Abstract
Toll-like receptors (TLRs) in the liver compartment 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 and the impact of TLRs found altered in NAFLD development. 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 in 21 NAFLD patients and 9 controls using 16S rRNA gene amplicon sequencing. Furthermore, TLR1−/− and C57BL/6 mice (n = 5–6/group) were pair-fed a liquid control or a fat-, fructose- and cholesterol-rich diet. 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, were significantly positively correlated with the prevalence of Holdemanella genus while negative correlations were found with Gemmiger and Ruminococcus genera. TLR1−/− mice were significantly protected from the development of diet-induced NAFLD when compared to wild-type mice. 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.
Highlights
Toll-like receptors (TLRs) in the liver compartment have repeatedly been attributed to the development of non-alcoholic fatty liver disease (NAFLD)
NAFLD patients suffered from a hepatic steatosis ranging from mild to moderate
While results of epidemiological studies suggest that overweight and insulin resistance are the key risk factors for the development of NAFLD, results of clinical and experimental studies suggest that changes of intestinal microbiota composition and intestinal barrier function may contribute to disease onset and progression
Summary
Toll-like receptors (TLRs) in the liver compartment have repeatedly been attributed to the development of non-alcoholic fatty liver disease (NAFLD). We determined TLR expression patterns in peripheral blood mononuclear cells (PBMCs) of NAFLD patients and controls, their relation to intestinal microbiota and the impact of TLRs found altered in NAFLD development. While intestinal microbiota composition and permeability differed significantly between NAFLD patients and healthy subjects, in PBMCs, only TLR1 expression differed between groups. NAS NAFLD activity score NASH Non-alcoholic steatohepatitis OTUs Operational taxonomic units PAMP Pathogen-associated molecular pattern PAI-1 Plasminogen activator inhibitor 1 PBMCs Peripheral blood mononuclear cells PCoA Principal Coordinates Analysis RDA Redundance analysis TBARS Thiobarbituric acid reactive substances TIR Toll/interleukin-1 receptor TIRAP TIR domain containing adaptor protein TLRs Toll-like receptors Tnfα Tumor necrosis factor alpha TRAM TRIF-related adaptor molecule TRIF TIR-domain-containing adapter-inducing interferon β VCTE Vibration controlled transient elastography. As molecular mechanisms involved in the onset as well as the progression of the disease are still not fully understood, universally accepted strategies for prevention and therapy still mainly focus on life-style interventions, being often afflicted with low compliance and high relapse rates while drug-based therapies are still limited
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