Karlsen TH, Rutter H, Carrieri P, et al. (2024). The EASL-Lancet Commission on liver health in Europe: prevention, case-finding, and early diagnosis to reduce liver-related mortality. Lancet 403:1522-1524.
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Karlsen TH (2022) Understanding COVID-19 through genome-wide association studies. Nature Genetics 54:368-369.
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Molinaro, Antonio; Braadland, Peder Rustøen; Carpino, Guido; Carreras, Alba; Nikolaidis, Marios & Hanzely, Petra
[Vis alle 40 forfattere av denne artikkelen]
(2026).
Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling.
Nature Metabolism.
8(9),
s. 1910–1925.
doi:
10.1038/s42255-026-01600-1.
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Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut–liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.
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Rønneberg, Jørgen Dybevik; Hjeltnes, Martine; Krieger, Josephine; Elias, Joshua E.; Stensland, Maria & Holm, Kristian
[Vis alle 15 forfattere av denne artikkelen]
(2026).
An epithelial GPR35 isoform supports tumor-associated transcriptional and metabolic phenotypes.
FEBS Letters.
ISSN 0014-5793.
s. 1–23.
doi:
10.1002/1873-3468.70423.
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Braadland, Peder Rustøen; Ali, Ahmad H.; Puchas, Philip; Juran, Brian D.; Atkinson, Elizabeth J. & Schlicht, Erik M.
[Vis alle 19 forfattere av denne artikkelen]
(2026).
Vitamin B6 predicts poor outcomes in geographically distinct populations with primary sclerosing cholangitis.
Journal of Hepatology.
ISSN 0168-8278.
85(2),
s. 227–237.
doi:
10.1016/j.jhep.2026.03.048.
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Background & Aims: Primary sclerosing cholangitis (PSC) has a variable disease course, complicating patient counseling and the timing of liver transplantation. Vitamin B6 deficiency predicts reduced liver transplantation-free survival in Scandinavian PSC cohorts. Here, we aimed to validate this observation in US and German PSC cohorts and to expand our analyses to include hepatic decompensation as a clinical outcome.
Methods: Serum active vitamin B6 (pyridoxal 5’-phosphate [PLP]) was analyzed using liquid chromatography-tandem mass spectrometry in retrospective cohorts of people with PSC from Norway (n = 315), the USA (n = 756), and Germany (n = 149). Cox proportional hazards and Fine and Gray competing risk models were fitted to estimate the ability of PLP to predict liver transplantation-free survival and the cumulative incidence of hepatic decompensation, respectively.
Results: The prevalence of vitamin B6 deficiency (PLP <20 nmol/L) in pre-transplant PSC was 50% in the Norway cohort and 25% in the USA cohort. The prevalence was higher among those with previous hepatic decompensation. The cumulative incidence of hepatic decompensation was higher in the USA cohort, while individuals in the Norway cohort were more commonly transplanted for indications other than hepatic decompensation. Despite differences in clinical practice, low PLP was consistently associated with shorter liver transplantation-free survival, and PLP added predictive value for liver transplantation or death from PSC over and above contemporary prediction models. Low PLP was also associated with a higher incidence of hepatic decompensation, which was mainly evident in the USA cohort, where decompensation was more common. The risk of both outcomes increased sharply within the deficient and marginal ranges and plateaued at sufficient PLP levels.
Conclusions: Vitamin B6 deficiency is common in PSC outside Scandinavia and is consistently associated with poor outcomes across geographically distinct PSC populations.
Impact and implications
We previously showed that vitamin B6 deficiency is prevalent and associated with reduced liver transplantation-free survival in Scandinavian PSC cohorts. The current work shows that these observations generalize to a US population and that low vitamin B6 is also associated with the development of hepatic decompensation. Our results indicate that vitamin B6 provides incremental value for predicting outcomes in PSC across geographically distinct populations and that efforts to restore B6 sufficiency should be focused on the many individuals who present with vitamin B6 levels within the marginal-to-definitive deficiency range.
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Ellmeier, Wilfried; Meijer, Marieke; Madrignani, Miriam; Simulescu, Loredana; Karlsen, Tom Hemming & Macintyre, Elizabeth
(2025).
