Browsing by Subject "Primary sclerosing cholangitis"

Now showing 1 - 6 of 6
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    Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l-histidine decarboxylase/histamine signaling
    (Nature Publishing Group, 2020-02-13) Kennedy, Lindsey; Meadows, Vik; Demieville, Jennifer; Hargrove, Laura; Virani, Shohaib; Glaser, Shannon; Zhou, Tianhao; Rinehart, Evan; Jaeger, Victoria; Kyritsi, Konstantina; Pham, Linh; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Primary sclerosing cholangitis (PSC) is characterized by biliary damage and fibrosis. Multidrug resistance-2 gene knockout (Mdr2−/−) mice and PSC patients have increased histamine (HA) levels (synthesized by l-histidine decarboxylase, HDC) and HA receptor (HR) expression. Cholestatic HDC−/− mice display ameliorated biliary damage and hepatic fibrosis. The current study evaluated the effects of knockout of HDC−/− in Mdr2−/− mice (DKO) on biliary damage and hepatic fibrosis. WT, Mdr2−/− mice and homozygous DKO mice were used. Selected DKO mice were treated with HA. We evaluated liver damage along with HDC expression and HA serum levels. Changes in ductular reaction were evaluated along with liver fibrosis, inflammation and bile acid signaling pathways. The expression of H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C was determined. In vitro, cholangiocyte lines were treated with HA with/without H1/H2 inhibitors before measuring: H1/H2HR, TGF-β1 and VEGF-C expression. Knockout of HDC ameliorates hepatic damage, ductular reaction, fibrosis, inflammation, bile acid signaling and H1HR/PKC-α/TGF-β1 and H2HR/pERK/VEGF-C signaling. Reactivation of the HDC/HA axis increased these parameters. In vitro, stimulation with HA increased HR expression and PKC-α, TGF-β1 and VEGF-C expression, which was reduced with HR inhibitors. Our data demonstrate the key role for the HDC/HA axis in the management of PSC progression.
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    Deconvolution analysis identified altered hepatic cell landscape in primary sclerosing cholangitis and primary biliary cholangitis
    (Frontiers Media, 2024-05-15) Pham, Hoang Nam; Pham, Linh; Sato, Keisaku; Medicine, School of Medicine
    Introduction: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are characterized by ductular reaction, hepatic inflammation, and liver fibrosis. Hepatic cells are heterogeneous, and functional roles of different hepatic cell phenotypes are still not defined in the pathophysiology of cholangiopathies. Cell deconvolution analysis estimates cell fractions of different cell phenotypes in bulk transcriptome data, and CIBERSORTx is a powerful deconvolution method to estimate cell composition in microarray data. CIBERSORTx performs estimation based on the reference file, which is referred to as signature matrix, and allows users to create custom signature matrix to identify specific phenotypes. In the current study, we created two custom signature matrices using two single cell RNA sequencing data of hepatic cells and performed deconvolution for bulk microarray data of liver tissues including PSC and PBC patients. Methods: Custom signature matrix files were created using single-cell RNA sequencing data downloaded from GSE185477 and GSE115469. Custom signature matrices were validated for their deconvolution performance using validation data sets. Cell composition of each hepatic cell phenotype in the liver, which was identified in custom signature matrices, was calculated by CIBERSORTx and bulk RNA sequencing data of GSE159676. Deconvolution results were validated by analyzing marker expression for the cell phenotype in GSE159676 data. Results: CIBERSORTx and custom signature matrices showed comprehensive performance in estimation of population of various hepatic cell phenotypes. We identified increased population of large cholangiocytes in PSC and PBC livers, which is in agreement with previous studies referred to as ductular reaction, supporting the effectiveness and reliability of deconvolution analysis in this study. Interestingly, we identified decreased population of small cholangiocytes, periportal hepatocytes, and interzonal hepatocytes in PSC and PBC liver tissues compared to healthy livers. Discussion: Although further studies are required to elucidate the roles of these hepatic cell phenotypes in cholestatic liver injury, our approach provides important implications that cell functions may differ depending on phenotypes, even in the same cell type during liver injury. Deconvolution analysis using CIBERSORTx could provide a novel approach for studies of specific hepatic cell phenotypes in liver diseases.
