Journal of Clinical and Translational Hepatology
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2023
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IF 3.6
Fulin Nian,Longyun Wu,Qiaoyun Xia,Peiying Tian,Chunmei Ding,Xiaolan Lu
Background and aims Non-alcoholic fatty liver disease (NAFLD) is closely associated with gut microbiota and has become the most common chronic liver disease worldwide, but the relationship between specific strains and NAFLD has not been fully elucidated. We aimed to investigate whether Akkermansia muciniphila and Bifidobacterium bifidum could prevent NAFLD, the effects of their action alone or in combination, possible mechanisms, and modulation of the gut microbiota. Methods Mice were fed with high-fat diets (HFD) for 20 weeks, in which experimental groups were pretreated with quadruple antibiotics and then given the corresponding bacterial solution or PBS. The expression of the glycolipid metabolism indicators, liver, and intestinal farnesol X receptors (FXR), and intestinal mucosal tight junction proteins were detected. We also analyzed the alterations of inflammatory and immune status and the gut microbiota of mice. Results Both strains were able to attenuate mass gain ( p <0.001), insulin resistance ( p <0.001), and liver lipid deposition ( p <0.001). They also reduced the levels of the pro-inflammatory factors ( p <0.05) and the proportion of Th17 ( p <0.001), while elevating the proportion of Treg ( p <0.01). Both strains activated hepatic FXR while suppressing intestinal FXR ( p <0.05), and elevating tight junction protein expression ( p <0.05). We also perceived changes in the gut microbiota and found both strains were able to synergize beneficial microbiota to function. Conclusions Administration of A. muciniphila or B. bifidum alone or in combination was protective against HFD-induced NAFLD formation and could be used as alternative treatment strategy for NAFLD after further exploration.
研究领域:
微生物学
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肝病学
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营养学
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免疫学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2015
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IF 2.532
Pan Chen,Jingjie Li,Xiaomei Fan,Hang Zeng,Rongrong Deng,Dongshun Li,Min Huang,Huichang Bi
Obstructive cholestasis is characterized by impairment of hepatic canalicular bile efflux and there are no clinically effective drugs to cure except surgeries. Previously we revealed that oleanolic acid (OA) protected against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice. Cholestasis caused by LCA is characterized by segmental bile duct obstruction, whether OA possesses the beneficial effect on completed obstructive cholestasis induced by bile duct ligation (BDL) remains unknown. In this study, we demonstrated that BDL-induced mice liver pathological change, and increase in serum levels of ALT, AST and ALP were all significantly reduced by OA (20 mg/kg, i.p.). Meanwhile, OA also lowered total bilirubin and total bile acids levels in serum, as well as total bile acids level in liver, in contrast, urinary total bile acids output was remarkably up-regulated by OA. Gene expression analysis showed that OA caused significant increased mRNA expression of MRP3 and MRP4 located at hepatic basolateral membrane , and restoration of MRP2 and BSEP located at hepatic cannalicular membrane. Furthermore, significant NRF2 protein accumulation in nucleus was also observed in OA treated mice. In mice primary cultured hepatocytes, the effects of OA on MRP2, MRP3 and MRP4 expression were directly proved to be mediated via NRF2 activation, and BSEP downregulation induced by OA was in part due to FXR antagonism. Luciferase assay performed in Hep G2 cells also illustrated that OA was a partial FXR antagonist. Taken together, we conclude that OA attenuates obstructive cholestasis in BDL mice, possibly via activation of NRF2-MRPs and FXR antagonism.