Shaping the future of European health research: policy recommendations of the Biomedical Alliance in Europe for Framework Programme 10 and beyond.
FEBS Letters.
ISSN 0014-5793.
599(12),
s. 1625–1633.
doi:
10.1002/1873-3468.70079.
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As Europe charts its course for the next funding programme for research, Framework Programme 10 (FP10), the stakes have never been higher. In order to increase European competitiveness in research and innovation and generate better outcomes for patients, the Biomedical Alliance in Europe urges policymakers to embrace health and biomedical research as a strategic investment. We call for strong funding to support the translational health research value and innovation chain. We advocate for reducing the administrative burden in grant applications, and for simplification and harmonization of the regulatory framework. In addition, we call for strengthening of strategic leadership, coordination, collaboration and training. FP10 promises to transform European health research into a driver of societal well‐being, economic growth and global leadership.
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ElAbd, Hesham; Pesesky, Mitchell; Innocenti, Gabriel; Chung, Brian K.; Mahdy, Aya K.H. & Kriukova, Valeriia
[Vis alle 40 forfattere av denne artikkelen]
(2025).
T and B cell responses against Epstein–Barr virus in primary sclerosing cholangitis.
Nature Medicine.
ISSN 1078-8956.
31(7),
s. 2306–2316.
doi:
10.1038/s41591-025-03692-w.
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Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC.
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Zompo, Fabio Del; Crouchet, Emilie; Ostyn, Tessa; Nehme, Zeina; Messé, Mélissa & Jühling, Frank
[Vis alle 36 forfattere av denne artikkelen]
(2025).
Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis.
Journal of Hepatology.
ISSN 0168-8278.
83(6),
s. 1305–1319.
doi:
10.1016/j.jhep.2025.08.005.
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Background & Aims
Primary sclerosing cholangitis (PSC) is a cholangiopathy associated with a high risk of progression to end-stage liver disease and hepatobiliary cancer. Its pathogenesis remains poorly understood, and current clinical management offers limited therapeutic options, primarily liver transplantation. Claudin-1 (CLDN1), a transmembrane protein highly expressed in liver epithelial cells, plays a critical role in cell-cell communication and signaling. We aimed to investigate the functional role of CLDN1 as both a mediator and potential therapeutic target for PSC using patient cohorts alongside murine and patient-derived intervention models.
Methods
CLDN1 expression patterns and associated cellular phenotypes were analyzed in liver tissues from five PSC patient cohorts using single-cell RNA sequencing, spatial transcriptomics, and multiplex proteomics. Proof-of-concept studies employing CLDN1-specific monoclonal antibodies (mAbs) and genetic loss-of-function approaches were performed in state-of-the-art mouse models of PSC and cholangiopathies. Perturbation studies in human cell-based models were conducted to explore underlying mechanisms.
Results
In liver tissues from patients with PSC, CLDN1 expression was markedly upregulated and correlated with disease progression. Spatial transcriptomics and proteomics revealed elevated CLDN1 expression in diseased cholangiocytes and cholestatic periportal hepatocytes, accompanied by activation of pro-inflammatory and pro-fibrotic signaling pathways. Therapeutic administration of CLDN1-specific mAbs or genetic knockout improved liver function in PSC mouse models by reducing hepatobiliary fibrosis and cholestasis. Mechanistic studies indicated that mAb treatment inhibited pro-inflammatory and pro-fibrotic signaling in cholangiocytes and hepatocytes perturbed in PSC liver tissues.
Conclusions
These findings demonstrate a functional role for CLDN1 in the pathogenesis of PSC and biliary fibrosis. In vivo proof-of-concept studies, combined with expression analyses in patients with PSC, support the clinical development of CLDN1-specific mAbs as a therapeutic strategy for PSC.
Impact and implications
Primary sclerosing cholangitis (PSC) is a chronic fibrosing cholangiopathy with limited therapeutic options. We identified the cell surface protein Claudin-1 as a key mediator and potential therapeutic target for PSC. In patients, Claudin-1 expression correlates with disease stage and clinical outcomes. Conditional liver epithelial-specific Claudin-1 knockout in mice reduced liver injury, fibrosis, and cholestasis. Monoclonal antibodies targeting Claudin-1 inhibited fibrosis, cholestasis, and the ductular reaction across advanced PSC mouse models by suppressing pro-inflammatory and fibrogenic signaling. These preclinical findings support the clinical development of Claudin-1-specific antibodies for PSC treatment and have significant implications for physicians, researchers, and drug developers in the field of biliary disease.
