Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity

Chen, Yanan; Zhou, Jingkai; Xu, Shoufang; Liu, Mei; Wang, Minglu; Ma, Yiyi; Zhao, Mingming; Wang, Zhan-You; Guo, Yingjie; Zhao, Limei

doi:10.1016/j.bcp.2019.113669

Cited by 19 publications

(13 citation statements)

References 38 publications

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“…[ 31 ] Particularly, due to the demand of long‐term use of medication for suppressing the seizures in epileptic patients, the antiepileptic drugs like VPA, gabapentin, and lamotrigine have been manifested to elicit cholestasis with a high probability. [ 32 , 33 ] Next, the therapeutic effect of the synthesized dual probiotics system toward high dose of VPA‐induced cholestasis and corresponding liver injury was evaluated. The therapeutic process with a strategy of halfway drugs administration to imitate real cholestasis occurrence and management in epileptic patients was shown in Figure 5 A .…”

Section: Resultsmentioning

confidence: 99%

“…The higher expression of Bsep in VPA‐treated group than control group could be ascribed to the activated adaptive mechanism of liver tissue in attempt to attenuate bile acid accumulation and protect against further liver injury. [ 32 ] Importantly, fecal BSH content in LCA/LGG‐LDB treatment was also higher in comparison to VPA‐treated group, meaning that more conjugated BAs were translated into hydrophobic deconjugated BAs after LCA/LGG‐LDB treatment, which could greatly promote BAs excretion from intestinal tract (Figure 6K ). Collectively, these data proved that LCA/LGG‐LDB can effectively ameliorate VPA‐induced cholestasis and liver injury through inhibiting hepatic BAs synthesis and promoting BAs excretion from liver and intestine.…”

Section: Resultsmentioning

confidence: 99%

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Hierarchy‐Assembled Dual Probiotics System Ameliorates Cholestatic Drug‐Induced Liver Injury via Gut‐Liver Axis Modulation

Chen

Cao

et al. 2022

Advanced Science

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Cholestatic drug‐induced liver injury (DILI) induced by drugs or other xenobiotics is a severe and even fatal clinical syndrome. Here, living materials of hierarchy‐assembled dual probiotics system are fabricated by sequentially encapsulating probiotic Lactobacillus delbrueckii subsp. bulgaricus (LDB) and Lactobacillus rhamnosus GG (LGG) into Ca2+‐complexed polymer microspheres for effective prevention of cholestatic DILI. Upon entering intestinal tract of the constructed living materials, LGG is released because of pH‐triggered dissolution of outer enteric polymer coating. The released LGG can inhibit hepatic bile acids (BAs) synthesis by activating intestinal farnesoid X receptor‐fibroblast growth factor 15（FGF‐15) signaling pathway. BAs excretion is also facilitated by LGG through increasing the abundance of bile salt hydrolase (BSH)‐active gut commensal bacteria. Furthermore, exposed positively‐charged chitosan shell can absorb the excessive BAs via electrostatic interaction, which leads to steady BAs fixation by the imprisoned LDB, decreasing the total BAs amounts in enterohepatic circulation. Together, the fabricated living materials, obtained here, can effectively prevent cholestatic DILI through dredging cholestasis via gut‐liver axis modulation. The therapeutic effect is demonstrated in α‐naphthylisothiocyanate and clinical antiepileptic drug valproate acid‐induced cholestatic DILI mouse models, which reveal the great potential for effective cholestatic DILI management.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Hierarchy‐Assembled Dual Probiotics System Ameliorates Cholestatic Drug‐Induced Liver Injury via Gut‐Liver Axis Modulation

Chen

Cao

et al. 2022

Advanced Science

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“…Metabolomic studies may help better understand the bioavailability of several ASMs, specifically how they are absorbed, metabolized, and transported. In additional, metabolomics may help to unravel possible interactions of ASMs used in polytherapy and the effect of concomitant treatments with other drugs and food intake 172,173 . Remarkably, we could only identify a single in vivo study assessing metabolites in patients with refractory compared with responsive epilepsy.…”

