Toll-like receptor 1: a target in non-alcoholic fatty liver disease?

Objective Toll-like receptors (TLRs) in liver have repeatedly been attributed to the development of non-alcoholic fatty liver disease (NAFLD). Knowledge on TLR expression in blood cells and their relation to intestinal microbiota and NAFLD development is limited. Here, we determined TLR expression patterns in peripheral blood mononuclear cells (PBMCs) of NAFLD patients and controls, their relation to intestinal microbiota composition and the impact of TLRs found altered in NAFLD development. Design Markers of intestinal permeability in blood and TLR mRNA expression in PBMCs were determined in 37 NAFLD patients and 15 age-matched healthy controls. Fecal microbiota composition was evaluated using 16S rRNA gene amplicon sequencing. In addition, TLR1-/- and C57BL/6 mice (n=6-8/group) were pair-fed a liquid control or fat-, fructose- and cholesterol-rich diet. Results Intestinal microbiota composition and markers of intestinal permeability like zonulin and bacterial endotoxin differed significantly between groups with the latter markers being significantly higher in NAFLD patients. Expression of TLR1-8 and 10 mRNA was detectable in PBMCs; however, only TLR1 expression, being higher in NAFLD patients, differed between groups being significantly positively correlated with the prevalence of Holdemanella genus while negative correlations were found with Gemmiger and Ruminococcus genera. TLR1-/- mice were significant protected from the development of diet-induced NAFLD when compared to wild-type mice. Conclusion In conclusion, while intestinal microbiota composition and permeability differed significantly between NAFLD patients and healthy subjects, in PBMCs only TLR1 expression differed between groups. Still, targeting these alterations might be a beneficial approach in the treatment of NAFLD in some patients.