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Chung, Brian K.; Jordens, Markus S.; Øgaard, Jonas Daniel Sjøberg; Reims, Henrik Mikael; Flateland, Benedicte & Luedde, Tom
[Vis alle 9 forfattere av denne artikkelen]
(2025).
Multimodal transcriptomics identifies metallothionein as a novel pathway in primary sclerosing cholangitis.
Hepatology.
ISSN 0270-9139.
doi:
10.1097/HEP.0000000000001432.
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Background and Aims:
Primary sclerosing cholangitis (PSC) is a chronic inflammatory bile duct disorder of unknown etiology characterized by uneven peribiliary infiltration and liver fibrosis. To localize potential disease pathways to specific microanatomical liver regions, we combined spatial and single-nuclei transcriptomics (snRNA-seq) to analyze biopsies from a spectrum of PSC and disease control explants.
Approach and Results:
Liver specimens from 23 PSC (transplant indications: 4 recurrent cholangitis, 7 dysplasia, 12 cirrhosis) and 7 disease controls with cirrhosis (4 metabolic dysfunction–associated steatohepatitis, MASH; 3 alcohol-associated liver disease, ALD) were analyzed by spatial transcriptomics (76,664 spots) and 16 of the same explants were also assessed by snRNA-seq (12 PSC, 2 MASH, 2 ALD; 91,891 nuclei). PSC livers expressed a robust signature of metallothionein (MT1E, MT1G, MT1H) and acute inflammation markers (SAA1, SAA2) at the parenchyma–fibrosis interface compared to disease controls. SnRNA-seq showed that the strongest metallothionein signal originated from a subtype of APOE+ hepatocytes that, by spatial transcriptomics and immunohistochemistry, were consistently localized to the edge of fibrotic lesions in PSC explants. Biliary inflammation induced by 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding in mice resulted in significant Mt1 liver expression and liver MT1G expression correlated with AST, ALT, ALP, and bilirubin levels at the time of liver transplantation.
Conclusions:
Combinatorial spatial and high-resolution single-nuclei transcriptomics on the largest number of PSC liver explants to date revealed metallothionein as a novel PSC pathway that could be interrogated in future studies aiming to develop effective therapeutic interventions for PSC.
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Zhu, Ci; Boucheron, Nicole; Al-Rubaye, Osamah; Chung, Brian K.; Thorbjørnsen, Liv Wenche & Köcher, Thomas
[Vis alle 26 forfattere av denne artikkelen]
(2025).
24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting TH17 pathogenicity and transdifferentiation.
Gut.
ISSN 0017-5749.
74(7),
s. 1079–1093.
doi:
10.1136/gutjnl-2024-333297.
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Background
24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC).
Objective
Since PSC strongly associates with T helper-type-like 17 (TH17)-mediated intestinal inflammation, we explored NorUDCA’s immunomodulatory potential on TH17 cells.
Design
NorUDCA’s impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) TH17. Pathogenicity of pTH17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC.
Results
NorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory ‘TH1-like-TH17’ cells, and enhanced TH17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA’s anti-inflammatory effect on TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA’s impact on TH17 inflammation was corroborated in the humanised NSG mouse model.
Conclusion
NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond.
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Fossdal, Guri; Braadland, Peder Rustøen; Hov, Johannes Espolin Roksund; Husebye, Eystein Sverre; Folseraas, Trine & Ueland, Per Magne
[Vis alle 10 forfattere av denne artikkelen]
(2025).
Mitochondrial dysfunction and lipid alterations in primary sclerosing cholangitis.
Scandinavian Journal of Gastroenterology.
ISSN 0036-5521.
60(2),
s. 165–173.
doi:
10.1080/00365521.2024.2447521.
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Objectives: Indications of mitochondrial dysfunction are commonly seen in liver diseases, but data are scarce in primary sclerosing cholangitis (PSC). Analyzing circulating and liver-resident molecules indirectly reflecting mitochondrial dysfunction, we aimed to comprehensively characterize this deficit in PSC, and whether this was PSC specific or associated with cholestasis.
