ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2021
·
IF 6.291
Xiaoying Lin,Wei Zhang,Lina He,Hongxin Xie,Bo Feng,Heyun Zhu,Jiating Zhao,Liwei Cui,Bai Li,Yu-Feng Li
Mercury (Hg) brings adverse effects to the environment and human beings and inorganic mercury (IHg) is a typical hepatic toxin. This work studied the impacts of IHg on gut microbes and metabolome together with its damage to liver and gut in rats through gut microbiome, metabolomics and metallomics. Sprague Dawley (SD) rats were orally exposed to 0.4 μg/mL IHg and sacrificed after 24 h. It was found that IHg perturbed greatly on the gut microbiota, such as increased pathogenic bacteria like G. bacillus . In addition, IHg also changed gut-liver axis related metabolites, which was confirmed by the secretion of a large number of inflammatory factors in both the gut and the liver. The changed gut-liver axis related metabolites correlated well to the changes of gut microbiome. In all, besides the direct deposition in liver of Hg, the perturbance to gut microbiome and alteration of gut-liver axis related metabolites by IHg also contributed to its hepatoxicity, which provides new insights about the hepatoxicity of chemicals. The strategy applied in this work may also be used to understand the hepatoxicity of other chemicals.
研究领域:
毒理学
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微生物学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Biao Yan,Yumiao Sun,Kaiyu Fu,Yindan Zhang,Lei Lei,Jun Men,Yongyong Guo,Shengmin Wu,Jian Han,Bingsheng Zhou
Glyphosate, one of the most widely used herbicide worldwide, is potentially harmful to non-target aquatic organisms. However, the environmental health risks regarding impacts on metabolism homeostasis and underlying mechanisms remain unclear. Here we investigated bioaccumulation, metabolism disorders and mechanisms in grass carp after exposure to glyphosate. Higher accumulation of glyphosate and its major metabolite, aminomethylphosphonic acid, in the gut was detected. Intestinal inflammation, barrier damage and hepatic steatosis were caused by glyphosate exposure. Lipid metabolism disorder was confirmed by the decreased triglyceride, increased total cholesterol and lipoproteins in serum and decreased visceral fat. Metabolomics analysis found that glyphosate exposure significantly inhibited bile acids biosynthesis in liver with decreased total bile acids content, which was further supported by significant downregulations of cyp27a1 , cyp8b1 and fxr . Moreover, the dysbiosis of gut microbiota contributed to the inflammation in liver and gut by increasing lipopolysaccharide, as well as to the declined bile acids circulation by reducing secondary bile acids. These results indicated that exposure to environmental levels of glyphosate generated higher bioaccumulation in gut, where evoked enterohepatic injury, intestinal microbiota dysbiosis and disturbed homeostasis of bile acids metabolism; then the functional dysregulation of the gut-liver axis possibly resulted in ultimate lipid metabolism disorder. These findings highlight the metabolism health risks of glyphosate exposure to fish in aquatic environment.
研究领域:
环境科学
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毒理学
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水生生物学
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代谢学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomolecules
·
2023
·Vol. 13
·期 10
·1464
·
IF 5.5
Xiaoyan Yuan,Junting Yang,Yuling Huang,Jia Li,Yuanyuan Li
There has been a growing interest in studying the communication of gut microbial metabolites between the gut and the liver as liver fibrosis progresses. Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, the effects of oral administration of IPA on hepatic fibrosis in different animal models have been conflicting. While some mechanisms have been proposed to explain these contradictory effects, the direct impact of IPA on hepatic fibrosis remains unclear. In this study, we found that IPA could directly activate LX-2 human hepatic stellate cells in vitro. IPA upregulated the expression of fibrogenic marker genes and promoted the features associated with HSCs activation, including proliferation and contractility. IPA also increased reactive oxygen species (ROS) in mitochondria and the expression of inflammation-related genes in LX-2 cells. However, when a ROS-blocking agent was used, these effects were reduced. p38 and JNK, the downstream signaling cascades of ROS, were found to be required for the activation of LX-2 induced by IPA. These findings suggest that IPA can directly activate hepatic stellate cells through ROS-induced JNK and p38 signaling pathways.Keywords:gut–liver axis;3-Indolepropionic acid;HSCs;liver fibrosis
研究领域:
胃肠病学
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肝病学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2022
·
IF 5.195
Hongkang Zhu,Wenhao Jiang,Chang Liu,Cheng Wang,Bin Hu,Yahui Guo,Yuliang Cheng,He Qian
Chlorogenic acid (CGA) is a functional phenolic acid widely used in food and medicine-related fields. It has been proved to be effective in the treatment of alcoholic liver disease (ALD). However, the exact mechanism by which CGA prevents ALD, especially from the crosstalk between gut and liver, has not been previously reported. This work was aimed to explore the protective effects of CGA against ALD and its relationships to gut-liver axis abnormalities. Experimental results showed the increased (p < 0.05) serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), low density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG) levels of mice fed with ethanol were ameliorated by supplementing with CGA. Moreover, CGA promoted the production of n-butyric acid by nearly 3 times (1.78 vs 0.62 nM, p < 0.01), a short-chain fatty acid that helps maintain the integrity of the intestinal barrier. Furthermore, CGA alleviated microbial dysbiosis , evidenced by the increased relative abundances of beneficial bacteria Muribaculaceae , Bacteroides , Alloprevotella , and Parabacteroides , and decreased that of opportunistic pathogens Eubacterium_nodatum , Eubacterium_ruminantium , and Anaerotruncus . Correlation analysis further elucidated the microbiota altered after CGA intervention was positively correlated with short-chain fatty acids and antioxidant indexes, while negatively correlated with inflammatory cytokines. In summary, these findings suggested the hepatoprotective effect of CGA was ascribed to the modulation of gut-liver axis homeostasis.
