Toll-like receptor 1 as a possible target in non-alcoholic fatty liver disease

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.

Composition of gut microbiota and non‐alcoholic fatty liver disease: A systematic review and meta‐analysis

“…A total of 38 studies 11–21,33,35,36,38–41,44–46,48,49,51–53,56,58–62,64–66,68–71,74,75,78,79,82,84 provided data for α‐diversity (Table 1), which was then assessed using eight indices, namely richness/evenness (Shannon [ n = 37, 3186 cases, and 3990 controls]）, Chao1 [ n = 16, 1002 cases, and 1824 controls], Simpson [ n = 12, 488 cases, and 419 controls]), estimates of richness (observed species [ n = 10, 836 cases, and 813 controls], richness [ n = 7, 791 cases, and 1354 controls], faith phylogenetic diversity [PD, n = 6, 761 cases, and 1936 controls], evenness [Pielou, n = 6, 552 cases, and 185 controls]), and abundance coverage estimator (ACE; n = 4, 64 cases and 73 controls).…”

“…A total of 38 studies [11][12][13][14][15][16][17][18][19][20][21]33,35,36,[38][39][40][41][44][45][46]48,49,[51][52][53]56,[58][59][60][61][62][64][65][66][68][69][70][71]74,75,78,79,82,84 provided data for α-diversity (Table 1), which was then assessed using eight indices, namely richness/evenness (Shannon T A B L E 2 Total analysis, stratified analysis, and sensitivity analysis among alpha diversity.…”

Pattern recognition receptors in the development of nonalcoholic fatty liver disease and progression to hepatocellular carcinoma: An emerging therapeutic strategy

“…TLR1 deficiency displayed significantly protective effect from the development of diet-induced NAFLD when compared to that in wild-type mice. Moreover, TLR1 expression was positively correlated with the level of Holdemanella genus, and was negative associated with the content of Gemmiger and Ruminococcus genera in NAFLD patients ( 49 ). Thus, TLR1 may be acted as a potential target in the treatment of NAFLD patients along with TLR1 high expression.…”

Fuzi-Lizhong Decoction Alleviates Nonalcoholic Fatty Liver Disease by Blocking TLR4/MyD88/TRAF6 Signaling

“…Several studies have described a close association between NAFLD development and many pathogenic events such as activation of the innate immune system and hepatic macrophage recruitment, which cause changes in lipid homeostasis [ 9 , 10 ]. Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen-associated molecular patterns and allow the host to detect microbial infection [ 11 ]. TLRs may be involved in NAFLD by regulating innate and adaptive immune responses [ 12 ].…”