研究领域:
肝病学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2025
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IF 8
Yao Guo,Guangjie Shu,Ziyang Zhang,Xiaoshuang Hu,Huiru Huang,Wenxin Lu,Miaomiao Zhu,Bing Liu,Shenshen Zhang
Cholesterol homeostasis dysregulation is a primary risk factor for atherosclerosis (AS) development. Fisetin, a flavonoid compound, has shown promise in regulating cholesterol homeostasis by enhancing transintestinal cholesterol excretion (TICE). This study aimed to investigate the regulatory effects and underlying mechanisms of fisetin in AS. In this study, ApoE −/− mice fed a high-fat diet (HFD) were employed to investigate the effects of fisetin on the prevention of AS. Various methods, including biochemical analyses, histopathological staining, lipid deposition assessment, untargeted lipidomics analysis and RNA sequencing, were employed to explore the underlying mechanisms. The results showed that treatment with fisetin notably reduced lipid deposition in the aortic root of HFD-treated ApoE −/− mice and attenuated hepatic lipid deposition and histopathological changes. This was accompanied by decreased serum levels of total cholesterol, triglyceride and LDL cholesterol. Fisetin also effectively mitigated HFD-induced oxidative stress and inflammation in mice. Hepatic lipidomics revealed significant alterations in lipid content and composition following fisetin treatment, including reductions in lipids associated with AS risk, such as cholesteryl ester (ChE), phosphatidylcholines (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), cardiolipin (CL), phosphatidylinositol (PI), and TG. Additionally, phosphatidylserine (PS) levels were increased. RNA sequencing of livers revealed that fisetin affected genes related to cholesterol metabolism and bile acid biosynthesis, including cytochrome P450 ( Cyp ) family and Nr1h4 ( Fxr ). Molecular docking analysis suggested FXR may be a potential target of fisetin. In the liver, cholesterol can be either converted into bile acids or pumped out to bile ducts by ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) for elimination. Fisetin treatment notably modulated the hepatic proteins related to cholesterol metabolism (HMGCR, PCSK9, LDLR, FXR, CYP27A1, CYP7A1, CYP8B1 and BSEP) and cholesterol excretion (ABCG5, ABCG8), maintaining cholesterol homeostasis. Additionally, fisetin increased the excretion of fecal neutral sterols, including cholesterol, dihydrocholesterol, and coprosterone. It also increased the expression of FXR, ABCG5, ABCG8, and LDLR, while decreasing NPC1L1 and PCSK9 levels in the jejunum, thereby stimulating the TICE pathway. These findings provide compelling evidence that fisetin reduces cholesterol levels and alleviates AS by stimulating FXR-mediated hepatic cholesterol metabolism and the TICE pathway. The findings suggest that fisetin-regulated cholesterol metabolism may represent a promising therapeutic strategy for the treatment of AS.
研究领域:
药理学
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心血管医学
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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
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yu-Chen Jiang,Jia-Yi Dou,Mei-Yan Xuan,Chong Gao,Zhao-Xu Li,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro, hepatic stellate cell (HSC) activation was stimulated with TGF-β and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo, C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial–mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.
研究领域:
药理学
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肝病学
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
·
2025
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IF 5.9
Haiying Cai,Menghui Lin,Kaiyi Chen,Yuanfeng Wu,Thanh Ninh Le,Junhui Zhang,Minjie Zhao
The circulating bile acids (BAs) play critical roles in regulating the glycolipid metabolism, inflammation, and other physiological functions. Male C57BL/6J mice were given high-fat diet (HFD) with 500 mg/kg and 2500 mg/kg caffeic acid phenethyl ester (CAPE) for 16 weeks (CAPE500 and CAPE2500). The results showed that both the two dose of CAPE treatment improved the glycolipid metabolism and inflammation in HFD-induced obese mice. The BA profile analysis revealed that CAPE2500 increased hepatic and serum circulating BA levels compared to HFD ( P- value of 0.347 and 0.467, respectively), while CAPE500 showed decreased serum circulating BA levels compare to CAPE2500 ( P- value of 0.0881), suggesting dose-specific ameliorative mechanisms of CAPE on obesity based on BA signaling. Further study found significantly lower bile salt hydrolase (BSH) activity in the ileal contents of the CAPE500 group compared to the HFD group, which resulted in suppressed intestinal FXR signaling and improved glycolipid metabolism through inhibiting ileal FXR-enhanced ceremide synthesis. However, CAPE2500 increased serum circulating BA levels by significantly decreasing BA excretion compared with the HFD and CAPE500 groups ( P < 0.0001 and P < 0.01, respectively), enhancing brown adipose tissue thermogenesis by activating the TGR5/UCP-1 signaling axis. Furthermore, CAPE also ameliorated the gut microbiota disorders and obesity induced by HFD. This study reveals a dose-specific effect of CAPE treatment on circulating BA content, ileal BSH-FXR signaling and gut microbiota, which improves glucose and lipid dyshomeostasis through different mechanisms.
