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Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice
Zhuoen He1,2, Yunong Zeng2, Shuyu Li2
1Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Background And Aims:
Drug-induced liver injury (DILI) is a common cause of acute liver failure and represents a significant global public health problem. When discussing the gut-liver axis, although a great deal of research has focused on the role of gut microbiota in regulating the progression of DILI, the gut commensal fungal component has not yet been functionally identified.
Methods:
Mice were pretreated with fluconazole (FC) to deplete the gut commensal fungi and were then subject to acetaminophen (APAP) gavage. In addition, transcriptome sequencing was performed to identify differentially expressed genes (DEGs) between control and fluconazole-pretreated groups of the mice challenged with APAP.
Results:
Gut commensal fungi ablation through fluconazole pretreatment predisposed mice to APAP-induced hepatotoxicity, characterized by elevated serum liver enzyme levels and more severe centrilobular necrosis, which appears to be caused by robust inflammation and oxidative stress. The 16S rDNA sequencing results indicated that Akkermansia muciniphila abundance had significantly decreased in gut fungi-depleted mice, whereas increased abundance of Helicobacter rodentium was observed. The gene interaction network between DEGs identified by the transcriptome sequencing highlighted a significant enrichment of Cyp2a5 in the liver of APAP-treated mice that were preadministrated with fluconazole. Pharmacological inhibition of Cyp2a5 by 8-methoxypsoralen (8-MOP) could significantly attenuate hepatic inflammation and oxidative stress in mice, thereby conferring resistance to acute liver injury caused by APAP administration.
Conclusion:
Our data highlighted the significance of gut commensal fungi in hepatic inflammation and oxidative stress of APAP mice, shedding light on promising therapeutic strategies targeting Cyp2a5 for DILI treatment.
Insights
Gut fungi depletion worsens drug-induced liver injury (DILI) by increasing inflammation and oxidative stress. Targeting Cyp2a5 offers a potential therapeutic strategy for DILI treatment.
Area of Science:
- Hepatology
- Microbiology
- Toxicology
Background:
- Drug-induced liver injury (DILI) is a major cause of acute liver failure.
- The role of gut microbiota in DILI is well-studied, but the contribution of gut commensal fungi remains unclear.
Purpose of the Study:
- To investigate the functional role of gut commensal fungi in acetaminophen-induced liver injury (APAP-LI).
- To identify potential therapeutic targets for DILI.
Main Methods:
- Mice were pretreated with fluconazole to deplete gut fungi before acetaminophen challenge.
- Transcriptome sequencing was used to identify differentially expressed genes (DEGs) in the liver.
- 16S rDNA sequencing analyzed changes in gut microbiota composition.
Main Results:
- Fungal depletion exacerbated APAP-induced hepatotoxicity, increasing liver enzymes, necrosis, inflammation, and oxidative stress.
- Fungal depletion altered gut microbiota, decreasing Akkermansia muciniphila and increasing Helicobacter rodentium.
- Transcriptome analysis revealed Cyp2a5 enrichment in the liver of fungal-depleted mice, and its inhibition attenuated liver injury.
Conclusions:
- Gut commensal fungi play a significant role in modulating hepatic inflammation and oxidative stress during APAP-induced liver injury.
- Targeting Cyp2a5 presents a promising therapeutic strategy for DILI.