Section: Final Remarksmentioning

confidence: 99%

“…In additional, metabolomics may help to unravel possible interactions of ASMs used in polytherapy and the effect of concomitant treatments with other drugs and food intake. 172 , 173 Remarkably, we could only identify a single in vivo study assessing metabolites in patients with refractory compared with responsive epilepsy. Thus, it is clear that this important field of investigation has a lot to offer in the future regarding the study of ASM pharmacoresistance in epilepsy.…”

Section: Final Remarksmentioning

confidence: 99%

Multi‐omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy

et al. 2021

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“…To study the downstream signaling pathway of FXR, we assessed the expression of cholesterol 7αhydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1), Sterol 27-hydroxylase (CYP27A1) and oxysterol 7α-hydroxylase (CYP7B1), which are important catalytic enzymes for the synthesis of BAs from cholesterol [35,36]. Then, we found that CYP7A1, a rate-limiting enzyme of the classical pathway of BA synthesis [37], was increased in LD-fed mice compared with ND-fed mice.…”

Section: Lr and Lp Treatments Reduced Ld-induced Gallstones And Metabmentioning

confidence: 99%

Alleviation of Cholesterol Gallstones by Lactobacillus Targeting the Gut Microbiota Depends on Global Farnesoid X Receptor-Mediated Bile Acid Metabolism

Wan¹,

Zhuang³

et al. 2020

Preprint

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Background Cholesterol gallstone (CGS) disease is characterized by an imbalance in bile acid (BA) metabolism and is closely associated with gut microbiota disorders. However, the role and mechanism by which probiotics targeting the gut microbiota attenuate CGS are still unknown. In this study, Lactobacillus reuteri CGMCC 17942 (LR) and L. plantarum CGMCC 14407 (LP) were individually administered to lithogenic diet (LD)-fed mice at a dosage of 109 CFU/day for 8 weeks. Results Both Lactobacillus strains significantly reduced LD-induced gallstones, hepatic steatosis, and hyperlipidemia. These strains modulated serum BA profiles, with significantly decreased conjugated primary BA taurine-β-muricholic acid (T-β-MCA), an FXR antagonist. At the molecular level, LR and LP increased Farnesoid X Receptor (FXR) expression in the liver but not in the ileum, increased the levels of ileum and liver fibroblast growth factor 15 (FGF15) and liver FGFR4, small heterodimer partner (SHP), and subsequently reduced cholesterol 7α-hydroxylase (CYP7A1) and cytochrome P450 family 7 subfamily B polypeptide 1 (CYP7B1) to inhibit BA synthesis in the liver. At the same time, the two strains enhanced BA transport by increasing the levels of multidrug-resistance-associated protein homologs (MRP) 3/4, multidrug-resistance-associated protein homologs (MRP) 3/4, hepatic multidrug resistance protein (MDR2) and bile salt export pump (BSEP) mRNA in the liver. In addition, both LR and LP reduced LD-associated gut microbiota dysbiosis. LR increased the relative abundance of Muribaculaceae, while LP increased that of Akkermansia. The changed gut microbiota was significantly negatively correlated with the grade and incidence of gallstones, hyperlipidemia, the level of T-β-MCA in serum, or the gene expression levels of Fxr in liver. Furthermore, the protective effects of the two strains were abolished by a global but not intestinal-specific FXR antagonist. Conclusions Taken together, our results suggested that Lactobacillus might relieve gallstones through FXR-dependent regulation of BA synthesis and transport.

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Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity

Cited by 19 publications

References 38 publications

Hierarchy‐Assembled Dual Probiotics System Ameliorates Cholestatic Drug‐Induced Liver Injury via Gut‐Liver Axis Modulation

Hierarchy‐Assembled Dual Probiotics System Ameliorates Cholestatic Drug‐Induced Liver Injury via Gut‐Liver Axis Modulation

Multi‐omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy

Alleviation of Cholesterol Gallstones by Lactobacillus Targeting the Gut Microbiota Depends on Global Farnesoid X Receptor-Mediated Bile Acid Metabolism

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