Journal
FOOD AND CHEMICAL TOXICOLOGY
Volume 166, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2022.113208
Keywords
Methamphetamine; Gut microbiota; Bile acid homeostasis; Hepatic inflammation; Obeticholic acid
Categories
Funding
- National Natural Science Foundation of China [82171877, 81971796]
- Guangdong Natural Science Foundation [2020A1515010370, 2021A1515012456]
- Department of Science and Technology of Guangzhou city [202002030043]
- Beijing Natural Science Foundation [7192121]
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This study identified the microbial mechanism of Meth-induced hepatic inflammation and suggested its inhibition as a potential therapeutic target for treating Meth-related hepatotoxicity.
Methamphetamine (Meth), an addictive psychostimulant of abuse worldwide, has been a common cause of acute toxic hepatitis in adults. Gut microbiota has emerged as a modulator of host immunity via metabolic pathways. However, the microbial mechanism of Meth-induced hepatic inflammation and effective therapeutic strategies remain unknown. Here, mice were intraperitoneally (i.p.) injected with Meth to induce hepatotoxicity. Cecal microbiome and bile acids (BAs) composition were analyzed after Meth administration. Fecal microbiota transplantation (FMT) technology was utilized to investigate the role of microbiota. Additionally, the protective effects of obeticholic acid (OCA), an agonist of farnesoid X receptor (FXR), were evaluated. Results indicated that Meth administration induced hepatic cholestasis, dysfunction and aroused hepatic inflammation by stimulating the TLR4/MyD88/NF-kappa B pathway in mice. Meanwhile, Meth disturbed the cecal microbiome and impaired the homeostasis of BAs. Interestingly, FMT from Meth administered mice resulted in serum and hepatic BA accumulation and transferred similar phenotypic changes into the healthy recipient mice. Finally, OCA normalized Meth-induced BA accumulation in both serum and the liver, and effectively protected against Meth-induced hepatic dysfunction and inflammation by suppressing the TLR4/MyD88/NF-kappa B pathway. This study established the importance of microbial mechanism and its inhibition as a potential therapeutic target to treat Methrelated hepatotoxicity.
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