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    Loss of apical sodium bile acid transporter alters bile acid circulation and reduces biliary damage in cholangitis
    (American Physiological Society, 2023) Meadows, Vik; Marakovits, Corinn; Ekser, Burcin; Kundu, Debjyoti; Zhou, Tianhao; Kyritsi, Konstantina; Pham, Linh; Chen, Lixian; Kennedy, Lindsey; Ceci, Ludovica; Wu, Nan; Carpino, Guido; Zhang, Wenjun; Isidan, Abdulkadir; Meyer, Alison; Owen, Travis; Gaudio, Eugenio; Onori, Paolo; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Primary sclerosing cholangitis (PSC) is characterized by increased ductular reaction (DR), liver fibrosis, hepatic total bile acid (TBA) levels, and mast cell (MC) infiltration. Apical sodium BA transporter (ASBT) expression increases in cholestasis, and ileal inhibition reduces PSC phenotypes. FVB/NJ and multidrug-resistant 2 knockout (Mdr2-/-) mice were treated with control or ASBT Vivo-Morpholino (VM). We measured 1) ASBT expression and MC presence in liver/ileum; 2) liver damage/DR; 3) hepatic fibrosis/inflammation; 4) biliary inflammation/histamine serum content; and 5) gut barrier integrity/hepatic bacterial translocation. TBA/BA composition was measured in cholangiocyte/hepatocyte supernatants, intestine, liver, serum, and feces. Shotgun analysis was performed to ascertain microbiome changes. In vitro, cholangiocytes were treated with BAs ± ASBT VM, and histamine content and farnesoid X receptor (FXR) signaling were determined. Treated cholangiocytes were cocultured with MCs, and FXR signaling, inflammation, and MC activation were measured. Human patients were evaluated for ASBT/MC expression and histamine/TBA content in bile. Control patient- and PSC patient-derived three-dimensional (3-D) organoids were generated; ASBT, chymase, histamine, and fibroblast growth factor-19 (FGF19) were evaluated. ASBT VM in Mdr2-/- mice decreased 1) biliary ASBT expression, 2) PSC phenotypes, 3) hepatic TBA, and 4) gut barrier integrity compared with control. We found alterations between wild-type (WT) and Mdr2-/- mouse microbiome, and ASBT/MC and bile histamine content increased in cholestatic patients. BA-stimulated cholangiocytes increased MC activation/FXR signaling via ASBT, and human PSC-derived 3-D organoids secrete histamine/FGF19. Inhibition of hepatic ASBT ameliorates cholestatic phenotypes by reducing cholehepatic BA signaling, biliary inflammation, and histamine levels. ASBT regulation of hepatic BA signaling offers a therapeutic avenue for PSC. NEW & NOTEWORTHY: We evaluated knockdown of the apical sodium bile acid transporter (ASBT) using Vivo-Morpholino in Mdr2KO mice. ASBT inhibition decreases primary sclerosing cholangitis (PSC) pathogenesis by reducing hepatic mast cell infiltration, altering bile acid species/cholehepatic shunt, and regulating gut inflammation/dysbiosis. Since a large cohort of PSC patients present with IBD, this study is clinically important. We validated findings in human PSC and PSC-IBD along with studies in novel human 3-D organoids formed from human PSC livers.
