to wild-type mice when raised under conventional conditions but were not different from wild type when raised GF. 263 A number of studies have also assessed the function of FFA3 using similar approaches.…”

How the microbiota shapes rheumatic diseases

“…Monosodium urate monohydrate crystals cause gout by activating the NLRP3 inflammasome, which leads to IL-1β production and neutrophil recruitment. In germ-free mice, the production of shortchain fatty acids that are necessary for adequate inflammasome assembly and IL-1β production is decreased 85 . This effect depends on the metabolite-sensing receptor free fatty acid receptor 2 (also known as G-protein coupled receptor 43) 85 .…”

“…In germ-free mice, the production of shortchain fatty acids that are necessary for adequate inflammasome assembly and IL-1β production is decreased 85 . This effect depends on the metabolite-sensing receptor free fatty acid receptor 2 (also known as G-protein coupled receptor 43) 85 . Overall, observations in some experimental models of arthritis show that microbial triggers by commensal bacteria are required to promote disease in genetically predisposed animals.…”