研究领域:
营养学
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分子生物学
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微生物学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Yadi Zhong,Yingjian Chen,Zhisen Pan,Kaijia Tang,Guangcheng Zhong,Jingyi Guo,Tianqi Cui,Tianyao Li,Siwei Duan,Xiaoying Yang,Yong Gao,Qi Wang,Dong Zhang
Acetaminophen (APAP) intake leads to excessive NAPQI deposition, stimulating inflammatory and oxidative stress and causing fatal liver injury. However, the detailed molecular mechanism involved is unknown, and effective therapeutic approaches remain insufficient. In this study, we discovered that treatment with ginsenoside Rc can prevent the inflammatory response caused by APAP and oxidative stress in mouse primary hepatocytes (MPHs), along with the corresponding changes in related genes. Additionally, Ginsenoside Rc effectively alleviates APAP-induced cellular apoptosis and NAPQI accumulation in MPHs. In vivo , Ginsenoside Rc administration remarkably attenuates APAP-induced hepatotoxicity, repairing liver damage and improving survival. Moreover, Ginsenoside Rc treatment modulates genes involved in APAP metabolism, leading to a decrease in NAPQI and resulting in the alleviation of fatal oxidative stress and inflammatory response after APAP exposure, along with the expression of their related indicators. Furthermore, our RNA-seq and molecular docking analysis implies that FXR expression and FXR transcriptional activity are stimulated by Ginsenoside Rc treatment. Notably, due to the lack of FXR in mice and MPHs, ginsenoside Rc can no longer play its original protective role against hepatotoxicity and cell damage caused by APAP, and it is difficult to improve the corresponding survival rate and prevent hepatic apoptosis, NAPQI generation, fatal oxidative stress, and the inflammatory response induced by APAP and the expression of related genes. In summary, our results indicate that Ginsenoside Rc could act as an effective FXR activator and effectively regulate FXR-induced antioxidant stress and eliminate inflammation while also having an anti-apoptotic function.
研究领域:
药理学
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毒理学
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分子生物学
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肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Zhenhui Chen,Huijuan Chen,Wanwen Huang,Xiaotong Guo,Lu Yu,Jiamin Shan,Xiaoshi Deng,Jiaxin Liu,Wendan Li,Wei Shen,Hongying Fan
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.
研究领域:
微生物学
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胃肠病学
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儿科
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代谢组学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Mengjie Kong,Yan Peng,Liyan Qiu
Non-alcoholic fatty liver disease (NAFLD) is currently a common chronic liver disease worldwide. By now, however, there isn't any FDA-approved specific drug for NAFLD treatment. It has been noticed that farnesoid X receptor (FXR), miR-34a and Sirtuin1 (SIRT1) is related to the occurrence and development of NAFLD. A oligochitosan-derivated nanovesicle (UBC) with esterase responsive degradability was designed to co-encapsulate FXR agonist (obeticholic acid, OCA) and miR-34a antagomir (anta-miR-34a) into the hydrophobic membrane and the center aqueous lumen of nanovesicles, respectively, by dialysis method. The action of UBC/OCA/anta-miR-34a loop on the regulation of lipid deposition via nanovesicles was evaluated on high-fat HepG2 cells and HFD-induced mice. The obtained dual drug-loaded nanovesicles UBC/OCA/anta-miR-34a could enhance the cellular uptake and intracellular release of OCA and anta-miR-34a, leading to the reduced lipid deposition in high-fat HepG2 cells. In NAFLD mice models, UBC/OCA/anta-miR-34a achieved the best curative effect on the recovery of body weight and hepatic function. Meanwhile, in vitro and vivo experiments validated that UBC/OCA/anta-miR-34a effectively activated the expression level of SIRT1 by enhancing the FXR/miR-34a/SIRT1 regulatory loop. This study provides a promising strategy for constructing oligochitosan-derivated nanovesicles to co-deliver OCA and anta-miR-34a for NAFLD treatment. Statement of significance This study proposed a strategy to construct oligochitosan-derivated nanovesicles to co-deliver obeticholic acid and miR-34a antagomir for NAFLD treatment. Based on the FXR/miR-34a/SIRT1 action loop, this nanovesicle effectively exerted a synergetic effect of OCA and anta-miR-34a to significantly regulate lipid deposition and recover liver function in NAFLD mice.
