Microbial metabolites indole derivatives sensitize mice to D-GalN/LPS induced-acute liver failure via the Tlr2/NF-κB pathway

Abstract

IntroductionAcute liver failure (ALF) is a clinical condition with many causes, fast progression, and a poor prognosis. Previous research has indicated that microbial factors have a role in ALF, but a clear picture has yet to emerge.MethodsTo investigate the specific involvement of microbial metabolites in ALF development, we pretreated D-GalN/LPS-induced ALF mice with indole derivatives, an influential class of gut microbial metabolites.ResultsContrary to their typical role as anti-inflammatory agents in the host, indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indolepropionic acid (IPA) gavage sensitize mice to D-GalN/LPS-induced-ALF with a rapid rise in serum transaminases and histologic lesion. For a clearer picture, we performed comprehensive analysis for the IAA therapy. IAA markedly amplified inflammatory response and cellular damage. The transcriptome analysis indicated the participation of the TNF-α/NF-κB signaling pathway. The structure of gut microbiota in ileum and the expression of Toll-like receptor 2 (Tlr2) in the liver were also significantly changed.DiscussionIn conclusion, IAA pretreatment can exacerbate D-GalN/LPS-induced ALF via probable Tlr2/NF-κB pathway involvement and ileac dysbiosis characterized by enriched gram-positive genus with potential pathogenesis. Microbial metabolites IAA may aggravate individual susceptibility to D-GalN/LPS-induced ALF. Further investigation of the underlying mechanism is needed, and intervention with indole derivatives and related commensal species should be undertaken with caution.

Polygonatum kingianum Polysaccharides Enhance the Preventive Efficacy of Heat-Inactivated Limosilactobacillus reuteri WX-94 against High-Fat-High-Sucrose-Induced Liver Injury and Gut Dysbacteriosis

“…In addition, the important roles of indole derivatives, indole-3-carbinol, and indole-lactic acid predominately produced by L. reuteri in liver protection have consistently been demonstrated, possibly via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, in agreement with our findings. ,,− …”

Calycosin inhibits hepatocyte apoptosis in acute liver failure by suppressing the TLR4/NF‐κB pathway: An in vitro study

“…Recent studies have found that TLRs play an important role in inflammation and are closely related to clinical inflammatory diseases 46,47 . The key role of TLRs in liver failure has been studied 48,49 . TLR4 has been reported to be a therapeutic target for prevention and treatment of liver failure 50,51 .…”

“… 46 , 47 The key role of TLRs in liver failure has been studied. 48 , 49 TLR4 has been reported to be a therapeutic target for prevention and treatment of liver failure. 50 , 51 In addition, studies have shown that TLR4 plays a key role in activating innate immunity by directly recognizing LPS.…”