The gut microbiota metabolite urolithin A inhibits NF-\u03baB activation in LPS stimulated BMDMs

Khalid N M Abdelazeem,Florian Lang,Sandra Beer-Hammer,M Zaher Kalo

doi:10.1038/s41598-021-86514-6

Khalid N M Abdelazeem, Florian Lang + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-86514-6

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Abstract

Inflammation is a natural defense process of the innate immune system, associated with the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-12 and TNFα; and enzymes including iNOS through the activation and nuclear translocation of NF-κB p65 due to the phosphorylation of IκBα. 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-κB 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 IκBα 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-κB and preserving DNA through maintaining intracellular calcium and ROS homeostasis.

Highlights

Antibiotic exposure in early life can lead to long-term alterations in the diversity, composition, and metagenomics content of the gut microbiota that may contribute to later onset of inflammatory bowel disease (IBD)[1,2]
The obtained results reveal a powerful anti-inflammatory effect of the gut microbiota urolithin A (UA), which is paralleled by suppression of MAPK and PI3K activation and impairment of IkBα phosphorylation as well as quenched production of pro-inflammatory miRNA, cytokines and mediators in LPS-stimulated bone marrow–derived macrophages (BMDMs) (Fig. 8)
Activation of TLR4-dependent signalling processes in macrophages was estimated with different methods, especially IκBα degradation and nuclear factor-κB (NF-κB) phosphorylation and nuclear translocation followed by a series of intracellular signaling pathways, which leads to the transcription/translation of inflammatory cytokines[44]

Summary

Introduction

Antibiotic exposure in early life can lead to long-term alterations in the diversity, composition, and metagenomics content of the gut microbiota that may contribute to later onset of inflammatory bowel disease (IBD)[1,2]. NF-kB is a key regulator and important player in linking inflammation to cancer development through its ability to upregulate various inflammatory molecules such as IL-1β, IL-6 and TNFα. It is a matchmaker between inflammation, IBD, cancer and d iabetes[7,8]. The bioavailability of ellagitannins and ellagic acid is very low They need further digestion by gut microbiota to produce bioactive molecules including urolithin compounds that can be absorbed[14,17,18]. Butyrate induces Treg cell differentiation in the gut mucosa, which reduces intestinal inflammation via secretion of anti-inflammatory cytokines such as IL-1021,22. It has been conventionally used to mimic the real infection triggering the release of inflammatory cytokines such as IL-1β, IL-6 or TNFα through activation of TLR4 s ignalling[26]

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