Dataset Information

Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.

ABSTRACT: Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym was analyzed in the presence of a simulated theoretical BSEP inhibitor. BSEP inhibition in humans is predicted to increase liver concentrations of conjugated chenodeoxycholic acid (CDCA) and sulfate-conjugated lithocholic acid (LCA) while the concentration of other liver BAs remains constant or decreases. On the basis of a sensitivity analysis, the most important unknowns are the level of BSEP expression, the amount of intestinal synthesis of LCA, and the magnitude of farnesoid-X nuclear receptor (FXR)-mediated regulation.

SUBMITTER: Woodhead JL

PROVIDER: S-EPMC4120015 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.

Woodhead J L JL Yang K K Brouwer K L R KL Siler S Q SQ Stahl S H SH Ambroso J L JL Baker D D Watkins P B PB Howell B A BA

CPT: pharmacometrics & systems pharmacology 20140709

Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym ...[more]

PMID: 25006780

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Project description:BACKGROUND:Improving civil registration and vital statistics (CRVS) systems requires strengthening the capacity of the CRVS workforce. The improvement of data collection and diagnostic practices must be accompanied by efforts to ensure that the workforce has the skills and knowledge to assess the quality of, and analyse, CRVS data using demographic and epidemiological techniques. While longer-term measures to improve data collection practices must continue to be implemented, it is important to build capacity in the cautious use of imperfect data. However, a lack of training programmes, guidelines and tools make capacity shortages a common issue in CRVS systems. As such, any strategy to build capacity should be underpinned by (1) a repository of knowledge and body of evidence on CRVS, and (2) targeted strategies to train the CRVS workforce. MAIN TEXT:During the 4 years of the Bloomberg Philanthropies Data for Health (D4H) Initiative at the University of Melbourne, an extensive repository of knowledge and practical tools to support CRVS system improvements was developed for use by various audiences and stakeholders (the 'CRVS Knowledge Gateway'). Complementing this has been a targeted strategy to build CRVS capacity in countries that comprised two approaches - in-country or regional training and a visiting Fellowship Program. These approaches address the need to build competence in countries to collect, analyse and effectively use good quality birth and death data, and a longer-term need to ensure that local staff in countries possess the comprehensive knowledge of CRVS strategies and practices necessary to ensure sustainable CRVS development. CONCLUSION:The Knowledge Gateway is a dynamic, useful and long-lasting repository of CRVS knowledge for countries and development partners to use to formulate and evaluate CRVS development strategies. Capacity-building through in-country or regional training and the University of Melbourne D4H Fellowship Program will ensure that CRVS capacity and knowledge is developed and maintained, facilitating improvements in CRVS data systems that can be used by policymakers to support better decision-making in health.

Project description: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 cholesterol gallstones are still unknown. In this study, Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407 were individually administered to lithogenic-diet (LD)-fed mice for 8 weeks. Both Lactobacillus strains significantly reduced LD-induced gallstones, hepatic steatosis, and hyperlipidemia. These strains modulated BA profiles in the serum and liver, which may be responsible for the activation of farnesoid X receptor (FXR). At the molecular level, L. reuteri and L. plantarum increased ileal fibroblast growth factor 15 (FGF15) and hepatic fibroblast growth factor receptor 4 (FGFR4) and small heterodimer partner (SHP). Subsequently, hepatic cholesterol 7α-hydroxylase (CYP7A1) and oxysterol 7α-hydroxylase (CYP7B1) were inhibited. Moreover, the two strains enhanced BA transport by increasing the levels of hepatic multidrug resistance-associated protein homologs 3 and 4 (Mrp3/4), hepatic multidrug resistance protein 2 (Mdr2), and the bile salt export pump (BSEP). In addition, both L. reuteri and L. plantarum reduced LD-associated gut microbiota dysbiosis. L. reuteri increased the relative abundance of Muribaculaceae, while L. plantarum increased that of Akkermansia. The changed gut microbiota was significantly negatively correlated with the incidence of cholesterol gallstones and the FXR-antagonistic BAs in the liver and serum and with the FXR signaling pathways. Furthermore, the protective effects of the two strains were abolished by both global and intestine-specific FXR antagonists. These findings suggest that Lactobacillus might relieve CGS through the FXR signaling pathways. IMPORTANCE Cholesterol gallstone (CGS) disease is prevalent worldwide. None of the medical options for prevention and treatment of CGS disease are recommended, and surgical management has a high rate of recurrence. It has been reported that the factors involved in metabolic syndrome are highly connected with CGS formation. While remodeling of dysbiosis of the gut microbiome during improvement of metabolic syndrome has been well studied, less is known about prevention of CGS formation after regulating the gut microbiome. We used the lithogenic diet (LD) to induce an experimental CGS model in C57BL/6J mice to investigate protection against CGS formation by Limosilactobacillus reuteri strain CGMCC 17942 and Lactiplantibacillus plantarum strain CGMCC 14407. We found that these L. reuteri and L. plantarum strains altered the bile acid composition in mice and improved the dysbiosis of the gut microbiome. These two Lactobacillus strains prevented CGS formation by fully activating the hepatic and ileal FXR signaling pathways. They could be a promising therapeutic strategy for treating CGS or preventing its recurrence.

Dataset Information

Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.

Publications

Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI.

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