Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice

Zhuoen He; Yunong Zeng; Shuyu Li; Lizhen Lin; Ruisi Zhou; Fangzhao Wang; Wenjiao Yang; Yuhao Wu; Junhao Yang; Ali Chen; Zhang Wang; Hong Yang; Xiaoshan Zhao; Wei Xiao; Lei Li; Shenhai Gong

doi:10.3389/fmicb.2022.944416

Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice

Front Microbiol. 2022 Jul 12:13:944416. doi: 10.3389/fmicb.2022.944416. eCollection 2022.

Authors

Zhuoen He^{1

2}, Yunong Zeng², Shuyu Li², Lizhen Lin², Ruisi Zhou², Fangzhao Wang², Wenjiao Yang³, Yuhao Wu², Junhao Yang⁴, Ali Chen⁵, Zhang Wang⁴, Hong Yang¹, Xiaoshan Zhao², Wei Xiao^{2

6}, Lei Li⁷, Shenhai Gong^{1

2}

Affiliations

¹ Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
² School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
³ Department of Simulation Center, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
⁴ School of Life Science, South China Normal University, Guangzhou, China.
⁵ School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou, China.
⁶ Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China.
⁷ Department of Respiratory and Critical Care Medicine, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China.

Abstract

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.

Keywords: Cyp2a5; acetaminophen; acute liver injury; gut fungi; inflammation; oxidative stress.