Betaine ameliorates intestinal injury by targeting the LPS/TLR4/MyD88 pathway and microbial communities of intestinal tract in acute liver failure

Abstract

Background: A growing body of evidence revealed that the gut microbiome has a marked impact in acute liver failure (ALF). Microbes and their products will translocate into enterocoelia and enter into circulation system from the damaged intestinal lumen. It will further aggravate liver injury by enhancing the spread of inflammation, tissue damage and sepsis. Betaine is a hepatoprotective drug which has anti-inflammatory and anti-oxidant effects. Here, we evaluated the impact of betaine on gut microbiota composition in ALF animal experiment. The potential protective effect of betaine by inhibiting Toll-like receptor 4 (TLR4) responses was explored as well.Results: Eighteen mice were randomly divided into normal, model, and betaine groups. The ALF-induced intestinal epithelial barrier disruption internal models were induced by D-galactosamine（D-Gal）and lpopolysaccharide (LPS). Betaine was administered intragastrically 1 week before exposure of D-Gal/LPS. LPS were solely applied with a rat small intestinal cell line IEC-18 to establish ALF-induced intestinal epithelial barrier disruption external model. Mice in the model group developed severe intestinal epithelial tissue injury than normal group, increased significantly in the protein levels of TLR4, MyD88, TRAF6 and TNF-a and the mRNA levels of TLR4 and MyD88, and decreased significantly in the protein and mRNA levels of (ZO)-1 and occludin. Whereas, all above indicators were improved significantly by administration of betaine than that in model. The degree of liver tissue pathological damage, liver function and serum inflammatory cytokines in betaine group were significantly reduced than that in model group. The permeability of mice intestinal epithelial and IEC-18 cell in models was improved in betaine group than models. A total of 509 Operational Taxonomic Units (OTUs) were produced from mice fecal samples according to 16s rRNA gene sequence analysis. There were 156 core microbiomes in fecal samples. There existed a total of 24 species contained 11 species at the genus level which had a significant difference between groups. The increased relative abundance of g-Enterorhabdus in the model group was detected compared with normal group. Betaine down-regulated the relative abundance of g-Enterorhabdus in model. The relative abundance of g-Bacteroides was the highest in normal group and the least in model group. The relative abundance of g-Prevotella was almost identical in normal and betaine group, and it was decreased in model group.Conclusion: Betaine effectively improved the intestinal mucosal barrier in acute liver failure. The mechanism was probably related to inhibit the LPS/TLR4/MyD88 signaling pathways, improved the intestinal mucosal barrier and then maintained the gut microbiota composition.