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Published on: May 2, 2018
Microbial metabolites indole derivatives sensitize mice to D-GalN/LPS induced-acute liver failure via the Tlr2/NF-κB
Ziyuan Zhou1, Baohong Wang1, Xiaxia Pan1
1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Introduction:
Acute 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.
Methods:
To 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.
Results:
Contrary 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.
Discussion:
In 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.
Insights
Gut microbial metabolites like indole-3-acetic acid (IAA) can worsen acute liver failure (ALF) in mice. This study found IAA exacerbates liver injury and inflammation, suggesting caution with indole derivative interventions.
Area of Science:
- Microbiology
- Hepatology
- Immunology
Background:
- Acute liver failure (ALF) is a severe condition with high mortality.
- Gut microbial metabolites are implicated in ALF, but their specific roles are unclear.
Purpose of the Study:
- To investigate the role of indole derivatives, a class of gut microbial metabolites, in the development of D-GalN/LPS-induced ALF.
- To elucidate the mechanisms by which indole derivatives influence ALF progression.
Main Methods:
- Mice were pretreated with indole derivatives (IAA, ILA, IPA) before D-GalN/LPS induction of ALF.
- Comprehensive analyses included serum transaminase levels, liver histology, transcriptome analysis, gut microbiota profiling, and TLR2 expression.
- Specific focus on indole-3-acetic acid (IAA) effects.
Main Results:
- Contrary to expectations, IAA, ILA, and IPA exacerbated D-GalN/LPS-induced ALF, causing increased serum transaminases and liver damage.
- IAA significantly amplified inflammatory responses and cellular damage, with transcriptome analysis pointing to TNF-α/NF-κB signaling.
- Ileal microbiota structure and hepatic Toll-like receptor 2 (Tlr2) expression were significantly altered.
Conclusions:
- Indole-3-acetic acid (IAA) pretreatment exacerbates D-GalN/LPS-induced ALF, likely through Tlr2/NF-κB pathway activation and ileal dysbiosis.
- Gut microbial metabolite IAA may increase susceptibility to ALF, highlighting the need for caution with indole derivative interventions.
- Further research is required to fully understand the mechanisms, and interventions involving indole derivatives and commensal species warrant careful consideration.
