O23 Toll-like receptor 5 signalling mediates pro-inflammatory and fibrogenic responses in non-alcoholic steatohepatitis (NASH)

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Introduction Non-alcoholic steatohepatitis (NASH) is a common, progressive inflammatory liver condition with no approved therapies. Hepatocyte lipotoxicity results in inflammation, immune (T cell) infiltration and stellate cell activation leading to fibrosis. Hepatic Toll-like receptors (TLR) sense gut-derived inflammatory signals such as lipopolysaccharide (via TLR4) and flagellin (TLR5) and may represent therapeutic targets in NASH. Flagellin and TLR5 have been implicated in murine NASH models and here we test the hypothesis that this pathway plays a pathogenic role in human disease. Methods Plasma TLR5 binding capacity and flagellin, stool Flic gene load (shotgun metagenomics sequencing) and hepatic TLR5 gene expression were measured in samples from 139 patients and 24 controls recruited from outpatient clinics and elective bariatric surgery. Lipotoxicity was modelled in vitro using oleic (1mM) and palmitic (0.5mM) acid in human hepatocyte-like (HepG2) and stellate (LX2) cells. Results Compared to controls, plasma TLR5-binding capacity was increased in advanced NASH fibrosis but not earlier stages of disease (TLR4-binding increased at all disease stages) as was flagellin concentration (538.3v 745.8pg/ml,p=0.004) which normalised in samples taken median 83 days following bariatric surgery (n=20, p=0.005). Stool Flic gene expression and hepatic TLR5 (but not TLR2 or TLR4) expression were increased in NASH, along with markers of intestinal permeability (FABP2, D-lactate). In vitro, TLR5 inhibition attenuated toxic lipid-mediated IL8 protein expression (all p<0.001, vs control) in HepG2. TLR5 inhibition also attenuated both flagellin- and toxic lipid-induced IL8 production in LX2 cells by 1.9-fold (p=0.019) and 2.1-fold (p=0.032) respectively. Although neither flagellin nor toxic lipids directly induced pro-collagen 1a1 production in LX2 cells, lipid-injured HepG2-conditioned media induced 3.2-fold increase in pro-collagen 1a1 production compared to control (p=0.0015). TLR5 inhibition in HepG2 cells prior to media transfer led to a reduction in LX2 pro-collagen 1a1 production (p=0.030). Similarly, lipid-injured HepG2-conditioned media induced Th1 differentiation of naïve T cells from healthy donors in a TLR5-dependent manner (p<0.001). Conclusions TLR5 signalling is activated in human NASH, reverses following bariatric surgery and is associated with mechanisms of lipid-mediated inflammation and stellate cell activation. This pathway has potential as a novel therapeutic target in NASH.

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