Polygonatum odoratum extract ameliorates acetaminophen-induced acute liver injury by modulating the gut-liver axis and remodeling microbial and ceramide metabolism to suppress hepatic ferroptosis: insights from multi-omics
PO confers hepatoprotection via the gut–liver axis, which is associated with changes in ceramide metabolism and ferroptosis-related markers, which is associated with changes in ceramide metabolism and ferroptosis-related markers.
Abstract
Context Drug-induced liver injury remains a major clinical challenge due to the lack of effective therapeutic options. Polygonatum odoratum extract (PO), derived from the traditional medicinal and edible plant Polygonatum odoratum (Mill.) Druce, has long been used in folk practices in forms such as herbal soups and tea infusions. However, its protective effect against acetaminophen (APAP)-induced liver injury has not yet been investigated. Objective This study evaluated the preventive effects of PO against APAP-induced acute liver injury in mice. Materials and Methods An APAP-induced acute liver injury model was established in C57BL/6 mice. The hepatoprotective effects of PO were validated via histopathological analysis, oxidative stress assays,and serum biomarkers Multi-omics approaches, including 16 S rDNA sequencing, transcriptomics, and network pharmacology, were integrated with molecular biology techniques and pseudo-germ-free (PGF) mouse models to elucidate the underlying mechanisms. Results PO significantly alleviated hepatic histopathological damage, oxidative stress, and reduced serum ALT, AST, and LDH. PO remodeling gut microbiota, mitigated colonic inflammation and oxidative stress, and improved intestinal morphology, effects abolished by microbiota depletion. Mechanistically, PO maybe inhibited hepatic ferroptosis via the gut microbiota–ceramide axis, evidenced by upregulation of GPX4 and FSP1, NRF2/KEAP1 pathway activation, downregulation of ACSL4, TFRC/TFR2, and DUOX2, restored iron homeostasis, and decreased lipid peroxidation and ROS. In vitro, PO demonstrated anti-ferroptotic effects in APAP- or RSL3-treated AML12 cells. Discussion and Conclusion PO confers hepatoprotection via the gut–liver axis, which is associated with changes in ceramide metabolism and ferroptosis-related markers.
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide, and the associated metabolic dysfunction may increase susceptibility to drug-induced liver injury (DILI). This study aimed to evaluate the hepatoprotective effects of the
Gentiana sino-ornata
Balf. f. ethyl acetate extract (GSEA) in mice exposed to a high-fat diet (HFD) and tetracycline.
The antioxidant and anti-inflammatory activities of GSEA were evaluated
in vitro
and
in vivo
. Subsequently, the blood-absorbed ingredients of GSEA were characterized using UHPLC-HRMS, followed by network pharmacology analysis and molecular docking to elucidate the potential mechanisms underlying its hepatoprotective effects. Finally, the predicted mechanisms were experimentally validated in a mouse model of HFD- and tetracycline-induced liver injury.
GSEA exhibited significant antioxidant and anti-inflammatory activities. Twenty-five blood-absorbed ingredients were tentatively identified as potentially bioactive, and the PI3K/Akt/FoxO1 signaling pathway was predicted as a pathway of GSEA against liver injury. Molecular docking further demonstrated favorable binding interactions between AKT1 and several major constituents, including sweroside, loganic acid, swertiamarin, and gentiopicroside.
In vivo
experiments showed that GSEA markedly alleviated HFD- and tetracycline-induced liver injury by suppressing the expression of inflammation- and glucolipid-metabolism-related genes, attenuating hepatic inflammation, modulating the gut microbiota, and partially regulating the PI3K/Akt/FoxO1 signaling pathway.
Collectively, these findings provide mechanistic evidence supporting the potential application of GSEA as a natural therapeutic agent for the prevention or treatment of liver injury associated with metabolic dysfunction and tetracycline exposure.
Mi Zhang, Zhao-Bin Xia, Qing Gu et al.· Frontiers in Pharmacology· 0 citations
BACKGROUND
Polygonum multiflorum Thunb. (PM) can induce hepatotoxicity, particularly with prolonged use. Traditional processing methods, notably steaming (SPM) and steaming with black bean decoction (PPM), are recognized for their ability to mitigate this toxicity; however, the underlying mechanisms, especially from the gut-liver axis perspective, remain poorly understood.
PURPOSE
This study aims to clarify the mechanism by which processing reduces PM-induced hepatotoxicity, with a particular focus on the regulation of the gut-liver axis.