研究领域:
药学
·
分子生物学
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肝病学
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纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Yihang Dai,Zhixin Jia,Cong Fang,Meixia Zhu,Xiaoning Yan,Yinhuan Zhang,Hao Wu,Menghan Feng,Lirong Liu,Beibei Huang,Yueting Li,Jie Liu,Hongbin Xiao
Objective: To explore the possible mechanisms of cholestasis induced by Polygoni Multiflori Radix (PM). Methods: Low and high doses of water extract of PM were given to mice by gavage for 8 weeks. The serum biochemical indexes of aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamyltransferase (GGT) alkaline phosphatase (ALP) and so on were detected in the second, fourth, sixth, and eighth weeks after administration. At the end of the eighth week of administration, the bile acid metabolic profiles of liver and bile were screened by high-performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS). Liver pathological changes were observed by hematoxylin and eosin staining. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA transcription of the target genes and Western blotting (WB) was used to the detect target protein expression. Results: Biochemical tests results showed the values of ALP and GGT were two and three times greater than the normal values respectively, and the value of R was less than 2. Histopathology also showed that PM caused lymphocyte infiltration, a small amount of hepatocyte necrosis and nuclear fragmentation in mouse liver. The proliferation of bile duct epithelial cells was observed in the high group. These results indicated that PM may lead to cholestatic liver injury. HPLC-QQQ-MS/MS analysis with the multivariate statistical analysis revealed significant alterations of individual bile acids in liver and gallbladder as compared to those of the control group. RT-qPCR showed that the transcription of Fxr , Shp , Bsep , Bacs , Mdr2 , and Ugt1a1 were downregulated and that of Cyp7a1 , Mrp3 , and Cyp3a11 was significantly upregulated in the treatment group. WB demonstrated that PM also markedly downregulated the protein expression of FXR, BSEP, and MDR2, and upregulated CYP7A1. Conclusion: PM inhibited the expression of FXR, which reduced the expression of MDR2 and BSEP, leading to the obstruction of bile acids outflow, and increased the expression of CYP7A1, resulting in an increase of intrahepatic bile acid synthesis, which can lead to cholestasis.
研究领域:
药理学
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肝病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhiyuan Zhang,Guoqiang Guan,Zixuan Tang,Weimin Wan,Zhipeng Huang,Yuefeng Wang,Jianzhao Wu,Bo Li,Mingli Zhong,Kefeng Zhang,Lixian Nong,Ya Gao,Houkang Cao
A B S T R A C T Ethnopharmacological relevance Cholestatic liver disease (CLD) is a disease characterized by cholestasis. Farnesoid X receptor (FXR) is a nuclear receptor that maintains homeostasis in bile acid metabolism. Studies have shown that gut microbiota interfered with the FXR pathway. Modulation of FXR to inhibit cholestasis has become a key measure in the treatment of CLD. In traditional folk medicine, Desmodium styracifolium (Osb.) Merr. was used as a primary treatment for gallstones, gonorrhea, jaundice, cholecystitis and other diseases. Modern pharmacological studies had also found that the herb has anti-calculus, anti-inflammatory, antioxidant, diuretic and liver damage. Therefore, we speculated that Desmodium styracifolium (Osb.) Merr. extracts (DME) could alleviate CLD through the FXR pathway and might be associated with the gut microbiota. However, studies of DME alleviating CLD through the FXR pathway have not been reported. Aim of study To study the effect and mechanism of DME in relieving CLD through in vivo and in vitro experiments. Materials and methods First, mice were administrated with alpha-naphthyl isothiocyanate (ANIT) to establish a CLD model in vivo . Meanwhile, HepG2 cells were induced by lithocholic acid (LCA) to establish the CLD model in vitro . To evaluate the therapeutic effect of DME on CLD mice, hematoxylin-eosin (HE) staining, and biochemical indicators were performed. The prototype of the blood components in mice serum was detected by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). 16S rDNA sequencing was used to analyze the gut microbiota. Finally, the protein and mRNA expression of the FXR pathway in mice liver tissues or HepG2 cells were detected by Western blot, qRT-PCR, or immunofluorescence. Results Pathological testing and biochemical indexes showed that DME significantly reduced serum ALT, AST, ALP, TBIL, DBIL, TBA and liver TBA levels, and attenuated liver tissue injury, necrosis and jaundice in CLD mice. In addition, MetagenomeSeq analysis of gut microbiota showed that DME significantly up-regulated the abundance of Parvibacter , down-regulated the abundance of Paenalcaligenes , and regulated bile acid homeostasis. In terms of mRNA expression, DME significantly upregulated the mRNA levels of Nr1h4, Abcb11, Cyp7a1 and Slc10a1. Meanwhile, in terms of protein expression, DME significantly up-regulated the protein expression levels of FXR, BSEP, CYP7A1 and NTCP, which regulated bile acid homeostasis. Finally, the molecular docking results showed that the components of DME, such as Lumichrome, Daidzein and Folic acid, all had good binding ability with FXR, and the surface plasmon resonance (SPR) results also showed that both Lumichrome and Daidzein had a relatively high affinity with FXR. Conclusion DME alleviated CLD through the FXR pathway, and the mechanisms might be associated with the gut microbiota.
