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

• Published in: Frontiers in microbiology 2023-01, Vol.13, p.1103998-1103998
• Main Authors: Zhou, Ziyuan, Wang, Baohong, Pan, Xiaxia, Lv, Jiawen, Lou, Zhuoqi, Han, Yuqiu, Yao, Yuanyuan, Chen, Jun, Wang, Qiangqiang, Li, Lanjuan
• Format: Article
• Language: English
• Subjects: acute liver failure; gut microbiota; indole derivatives; microbial metabolites; Microbiology; NF-κB; toll-like receptor 2
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2022.1103998

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. 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. 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. 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.