METHODS
We employed a comprehensive approach integrating histopathological examination, multi-omics analyses (including 16S rRNA sequencing, transcriptomics, and metabolomics), and molecular analysis to investigate the distinct effects of PM, SPM, and PPM in a mouse model.
RESULTS
PM caused significant liver injury, characterized by elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and severe pathological damage. This damage was marked by intestinal barrier disruption (decreased tight junction protein-1 (ZO-1) and occludin), systemic inflammation (elevated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels), and activation of the hepatic nuclear factor-kappa B (NF-κB) pathway. Multi-omics analysis revealed that PM induced severe GM dysbiosis (e.g., reduction in the Lactobacillus and a significant increase in the unclassified_f_Oscillospiraceae), a marked decrease in short-chain fatty acids (SCFAs) (e.g., a 72% reduction in butyrate), and disruption of the hepatic bile acid profile. Notably, the two processed products, particularly PPM, significantly reversed these alterations. Compared to the PM group, PPM treatment reduced serum ALT by 82% and exerted extensive protective effects. It restored beneficial bacteria, increased SCFAs levels, normalized bile acid metabolism, and suppressed the hepatic fibrogenic/NF-κB inflammatory axis. This detoxifying effect may be associated with reduced systemic exposure to toxic stilbene glycosides and anthraquinones in the processed PM groups compared to the PM group.
CONCLUSION
This study suggests that processing, particularly with black bean decoction (PPM), can alleviate PM-induced hepatotoxicity by reshaping the GM, restoring its metabolic products (SCFAs), normalizing bile acid signaling, and downregulating the FXR/NF-κB inflammatory axis within the gut-liver axis. These findings provide a mechanistic basis for the clinical preference for processed PM products and highlight the importance of stringent quality control, while also underscoring that residual risk may persist, particularly in susceptible populations.
Andong Dong, Yaya Bai, Yang Xiao et al.· Journal of Ethnopharmacology· 0 citations
Excessive use of acetaminophen (APAP) significantly contributes to drug-induced liver injury (DILI). Auricularia heimuer polysaccharides have significant hepatoprotective potential, however their mode of action in mitigating DILI is not yet elucidated. This study isolated and purified a novel polysaccharide, Ahp-1, from the fruiting bodies of A. heimuer, with a molecular weight of 270.161 kDa. Structural analysis revealed that the principal glycosidic linkages in Ahp-1 are 6-Gal, 6-Glc, t-Fuc, and 2,6-Gal, which form dimers by cross-linking of polysaccharide chains. Animal studies indicated that Ahp-1 reduces oxidative stress, elevates the relative abundance of beneficial bacteria within the gut microbiota, regulates microbial balance, and promotes the synthesis of favorable metabolites like Trigonelline. Moreover, following fecal microbiota transplantation (FMT), Ahp-FMT augments tight junction proteins and short-chain fatty acids (SCFAs), thus restoring the intestinal barrier. This subsequently stimulates the AMPK/GSK3β and Nrf2/HO-1 signaling pathways to mitigate DILI. These results provide novel opportunities for using A. heimuer polysaccharides as functional foods or hepatoprotective agents.
Ying-Di Dai, De-Tian Li, Si-Jia Ma et al.· Food Science and Human Welln...· 0 citations
ETHNOPHARMACOLOGICAL RELEVANCE
Persicaria capitata, a vital Miao medicine, is traditionally employed to "clear heat and promote diuresis" and "detoxify". In traditional theory, alcoholic liver injury (ALI) is categorized as a "Damp-Heat accumulation" syndrome, often manifesting as damp-heat jaundice. The traditional application of P. capitata in treating jaundice and inflammatory conditions provides a rationale for its hepatoprotective use.
AIM OF THE STUDY
To provide a scientific basis for the traditional use of P. capitata by systematically investigating the protective effects of its water extract (WP) on ALI and exploring the associated molecular mechanisms.
MATERIALS AND METHODS
An ALI mouse model was established by alcohol feeding for 28 days. Mice were orally administered with WP (175, 350, 700 mg/kg/day). Liver and intestinal functions were assessed by biochemical assays, histology, transcriptomics, 16S rRNA sequencing, and Western blotting.
RESULTS
WP significantly reduced serum ALT, AST, and hepatic lipid levels while alleviating oxidative stress. Mechanistically, WP regulated the gut-liver axis by maintaining intestinal barrier integrity (increased ZO-1 and Occludin expression) and enriching beneficial Akkermansia bacteria. This restoration of the intestinal barrier subsequently suppressed hepatic inflammatory responses and hepatocyte apoptosis by blocking the LPS-TLR4/NF-κB signaling cascade while simultaneously promoting the PI3K-Akt survival pathway.