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    Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development
    (MDPI, 2022) Ceci, Ludovica; Zhou, Tianhao; Lenci, Ilaria; Meadows, Vik; Kennedy, Lindsey; Li, Ping; Ekser, Burcin; Milana, Martina; Zhang, Wenjun; Wu, Chaodong; Sato, Keisaku; Chakraborty, Sanjukta; Glaser, Shannon S.; Francis, Heather; Alpini, Gianfranco; Baiocchi, Leonardo; Medicine, School of Medicine
    The poor prognosis of cholangiocarcinoma in humans is related to several factors, such as (i) the heterogeneity of the disease, (ii) the late onset of symptoms and (iii) the limited comprehension of the carcinogenic pathways determining neoplastic changes, which all limit the pursuit of appropriate treatment. Several risk factors have been recognized, including different infective, immune-mediated, and dysmorphogenic disorders of the biliary tree. In this review, we report the details of possible mechanisms that lead a specific premalignant pathological condition to become cholangiocarcinoma. For instance, during liver fluke infection, factors secreted from the worms may play a major role in pathogenesis. In primary sclerosing cholangitis, deregulation of histamine and bile-acid signaling may determine important changes in cellular pathways. The study of these molecular events may also shed some light on the pathogenesis of sporadic (unrelated to risk factors) forms of cholangiocarcinoma, which represent the majority (nearly 75%) of cases.
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    Primary Sclerosing Cholangitis-Autoimmune Hepatitis Overlap Syndrome: Significant Barriers in Liver Disease Diagnosis and Treatment Experienced by the Latino Community
    (Springer, 2023-03-14) Guifarro, Daniel A.; De Oliveira-Gomes, Diana; Beas, Renato; Yibirin-Wakim, Marcel J.; Montalvan-Sanchez, Eleazar E.; Medicine, School of Medicine
    Overlap syndrome (OS) is a term that comprises the presentation of multiple hepatic disease characteristics in the same patient, such as the presence of autoimmune hepatitis (AIH) features in addition to primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC). Standard therapy for AIH is immunosuppression, while ursodeoxycholic acid is the preferred treatment for PBC. Additionally, liver transplantation (LT) may be considered in severe cases. Hispanics have been found to have a higher prevalence of chronic liver disease and develop more complications associated with portal hypertension at the time of listing for LT. Despite being the fastest-growing population in the USA, Hispanics have a higher probability of not receiving an LT due to issues with social determinants of health (SDOH). It has been reported that Hispanics are more likely to be removed from the transplant list. We report a case of a 25-year-old female immigrant from a Latin American developing country who presented with symptoms consistent with worsening liver disease after years of inappropriate workup and late diagnosis due to barriers within the healthcare system. The patient had a history of unresolved jaundice and pruritus and presented with worsening of her previous symptoms and new onset abdominal distention, bilateral leg edema, and telangiectasias. Laboratory and imaging studies confirmed the diagnosis of AIH and primary sclerosing cholangitis (PSC-AIH syndrome). The patient was started on steroids, azathioprine, and ursodeoxycholic acid, showing improvement. Due to her migratory status, she could not receive an appropriate diagnosis and follow up with a single provider or healthcare institution, putting her at increased risk for life-threatening complications. Although medical management is the first step, the probability of future liver transplants exists. The patient is still undergoing liver transplant evaluation and completing a workup since she was found to have an elevated model for end-stage liver disease (MELD) score. Even with the introduction of new scores and policies that aim to reduce disparities in LT, Hispanic patients are still at higher risk of being removed from the waitlist because of death or clinical deterioration compared to non-Hispanics. To this day, Hispanics have the highest percentage of waitlist deaths (20.8%) of all ethnicities and the lowest overall rate for undergoing LT. Understanding and addressing the causes that could contribute to and explain this phenomenon is essential. Increasing awareness of this problem is vital to promote more research on LT disparities.
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    Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC
    (BMJ, 2023) Awoniyi, Muyiwa; Wang, Jeremy; Ngo, Billy; Meadows, Vik; Tam, Jason; Viswanathan, Amba; Lai, Yunjia; Montgomery, Stephanie; Farmer, Morgan; Kummen, Martin; Thingholm, Louise; Schramm, Christoph; Bang, Corinna; Franke, Andre; Lu, Kun; Zhou, Huiping; Bajaj, Jasmohan S.; Hylemon, Phillip B.; Ting, Jenny; Popov, Yury V.; Hov, Johannes Roksund; Francis, Heather L.; Sartor, Ryan Balfour; Medicine, School of Medicine
    Objective: Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2-/- ) mice and microbial profiles in PSC patient cohorts. Design: We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients. Results: GF mdr2-/- mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients' clinical severity by Mayo risk scores. Conclusions: We identified novel functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.