Spermidine reproduces the anti‐inflammatory effects of intermittent fasting and prevents urate and calcium pyrophosphate crystal‐induced inflammation

BackgroundGout due to the formation of monosodium urate (MSU) crystals and calcium pyrophosphate (CPP) deposition disease are two major types of microcrystalline pathologies in adults. They are responsible for recurrent flares that rely on interleukin (IL)‐1β via activation of the NLRP3 inflammasome. Intermittent fasting (IF) is a non‐pharmacological intervention that improves age‐related diseases and reduces inflammation.MethodsIn air pouch model, crystal‐induced inflammation was compared between mice fed ad libitum and mice under IF. Systemic (liver and serum) and local (air pouch cavity) modifications were evaluated by metabolomics analysis. The anti‐inflammatory potential of metabolites was tested in vitro and in vivo.Resultswe observe that 2 non‐consecutive days of fasting during one week significantly prevents the inflammation provoked by MSU and CPP crystal injection into air pouch cavity in mouse model. This short‐term fasting is associated with increased serum abundances of numerous anti‐inflammatory metabolites, including β‐hydroxybutyrate and spermidine (SPD), a polyamine able to reproduce biological effects of IF. Conversely, crystal stimulation in ad libitum fed mice decreases the local production of these metabolites in the air pouch membrane. Supplementation of SPD reproduces the anti‐inflammatory effect of IF and prevents crystal‐induced inflammation through inhibition of NF‐κB and NLRP3 inflammasome. Finally, downregulation of SAT1 (spermidine/spermine acetyltransferase 1), which encodes the enzyme that degrades SPD, reduces IL‐1β production induced by crystal stimulation.ConclusionIn summary, we have identified several metabolites that recapitulate the anti‐inflammatory effects of IF and could be used as IF mimetics to prevent microcrystal inflammation.image