研究领域:
药理学
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肝病学
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微生物学
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营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Tingting Yan,Jinghe Sun,Yuying Zhang,Chengrong Wen,Jingfeng Yang
Enteromorpha prolifera polysaccharide (EP2) protection against acute alcoholic liver injury (AALI) in mice was investigated. By integration of physiological indicators, gut microbiota, and short-chain fatty acids (SCFAs), the mechanism of EP2 in alleviating AALI was disclosed. The results showed that EP2 significantly ameliorated alcohol-induced abnormal transaminase activities, liver and intestinal systemic inflammation, and intestinal environmental disorders. EP2 significantly reduces liver and serum LPS contents by 1.69-fold and 1.54-fold. Furthermore, inhibition of the NF-κB signaling pathway by EP2 reduced the production of proinflammatory cytokines such as TNF-α (1.83-fold), IL-6 (11.09-fold), and IL-1β (1.99-fold). EP2 restored SCFAs to normal levels by upregulating the abundance of beneficial bacteria (Colidextribacter, Ruminococcus, unclassified_Lachnospiraceae, and Akkermansia). The alleviation of AALI by EP2 occurs through protection of the intestinal mucosal barrier and reduction of LPS permeating in serum. The decrease in LPS inactivates the NF-κB signaling pathway and prevents inflammation. In short, EP2 regulates the gut–liver axis and inflammation, alleviating effects in AALI mice.
研究领域:
药理学
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肝病学
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微生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Linlin Qu,Xiaoxuan Ma,Daidi Fan
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Our previous reports showed that ginsenoside Rk3 provided excellent efficacy in alleviating the intestinal inflammatory response and protecting the liver, but its mechanism for HCC prevention remains to be explored. Here, the results suggested that Rk3 displayed potent antitumor effects against a dimethyl nitrosamine- and CCl4-induced HCC mouse model. Results revealed that Rk3 application inhibited liver injury, fibrosis, and cirrhosis. In parallel, Rk3 lowered the inflammatory response by decreasing the expression of inflammatory cytokines, inducing apoptosis, and blocking the cell cycle. Meanwhile, Rk3 effectively ameliorated the gut microbiota dysbiosis. Furthermore, correlation analysis revealed that the LPS-TLR4 signaling pathway, which was inhibited by Rk3, plays a key role in preventing HCC. To conclude, our research provides valuable insights into how Rk3 application targets the gut-liver axis and suppresses HCC development, suggesting that Rk3 might be a promising candidate for clinical treatment of HCC.
研究领域:
肿瘤学
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药理学
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胃肠病学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 14
·6666
·
IF 4.9
Siqi Zhang,Fei Tang,Zhe Zhou,Linhui Li,Yang Tang,Kaiwen Fu,Yang Tan,Ling Li
Liver fibrosis remains a critical health concern with limited therapeutic options. Kaempferol (Kae) is a natural flavonoid widely present in natural plants, yet its role in modulating gut–liver axis interactions during fibrosis is unexplored. This study investigates the hepatoprotective effects of Kae on alleviating carbon tetrachloride (CCl4)-induced liver fibrosis, and its underlying mechanisms, focusing on oxidative stress, gut microbiota, and short-chain fatty acids (SCFAs), are revealed. A mouse model of hepatic fibrosis was built by the subcutaneous injection of CCl4. Meanwhile, Kae was administered by gavage at doses of 25, 50, and 100 mg/kg body weight. Serum biomarkers, liver histopathology, oxidative damage markers, and nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling were analyzed. AML12 hepatocytes were pretreated with Kae or SCFAs (acetate, propionate, butyrate) before H2O2-induced oxidative injury. The changes in gut microbiota and the levels of SCFAs were assessed via 16S rRNA sequencing and GC-MS, respectively. Kae effectively alleviated the destruction of the liver morphology and tissue structure, reduced the infiltration of inflammatory cells, collagen deposition in the liver, and the expression of fibrotic factors, and downregulated the oxidative stress level in the liver of mice with liver fibrosis by activating the Nrf2/Keap1/HO-1 pathway (p< 0.05 or 0.01). In vitro, Kae significantly mitigated H2O2-induced cytotoxicity and oxidative damage (p< 0.05 or 0.01). Furthermore, Kae restored gut microbiota diversity, increased beneficial genera (e.g.,Lactobacillus), and elevated both intestinal and hepatic SCFA levels (p< 0.01). The discrepant SCFA pretreatment similarly protected AML12 cells by activating Nrf2 signaling (p< 0.05 or 0.01). Our research suggests that Kae could inhibit CCl4-induced liver fibrosis by restoring the levels of intestinal metabolite SCFAs to reduce oxidative damage.