研究领域:
药理学
·
肝病学
·
分子生物学
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Wang Jiahua,Zang Juan,Yu Yang,Liu Yang,Cao Huimin,Guo Ruibo,Zhang Lu,Liu Mo,Zhang Zixu,Li Xuetao,Kong Liang
Background: The preservation of the Lingguizhugan (LGZG) decoction and patient compliance issue often limit the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Hence, herein, an LGZG oral solution was developed for alleviating MASLD. Additionally, the potential mechanisms underlying LGZG-mediated MASLD mitigation were explored.Methods: A MASLD mouse model was constructed using oleic and palmitic acid-induced LO2 cells and a high-fat diet. The apoptosis, lipid deposition, and mouse liver function were analyzed to assess the therapeutic effects of the LGZG oral solution on MASLD. Serum untargeted metabolomics, gut microbiota, bile acid (BA) metabolism, immunohistochemistry, and Western blotting analyses were performed to investigate the potential mechanism of action of LGZG oral solution on MASLD.Results: The LGZG oral solution ameliorated lipid deposition, oxidative stress, inflammation, and pathological damage. Serum untargeted metabolomics results revealed the LGZG-mediated regulation of the primary BA biosynthetic pathway. The 16S ribosomal RNA sequencing of the fecal microbiota showed that LGZG oral solution increased the relative abundance of the BA metabolism-associated Bacteroides, Akkermansia, and decreased that of Lactobacillus. Additionally, the BA metabolism analysis results revealed a decrease in the total taurine-α/β-muricholic acid levels, whereas those of deoxycholic acid were increased, which activated specific receptors in the liver and ileum, including farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5). Activation of FXR resulted in an increase in short heterodimer partner and subsequent inhibition of cholesterol 7α-hydroxylase and sterol regulatory element-binding protein-1c expression, and activation of FXR also results in the upregulation of fibroblast growth factor 15/19 expression, and consequently inhibition of cholesterol 7α-hydroxylase, which correlated with hepatic BA synthesis and lipogenesis, ultimately attenuating lipid deposition and bile acid stasis, thereby improving MASLD.Conclusion: Altogether, the findings of this study suggest that modulating microbiota–BA–FXR/TGR5 signaling pathway may be a potential mechanism of action of LGZG oral solution for the treatment of MASLD.
研究领域:
药理学
·
肝病学
·
代谢学
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微生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2023
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IF 13.6
Zhiyuan Meng,Sen Yan,Wei Sun,Jin Yan,Miaomiao Teng,Ming Jia,Sinuo Tian,Zhiqiang Zhou,Wentao Zhu
As the most commonly used organochlorine pesticide nowadays, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet. This study found that the CHI based on ADI level could induce obesity in mice. In addition, CHI could induce an imbalance in the gut microbiota of mice. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the CHI could induce obesity in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, CHI could disturb the bile acids (BAs) metabolism of mice, causing the inhibition of the signal response of BAs receptor FXR and leading to glycolipid metabolism disorders in liver and epiWAT of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the CHI-induced obesity in mice. In conclusion, CHI was found to induce obesity in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of obesity, demonstrating the key role of gut microbiota in the toxic effects of pesticides.
研究领域:
毒理学
·
微生物学
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代谢学
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药理学
✓ 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）