Materials and methods: We retrospectively included plasma from 191 non-transplant patients with large-duct PSC and 100 healthy controls and explanted liver tissue extracts from 24 PSC patients and 18 non-cholestatic liver disease controls. Using mass spectroscopy, we profiled lipids and fatty acids, carnitine, acylcarnitines, and metabolites in the tryptophan-kynurenine-nicotinamide pathway.
Results: Hierarchal clustering of fatty acid levels identified patients with PSC and healthy controls as separate clusters. Compared to healthy controls, PSC patients had increased levels of monounsaturated fatty acids (MUFA) and palmitate (C16:0) in plasma, but reduced levels of long-chain saturated fatty acids (SFAs). These findings were more pronounced in PSC patients with cholestasis. Several n-3 polyunsaturated fatty acids were elevated in PSC but not associated with cholestasis. Acylcarnitine ratios C2/C5 and C2/C3 were elevated while C2/C16 was reduced in PSC, indicating impaired mitochondrial fatty acid oxidation of medium-long chained fatty acids. Levels of intermediates in the tryptophan-kynurenine pathway indicated impaired NAD biosynthesis, suggesting impaired energy supply to mitochondria in PSC.
Conclusions: We found that mitochondrial dysfunction was prominent in PSC and associated with increasing cholestasis. Whether this is merely a marker of liver disease and severity, or an underlying driver and potential therapeutic target in PSC remains to be explored.
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Karlsen, Tom Hemming; Jørgensen, Kristin Kaasen & Bergquist, Annika
(2024).
Medical treatment of Primary Sclerosing Cholangitis: what have we learned and where are we going?
Hepatology.
ISSN 0270-9139.
doi:
10.1097/HEP.0000000000001172.
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It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to a poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and the lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article, we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for ideal phase II and phase III study designs, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism toward hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate the prescription of compounds to people with PSC based on low-quality evidence.
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Karlsen, Tom Hemming; Vreim, Kristine; Røksund, Ola Drange; Vollsæter, Maria; Muralitharan, Praveen & Ellingsen, Thor Andre
[Vis alle 9 forfattere av denne artikkelen]
(2024).
A speech therapy treatment protocol for exercise induced laryngeal obstruction.
Frontiers in Pediatrics.
12.
doi:
10.3389/fped.2024.1356476.
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Background: Exercise induced laryngeal obstruction (EILO) is a common cause of exertional breathing problems in young individuals, relevant to 5%–7% of young people. It is caused by paradoxical inspiratory adduction of laryngeal structures and diagnosed by continuous visualization of the larynx during high intensity exercise. Empirical data suggest that EILO consists of different subtypes that require different therapeutic approaches. Currently applied treatment approaches do not rest on randomized controlled trials (RCTs), and thus evidence-based guidelines cannot be established. This protocol describes the speech therapy treatment approach which is applied to EILO patients in a large prospective RCT called HelpILO. Methods and analysis: Consenting patients consecutively diagnosed with EILO at Haukeland University Hospital are randomized into four treatment arms. Speech therapy is represented in two of these, provided in a structured manner based on general speech therapy principles and abdominal breathing, combined with experience obtained with these patients at our hospital during the last decades. The main outcome measure of HelpILO is changes of laryngoscopically visualized laryngeal adduction, rated at peak exercise before vs. after interventions, using a validated scoring system. Ethics and dissemination: Despite widespread use of speech therapy in patients with EILO, this approach is insufficiently tested in RCTs, and the study is therefore considered ethically appropriate. The study will provide knowledge listed as a priority in a recent statement issued by major respiratory and laryngological societies and requested by clinicians and researchers engaged in this area. The results will be presented at relevant conferences, patient fora, and media platforms, and published in relevant peer reviewed international journals.
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Yang, Mingyi; Kaarbø, Mari; Myhre, Vegard; Reims, Henrik Mikael; Karlsen, Tom Hemming & Wang, Junbai
[Vis alle 13 forfattere av denne artikkelen]
(2024).
Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients.
Journal of Clinical Immunology.
ISSN 0271-9142.
44(6),
s. 1–16.
doi:
10.1007/s10875-024-01726-5.