CONCLUSIONS
By modulating the gut-liver axis-specifically through the restoration of intestinal barrier integrity and the regulation of TLR4/NF-κB and PI3K-Akt signaling-P. capitata effectively mitigates ALI. This study provides a mechanistic rationale for its traditional use and supports its development as a promising intervention for alcoholic liver-related pathologies.
Lu Hu, Jin Li, Ya-Xin Yang et al.· Journal of Ethnopharmacology· 0 citations
ETHNOPHARMACOLOGICAL RELEVANCE
Paliurus ramosissimus (PR) is a traditional folk medicinal plant recorded in Zhonghua Bencao (Chinese Materia Medica) and local medicinal records. In this study, Paliurus ramosissimus extract (PRex) was defined as an ethanol extract prepared from PR leaves. PR leaves have traditionally been used for heat-clearing and detoxification and for relieving swelling and pain. These traditional uses are closely related to inflammation-associated conditions. Because colitis-associated colorectal cancer (CAC) is characterized by chronic intestinal inflammation and mucosal injury, PR provides an ethnopharmacological rationale for evaluating PRex in an experimental CAC model.
AIM OF THE STUDY
This study aimed to evaluate the protective effects of PRex in an AOM/DSS-induced CAC mouse model and to explore whether PRex-related phenotypic changes are associated with PPAR-related metabolic pathways and gut microbiota alterations.
MATERIALS AND METHODS
An AOM/DSS-induced CAC mouse model was established. The main mechanistic analysis included the Control, Model, and PRex 820 mg/kg groups, while Wuwei Kushen and Aspirin were used as pharmacodynamic reference groups for phenotypic evaluation. Betulinic acid was used as a single-marker quality-control compound for HPLC-ELSD-based batch quality control of PRex. General condition, disease activity index (DAI), colon length, histopathological changes, and PCNA expression were evaluated. RNA-seq and 16S rRNA sequencing were performed to characterize host transcriptomic and gut microbiota changes. qRT-PCR and Western blotting were used for preliminary molecular assessment, and external GEO datasets were analyzed to provide contextual evidence for candidate gene expression and co-expression patterns.
RESULTS
HPLC-ELSD analysis showed that the betulinic acid content in this batch of PRex was 63.6 mg/g. PRex was associated with partial phenotypic improvement, including increased colon length and reduced PCNA-positive proliferative activity. However, the total histopathological injury score showed only a non-significant decrease compared with the Model group. Transcriptomic analysis identified PRex-associated opposite-direction genes enriched mainly in metabolism-related pathways, including the PPAR signaling pathway, retinol metabolism, and glycolysis/gluconeogenesis. 16S rRNA sequencing showed that PRex treatment was associated with shifts in gut microbiota composition and PICRUSt2-predicted functional profiles. Exploratory comparison suggested a possible overlap between host transcriptomic pathways and predicted microbial functional pathways. qRT-PCR preliminarily supported the expression trends of PPARα, CD36, FABP4, and PCK1, while Western blotting provided supportive semi-quantitative information.
CONCLUSION
PRex was associated with partial phenotypic improvement in AOM/DSS-induced CAC mice, mainly reflected by increased colon length and reduced PCNA-positive proliferative activity, whereas the total histopathological injury score was not significantly reduced. Transcriptomic analysis, 16S rRNA sequencing, and preliminary molecular assessment suggested that PRex intervention was associated with changes in PPAR-related metabolic pathways and gut microbiota profiles. PPARα, CD36, FABP4, and PCK1 may represent candidate molecules associated with PRex treatment. However, these findings should be interpreted as exploratory and hypothesis-generating, and further dose-response, toxicological, pharmacokinetic, and causal validation studies are required.
Jiahua Peng, Huan Zhao, Jingyi Hu et al.· Journal of Ethnopharmacology· 0 citations
Gul-BuOH affords dose-dependent protection against Cd-induced liver injury by modulating oxidative stress, inflammation, metal detoxification, and metabolic pathways, supporting the traditional use of G. ulmifolia and its potential as a multi-target hepatoprotective agent.
O. A. Elsabagh, Abdelbaset M. Elgamal, Heba A. Hassan et al.· PLoS ONE· 0 citations
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