Bile Acid Uptake Transporters as Targets for Therapy

Slijepćević, D; Graaf, Stan F.J. van de

doi:10.1159/000450983

Cited by 64 publications

(56 citation statements)

References 81 publications

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“…Pharmacologic inhibition of ASBT is an evolving potential approach to the treatment of constipation, cholestasis, diabetes, and fatty liver disease. (14) The findings of the current study should be considered in the context of recent related investigations of cholestatic liver disease. The only peer-reviewed published report of an ASBTi is in adults with PBC.…”

Section: Discussionmentioning

confidence: 78%

Placebo‐Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome

Shneider

Spino

Kamath

et al. 2018

Hepatology Communications

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Medically refractory, severe, cholestasis‐induced pruritus in Alagille syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille syndrome. Thirty‐seven children with Alagille syndrome were randomly assigned to double‐blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch‐reported outcome instrument [ItchRO]) and clinician report (range, 0‐4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the a priori first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was –0.47 (95% confidence interval [CI], –1.14, 0.20; P = 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, –0.89; 95% CI, –1.70, –0.08; P = 0.032; and mean adjusted difference, –0.91; 95% CI, –1.62, –0.19; P = 0.014) but not 280 µg/kg/day (mean adjusted difference, –0.04; 95% CI, –0.94, 0.86; P = 0.44) or all doses combined (mean adjusted difference, –0.61; 95% CI, –1.24, 0.20; P = 0.055). A 1‐point reduction in pruritus was more common in maralixibat‐treated versus placebo‐treated participants (caregiver ItchRO, 65% versus 25%; P = 0.06; clinician score, 76% versus 25%; P = 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Conclusion: Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille syndrome.

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Section: Discussionmentioning

confidence: 78%

Placebo‐Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome

Shneider

Spino

Kamath

et al. 2018

Hepatology Communications

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“…65 Bile acids prevent intestinal bacterial overgrowth, both directly (via membrane damaging effects) and indirectly (via production of antimicrobial proteins). As such, bile acids modulate the composition of the gut microbiome.…”

Section: Postulated Mechanisms Linking the Gut Microbiome To Nafldmentioning

confidence: 99%

Emerging Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease: From Composition to Function

Sharpton

Ajmera

Loomba

2019

Clinical Gastroenterology and Hepatology

144

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The gut microbiome, a diverse microbial community in the gastrointestinal tract, plays a pivotal role in the maintenance of health. The gut microbiome metabolizes dietary and host-derived molecules to produce bioactive metabolites, which have a wide array of effects on host metabolism and immunity. 'Dysbiosis' of the gut microbiome, commonly considered as perturbation of microbiome diversity and composition, has been associated with intestinal and extra-intestinal diseases, including nonalcoholic fatty liver disease (NAFLD). A number of endogenous and exogenous factors, such as nutritional intake and xenobiotic exposure, can alter the gut microbiome. We will review the evolving methods for studying the gut microbiome and how these profiling techniques have been utilized to further our understanding of the gut microbial community composition and functional potential in the clinical spectrum of NAFLD. We will highlight microbiome-host interactions that may contribute to the pathogenesis of NAFLD, with a primary focus on mechanisms related to the metabolic output of the gut microbiome. Finally, we will discuss potential therapeutic implications of the gut microbiome in NAFLD.

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“…(116,117) In addition to their effects on the host, bile acids prevent intestinal bacterial overgrowth, both directly through membrane-damaging effects and indirectly through induction of antimicrobial protein expression; thus, they also play an important role in shaping gut microbiome membership. (118) Indeed, microbial bile acid resistance offers a fitness advantage in the gut and is commonly complemented by the capacity to deconjugate bile acids and convert primary bile acids to secondary bile acids. Germ-free mice or antibiotic-treated mice exhibit low concentrations of conjugated bile acids, pointing to a central role of gut microbiome in regulating bile acid composition.…”

Section: Bile Acid Transformations By the Gut Microbiotamentioning

confidence: 99%

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

et al. 2018

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The gut microbiome, the multispecies community of microbes that exists in the gastrointestinal tract, encodes several orders of magnitude more functional genes than the human genome. It also plays a pivotal role in human health, in part due to metabolism of environmental, dietary, and host‐derived substrates, which produce bioactive metabolites. Perturbations to the composition and associated metabolic output of the gut microbiome have been associated with a number of chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). Here, we review the rapidly evolving suite of next‐generation techniques used for studying gut microbiome composition, functional gene content, and bioactive products and discuss relationships with the pathogenesis of NAFLD.

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Bile Acid Uptake Transporters as Targets for Therapy

Cited by 64 publications

References 81 publications

Placebo‐Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome

Placebo‐Controlled Randomized Trial of an Intestinal Bile Salt Transport Inhibitor for Pruritus in Alagille Syndrome

Emerging Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease: From Composition to Function

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

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