Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice

Truong, Jennifer; Li, Jianing; Qin, Li; Pachura, Kimberly; Rao, Anuradha; Gumber, Sanjeev; Fuchs, Claudia; Feranchak, Andrew P.; Karpen, Saul J.; Trauner, Michael; Dawson, Paul A.

doi:10.1172/jci.insight.149360

Cited by 5 publications

(4 citation statements)

References 79 publications

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“… 45 NorUDCA (a side chain shortened synthetic version of UDCA) has shown promising results in a recent phase 2 clinical trial of primary sclerosing cholangitis. 2 In some disease models of biliary obstruction and primary sclerosing cholangitis, norUDCA treatment showed enhanced protective effects compared to UDCA, 3 4 5 which may be attributed to norUDCA’s ability to undergo cholehepatic shunting and enhance biliary bicarbonate secretion, 7 immunomodulation, 46 and promotion of cellular proliferation and tight junction integrity. 21 47 However, very little is known about the molecular mechanistic role of either norUDCA or UDCA on cholangiocyte injury and reactive phenotype activation under cholestatic conditions.…”

Section: Discussionmentioning

confidence: 99%

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A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway

Islam,

Israr,

Taleb

et al. 2024

Hepatology Communications

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Background: Ductular reactivity is central to the pathophysiology of cholangiopathies. Mechanisms underlying the reactive phenotype activation by exogenous inflammatory mediators and bile acids are poorly understood. Methods: Using human extrahepatic cholangiocyte organoids (ECOs) we developed an injury model emulating the cholestatic microenvironment with exposure to inflammatory mediators and various pathogenic bile acids. Moreover, we explored roles for the bile acid activated Sphingosine-1-phosphate receptor 2 (S1PR2) and potential beneficial effects of therapeutic bile acids UDCA and norUDCA. Results: Synergistic exposure to bile acids (taurocholic acid, glycocholic acid, glycochenodeoxycholic acid) and TNF-α for 24 hours induced a reactive state as measured by ECO diameter, proliferation, lactate dehydrogenase activity and reactive phenotype markers. While NorUDCA and UDCA treatments given 8 hours after injury induction both suppressed reactive phenotype activation and most injury parameters, proliferation was improved by NorUDCA only. Extrahepatic cholangiocyte organoid stimulation with S1PR2 agonist sphingosine-1-phosphate reproduced the cholangiocyte reactive state and upregulated S1PR2 downstream mediators; these effects were suppressed by S1PR2 antagonist JET-013 (JET), downstream mediator extracellular signal-regulated kinase 1/2 inhibitor, and by norUDCA or UDCA treatments. JET also partially suppressed reactive phenotype after bile acid injury. Conclusions: We developed a novel model to study the reactive cholangiocyte state in response to pathological stimuli in cholestasis and demonstrated a contributory role of S1PR2 signaling in both injury and NorUDCA/UDCA treatments. This model is a valuable tool to further explore the pathophysiology of human cholangiopathies.

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Section: Discussionmentioning

confidence: 99%

“… 2 3 4 5 6 Since norUDCA is resistant to side chain conjugation, it does not require conjugated bile acid transporters to enter the bile acid pool and appears to engage the cholehepatic shunt. 7 …”

Section: Introductionmentioning

confidence: 99%

A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway

Islam,

Israr,

Taleb

et al. 2024

Hepatology Communications

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“…The conditions in animal rooms used in this study fall within the standards set by the “Guide for the Care and Use of Laboratory Animals.” C57BL/6J mice (Jackson no. 000664, referred to as B6), C57BL/6J- Gpbar1 -/- mice 71 (kindly provided by Wendong Huang, Beckman Research Institute of City of Hope; referred to as Tgr5 -/- ) and C57BL/6NJ- Slc10a -/- mice 72 (kindly provided by Paul Dawson, Emory University; referred to as Asbt -/- ) mice were used.…”

Section: Experimental Methodsmentioning

confidence: 99%

Metabolic immaturity of newborns and breast milk bile acid metabolites are the central determinants of heightened neonatal vulnerability to norovirus diarrhea

Peiper,

Aparicio,

Phophi

et al. 2024

Preprint

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Noroviruses are the leading global cause of acute gastroenteritis, responsible for 685 million annual cases. While all age groups are susceptible to noroviruses, children are vulnerable to more severe infections than adults, underscored by 200 million pediatric cases and up to 200,000 deaths in children annually. Understanding the basis for the increased vulnerability of young hosts is critical to developing effective treatments. The pathogenic outcome of any enteric virus infection is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors. A central mediator in these complex relationships are host- and microbiota-derived metabolites. Noroviruses bind a specific class of metabolites, bile acids, which are produced by the host and then modified by commensal bacterial enzymes. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Considering these opposing effects, the microbiota-regulated balance of the bile acid pool may be a key determinant of the pathogenic outcome of a norovirus infection. The bile acid pool in newborns is unique due to immaturity of host metabolic pathways and developing gut microbiota, which could underlie the vulnerability of these hosts to severe norovirus infections. Supporting this concept, we demonstrate herein that microbiota and their bile acid metabolites protect from severe norovirus diarrhea whereas host-derived bile acids promote disease. Remarkably, we also report that maternal bile acid metabolism determines neonatal susceptibility to norovirus diarrhea during breastfeeding by delivering proviral bile acids to the newborn. Finally, directed targeting of maternal and neonatal bile acid metabolism can protect the neonatal host from norovirus disease. Altogether, these data support the conclusion that metabolic immaturity in newborns and ingestion of proviral maternal metabolites in breast milk are the central determinants of heightened neonatal vulnerability to norovirus disease.

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“…UDCA treatment reverses cholangiopathy and biliary fibrosis in female Cyp2c70 deficient mice [46], while it also prevents development of cholestasis in neonatal Cyp2c70 deficient mice [47]. norUDCA, which is able to undergo cholehepatic shunting independent of bile salt transporters such as ASBT, increased bile flow, biliary bicarbonate concentration and bicarbonate flow in mice [48 ▪ ]. Besides anticholestatic effects, norUDCA also attenuates a CD8 + T cell-driven hepatic immune response, which is also relevant in treating immune-mediated cholestatic liver diseases [49].…”

Section: Pre-clinical Researchmentioning

confidence: 99%

Targeting bile salt homeostasis in biliary diseases

Trampert,

Kunst,

van de Graaf

2024

Current Opinion in Gastroenterology

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Purpose of review Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed. Recent findings Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na+-taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes. Summary Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

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Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice

Cited by 5 publications

References 79 publications

A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway

A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway

Metabolic immaturity of newborns and breast milk bile acid metabolites are the central determinants of heightened neonatal vulnerability to norovirus diarrhea

Targeting bile salt homeostasis in biliary diseases

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