Abstract
Acetaminophen (APAP) overdose-induced acute liver injury (ALI) is characterized by extensive oxidative stress, and the clinical interventions for this adverse effect remain limited. Astilbin is an active compound found in the rhizome of Smilax glabra Roxb. with anti-inflammatory and antioxidant activities. Due to its low oral bioavailability, astilbin can accumulate in the intestine, which provides a basis for the interaction between astilbin and gut microbiota (GM). In the present study we investigated the protective effects of astilbin against APAP-induced ALI by focusing on the interaction between astilbin and GM. Mice were treated with astilbin (50 mg·kg−1·d−1, i.g.) for 7 days. After the last administration of astilbin for 2 h, the mice received APAP (300 mg/kg, i.g.) to induce ALI. We showed that oral administration of astilbin significantly alleviated APAP-induced ALI by altering the composition of GM and enriching beneficial metabolites including hydroxytyrosol (HT). GM depletion using an “antibiotics cocktail” or paraoral administration of astilbin abolished the hepatoprotective effects of astilbin. On the other hand, administration of HT (10 mg/kg, i.g.) caused similar protective effects in APAP-induced ALI mice. Transcriptomic analysis of the liver tissue revealed that HT inhibited reactive oxygen species and inflammation-related signaling in APAP-induced ALI; HT promoted activation of the Nrf2 signaling pathway to combat oxidative stress following APAP challenge in a sirtuin-6-dependent manner. These results highlight that oral astilbin ameliorates APAP-induced ALI by manipulating the GM and metabolites towards a more favorable profile, and provide an alternative therapeutic strategy for alleviating APAP-induced ALI.
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Data availability
The 16s data and RNA-seq data have been deposited in the Genome Sequence Archive (GSA) database in BIG Data Center (http://bigd.big.ac.cn/gsa) with the accession number of CRA026498 for 16s data and CRA026499 for RNA-seq data. Data will be made available on request.
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Funding
This study was supported by the Guangdong Basic and Applied Basic Research Foundation (2022B1515130004) and the Characteristic Innovation Project of the Guangdong Provincial Department of Education (2022KTSCX020) to YC; the Guangzhou Key Research and Development Program (2023B03J1245) to PC; the National Natural Science Foundation of China (82302092) and the Guangdong Basic and Applied Basic Research Foundation (2022A1515110070) to PG; the China Postdoctoral Science Foundation (2023M741602) to QY.
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QY, WHH, LX, TC, RFL, and JJH performed the experiments and analyzed the data; JYG, GZT, and FLW provided technical support; PG, PC, and YC designed the study, interpreted the data, drafted, and edited the manuscript, and supervised the study.
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Yang, Q., He, Wh., Xie, L. et al. Oral administration of astilbin mitigates acetaminophen-induced acute liver injury in mice by modulating the gut microbiota. Acta Pharmacol Sin 46, 416–429 (2025). https://doi.org/10.1038/s41401-024-01383-9
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DOI: https://doi.org/10.1038/s41401-024-01383-9