研究领域:
药理学
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肝脏病学
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微生物学
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生物化学
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分子生物学
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营养科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2022
·
IF 9.988
Zhiying Miao,Zhiruo Miao,Xiaohua Teng,Shiwen Xu
As a widespread aquatic environmental contaminant, Lead (Pb) can provoke hepatic injury in various animals. Melatonin (MT) plays a crucial role in the regulation of inflammatory response. Accumulating evidence elucidates exogenous toxins can elicit hepatic lipid metabolic disorders by influencing the gut microbiome. Nevertheless, the effects of Pb on gut microbiota and hepatic lipid metabolism of the common carps, and whether MT can prevent and cure Pb-induced toxicity via regulating microbiome remains unknown. Here, metagenomic and transcriptomic analysis were subsequently implemented to identify the Pb exposure-triggered prominent alternation of gut-liver signal. In the present study the severe intestinal injury and fatty liver formation caused by Pb in common carp were preliminarily determined. Metagenomic analysis confirmed that the gut microbiome dominant phyla, family and genus of the common carps were Fusobacteria , Fusobacteriaceae and Cetobacterium . Meanwhile, lipopolysaccharide (LPS) biosynthesis pathway was regarded as one of the main responsible for Pb exposure. Subsequently, LPS was demonstrated as the Pb-triggered microbial-derived signal of the common carps by ELISA analysis, and involves in the hepatic metabolic disorders via deteriorating the intestinal barrier. Additionally, it confirmed that hepatocytes ferroptosis associated with Pb-evoked fatty liver of the common carps, and the aggravation of lysosomal dyshomeostasis as well as inhibition of AMPK phosphorylation were referred to lipid metabolic disorders. The results of the present study demonstrated microbial-derived signal induced by aquatic Pb contaminant cause fatty liver formation in the common carps, and the protective effects of MT on Pb toxicity were performed by receding LPS over-synthesis, restraining microbiota-sourced LPS transport, along with attenuation of hepatocytes ferroptosis.
研究领域:
环境毒理学
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水生生物学
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分子生物学
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微生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Xingyao Pei,Shusheng Tang,Haiyang Jiang,Wenjuan Zhang,Gang Xu,Zonghui Zuo,Zhenhui Ren,Chun Chen,Yao Shen,Cun Li,Daowen Li
The risks of Zinc oxide nanoparticles (ZnO NPs) applications in biological medicine, food processing industry, agricultural production and the biotoxicity brought by environmental invasion of ZnO NPs both gradually troubled the public due to the lack of research on detoxification strategies. TFEB-regulated autophagy-pyroptosis pathways were found as the crux of the hepatotoxicity induced by ZnO NPs in our latest study. Here, our study served as a connecting link between preceding toxic target and the following protection mechanism of Paeoniflorin (PF). According to a combined analysis of network pharmacology/molecular docking-intestinal microbiota-metabolomics first developed in our study, PF alleviated the hepatotoxicity of ZnO NPs from multiple aspects. The hepatic inflammatory injury and hepatocyte pyroptosis in mice liver exposed to ZnO NPs was significantly inhibited by PF. And the intestinal microbiota disorder and liver metabolic disturbance were rescued. The targets predicted by bioinformatics and the signal trend in subacute toxicological model exhibited the protectiveness of PF related to the SIRT1-mTOR-TFEB pathway. These evidences clarified multiple protective mechanisms of PF which provided a novel detoxification approach against ZnO NPs, and further provided a strategy for the medicinal value development of PF.
