The gut microbiota metabolite urolithin A inhibits NF-κB activation in LPS stimulated BMDMs

Inflammation is a natural defense process of the innate immune system, associated with the release of proinflammatory cytokines such as interleukin-1 beta, interleukin-6, interleukin-12 and TNF alpha; and enzymes including iNOS through the activation and nuclear translocation of NF-kappa B p65 due to the phosphorylation of I kappa B alpha. Regulation of intracellular Ca2+ is considered a promising strategy for the prevention of reactive oxygen species (ROS) production and accumulation of DNA double strand breaks (DSBs) that occurs in inflammatory-associated-diseases. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A (UA) has received an increasing attention as a novel candidate with anti-inflammatory and anti-oxidant effects. Here, we investigated the effect of UA on the suppression of pro-inflammatory molecules and NF-kappa B activation by targeting TLR4 signalling pathway. We also identified the influence of UA on Ca2+ entry, ROS production and DSBs availability in murine bone-marrow-derived macrophages challenged with lipopolysaccharides (LPS). We found that UA inhibits I kappa B alpha phosphorylation and supresses MAPK and PI3K activation. In addition, UA was able to reduce calcium entry, ROS production and DSBs availability. In conclusion, we suggest that urolithin A is a promising therapeutic agent for treating inflammatory diseases through suppression of NF-kappa B and preserving DNA through maintaining intracellular calcium and ROS homeostasis.

Automated summary

The research highlights that urolithin A (UA) shows promising therapeutic potential for treating inflammatory diseases by inhibiting pro-inflammatory molecules and NF-kappa B activation, as well as maintaining intracellular calcium and ROS homeostasis.