Host microbiota dictates the proinflammatory impact of LPS in the murine liver

Su Suriguga,Theerut Luangmonkong,Henricus A.M Mutsaers,Geny M.M Groothuis,Peter Olinga

doi:10.1016/j.tiv.2020.104920

Su Suriguga, Theerut Luangmonkong + Show 3 more

Open Access

https://doi.org/10.1016/j.tiv.2020.104920

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Abstract

Gut microbiota can impact liver disease development via the gut-liver axis. Liver inflammation is a shared pathological event in various liver diseases and gut microbiota might influence this pathological process. In this study, we studied the influence of gut microbiota on the inflammatory response of the liver to lipopolysaccharide (LPS). The inflammatory response to LPS (1–10 μg/ml) of livers of specific-pathogen-free (SPF) or germ-free (GF) mice was evaluated ex vivo, using precision-cut liver slices (PCLS). LPS induced a more pronounced inflammatory response in GF PCLS than in SPF PCLS. Baseline TNF-α gene expression was significantly higher in GF slices as compared to SPF slices. LPS treatment induced TNF-α, IL-1β, IL-6 and iNOS expression in both SPF and GF PCLS, but the increase was more intense in GF slices. The anti-inflammatory markers SOCS3 and IRAK-M gene expression was significantly higher in GF PCLS than SPF PCLS at 24h with 1 µg/ml LPS treatment, and IL-10 was not differently expressed in GF PCLS than SPF PCLS. In addition, TLR-4 mRNA, but not protein, at basal level was higher in GF slices than in SPF slices. Taken together, this study shows that, in mice, the host microbiota attenuates the pro-inflammatory impact of LPS in the liver, indicating a positive role of the gut microbiota on the immune homeostasis of the liver.

Highlights

Inflammation of the liver, can be caused by alcohol abuse, viral infections and the metabolic syndrome, and the gut-liver axis is widely implicated in disease progression (Seki and Schwabe, 2015)
pathogen-associated molecular patterns (PAMPs) are recognized by pattern recognition receptors (PRRs), which are responsible for sensing invading pathogens and orchestrating the innate immune response (Arrese et al, 2016; Takeuchi and Akira, 2010)
The aim of this study is to investigate the influence of the gut microbiota on the inflammatory response of the liver to LPS

Summary

Introduction

Inflammation of the liver, can be caused by alcohol abuse, viral infections and the metabolic syndrome, and the gut-liver axis is widely implicated in disease progression (Seki and Schwabe, 2015). Blood from the gut can reach the liver via the hepatic portal vein carrying with it microbiota-derived exogenous molecules (for example, lipopolysaccharide and lipoteichoic acid), known as pathogen-associated molecular patterns (PAMPs) (Chassaing et al, 2014). PAMPs are recognized by pattern recognition receptors (PRRs), which are responsible for sensing invading pathogens and orchestrating the innate immune response (Arrese et al, 2016; Takeuchi and Akira, 2010). 10 have been identified in human and 13 in mouse (West et al, 2006). Among these TLRs, TLR-4 has attracted particular interest in terms of hepatic inflammation and fibrogenesis due to its ligand, LPS, which is involved in the development of various liver diseases (Su, 2002). TLR-4 is expressed in almost every type of liver cell, including hepatocytes, Kupffer cells, hepatic stellate cells, biliary epithelial cells and sinusoidal endothelial cells (Kesar and Odin, 2014)

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