研究领域:
毒理学
·
药理学
·
分子生物学
·
微生物学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Yuan Yuan,Xiaoxuan Yin,Lu Li,Ziyue Wang,Haiyang Yan
ABSTRACT Glycidol (CAS: 556-52-5), a known carcinogen and genotoxicant, is often found in refined vegetable oils. Human exposure predominantly occurs through consumption of these oils and their byproducts, which contain glycidyl esters (GEs). Upon ingestion, GEs are metabolized to release glycidol, posing substantial health hazards. Historical studies have reported the tumorigenic properties of glycidol across various organs in mice models, encompassing the stomach, liver, lungs, brain, mammary gland, and skin. In this study, we employed a Balb/c mice model to investigate the hepatotoxic effects of glycidol following exposure to escalating doses (0, 25, 50, and 100 mg/kg bw/day). The hepatotoxicity was evidenced by a significant elevation in liver enzymes (ALT, AST), indicative of liver cell damage. Furthermore, biochemical analysis revealed heightened levels of oxidative stress indicators (SOD, MDA, GSH) and the upregulation of endoplasmic reticulum stress proteins, underscoring the cellular stress response. The induction of hepatocyte apoptosis served as a direct marker of liver damage caused by glycidol exposure. Additionally, glycidol altered the composition of intestinal microbiota and short-chain fatty acids (SCFAs), which unbalanced homeostasis. Gut barrier integrity markers (ZO-1, Claudin-1, Occludin, TLR4, LPS) indicated increased permeability of harmful substances to the liver via the gut-liver axis, which exacerbated hepatic injury. These findings highlight glycidol's disruption of gut homeostasis and its hepatotoxic potential.
研究领域:
毒理学
·
肝病学
·
微生物学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Wan Wang,Xu Zhao,Yue Ma,Jing Zhang,Cong Xu,Jiage Ma,Muhammad Altaf Hussain,Juncai Hou,Shanshan Qian
Excessive drinking has been listed by the World Health Organization as the fifth major risk factor; especially the liver, as the core organ of alcohol metabolism, is prone to organic lesions. Probiotics have received attention due to their bioactivity for liver protection. The beneficial effects of probiotics on hosts are related to their physiological functions. Therefore, based on the concept of second-generation synbiotes, this study explored the protective effects of four dietary polyphenols on the stress tolerance, hydrophobicity, adhesion, and digestive characteristics of L. rhamnosus 1.0320. L. rhamnosus 1.0320 had the best synergistic effect with dihydromyricetin (DMY). Therefore, this combination was selected as a synbiotic supplement to explore the protective effect on acute alcohol exposure-induced hepatic impairment. The results showed that L. rhamnosus 1.0320 combined with DMY restored the intestinal barrier by upregulating short-chain fatty acid levels and activated the adenosine 5′-monophosphate-activated protein kinase-mediated lipid metabolism pathway to inhibit oxidative stress, inflammation, and lipid accumulation in the liver. Furthermore, 109 CFU/mouse/d L. rhamnosus 1.0320 and 50 mg/kg/d DMY by gavage were identified as the optimal doses for protection against acute alcohol expose-induced hepatic impairment. This study provides new insights into alleviating acute alcoholic hepatic impairment by targeting intestinal metabolites through the gut-liver axis.
研究领域:
微生物学
·
药理学
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营养学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Honglei Zhang,Yun Lu,Yuanlei Zhang,Jiayu Dong,Su Jiang,Yunping Tang
Objective This study explores the therapeutic effects and mechanisms of DHA-enriched phosphatidylserine (DHA-PS) on liver injury induced by cyclophosphamide (CTX) in mice, focusing on the gut-liver axis. Methods A mouse model was established by administering CTX (80 mg/kg) intraperitoneally for 5 days. DHA-PS (50 or 100 mg/kg) was administered for the next 7 days to assess its reparative impact on liver damage. Results The findings revealed significant improvements in liver biochemical indices, inflammatory markers, and oxidative stress levels in the mice treated with DHA-PS. Through non-targeted metabolomics analysis, DHA-PS mitigated CTX-induced metabolic disruptions by modulating lipid, amino acid, and pyrimidine metabolism. Immunofluorescence analysis further confirmed that DHA-PS reduced the expression of liver-associated inflammatory proteins by inhibiting the TLR4/NF-κB pathway. Additionally, DHA-PS restored the intestinal barrier, evidenced by adjustments in the levels of intestinal lipopolysaccharide (LPS), secretory immunoglobulin A (sIgA), and tight junction proteins (Claudin-1, Occludin, and ZO-1). It also improved gut microbiota balance by enhancing microbial diversity, increasing beneficial bacteria, and altering community structures. Conclusion These results suggest that DHA-PS could be a potential therapeutic agent or functional food for CTX-induced liver injury through its regulation of the gut-liver axis.
研究领域:
药理学
·
肝病学
·
胃肠病学
·
免疫学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）