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Purpose A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. Methods DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). Results The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. Conclusion This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.
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Frank, Anna Katharina; Chung, Brian K.; Novales, Miguel Larraz Lopez De; Engesæter, Lise Katrine; Hoyle, Henry William & Øgaard, Jonas Daniel Sjøberg
[Vis alle 15 forfattere av denne artikkelen]
(2024).
Single-Cell Transcriptomic Profiling of Cholangiocyte Organoids Derived from Bile Ducts of Primary Sclerosing Cholangitis Patients.
Digestive Diseases and Sciences.
ISSN 0163-2116.
69,
s. 3810–3823.
doi:
10.1007/s10620-024-08570-y.
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Background and Aims Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disorder without effective medical treatment which is characterized by inflammation and fibrotic structures around the bile ducts. Biliary epithelial cells (cholangiocytes) are the target and potential disease drivers in PSC, yet little is known if cholangiocytes from PSC patients differ from non-PSC controls. To characterize cholangiocytes at early rather than end-stage disease, cholangiocyte organoids (COs) were derived from diseased bile ducts of PSC patients and compared to organoids generated from disease controls. Methods Cholangiocytes were obtained during endoscopic retrograde cholangiopancreatography (ERCP) brushing of diseased bile duct areas and expanded as organoids using previously established culture methods. Stable CO lines were analyzed for cell type identity, basic cholangiocyte function, and transcriptomic signature. Results We demonstrate that cholangiocytes, derived from the damaged area within the bile ducts of PSC patients, can be expanded in culture without displaying functional or genetic disease-related features. We further show that COs from patients who later were diagnosed with dysplasia exhibit higher expression of the cancer-associated genes PGC, FXYD2, MIR4435-2HG, and HES1. Conclusions Our results demonstrate that PSC organoids are largely similar to control organoids after culture and highlight the significance of COs as a tool for regenerative medicine approaches as well as their potential for discovering new potential biomarkers for diagnosing cholangiocarcinoma.
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Grimsrud, Marit Mæhle; Forster, Michael; Goeppert, Benjamin; Hemmrich-Stanisak, Georg; Sax, Irmi & Grzyb, Krzysztof
[Vis alle 21 forfattere av denne artikkelen]
(2024).
Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.
Hepatology communications..
8(7).
doi:
10.1097/HC9.0000000000000461.
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Background: People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. Methods: We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. Results: We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. Conclusions: In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.
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Braadland, Peder Rustøen; Bergquist, Annika; Kummen, Martin; Bossen, Lars; Engesæter, Lise Katrine & Reims, Henrik Mikael
[Vis alle 21 forfattere av denne artikkelen]
(2023).
Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation.
Journal of Hepatology.
ISSN 0168-8278.
79(4),
s. 955–966.
doi:
10.1016/j.jhep.2023.05.038.
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Background and aims We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5’-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). Methods We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. Results In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. Conclusions Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. Impact and implications We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.
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Grant, Caroline W; Juran, Brian D; Ali, Ahmad H; Schlicht, Erik M; Bianchi, Jackie K & Hu, Xin
[Vis alle 19 forfattere av denne artikkelen]
(2023).
Environmental chemicals and endogenous metabolites in bile of USA and Norway patients with primary sclerosing cholangitis.
Exposome.
3(1).
doi:
10.1093/exposome/osac011.
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Abstract Primary sclerosing cholangitis (PSC) is a complex bile duct disorder. Its etiology is incompletely understood, but environmental chemicals likely contribute to risk. Patients with PSC have an altered bile metabolome, which may be influenced by environmental chemicals. This novel study utilized state-of-the-art high-resolution mass spectrometry (HRMS) with bile samples to provide the first characterization of environmental chemicals and metabolomics (collectively, the exposome) in PSC patients located in the United States of America (USA) (n = 24) and Norway (n = 30). First, environmental chemical- and metabolome-wide association studies were conducted to assess geographic-based similarities and differences in the bile of PSC patients. Nine environmental chemicals (false discovery rate, FDR &lt; 0.20) and 3143 metabolic features (FDR &lt; 0.05) differed by site. Next, pathway analysis was performed to identify metabolomic pathways that were similarly and differentially enriched by the site. Fifteen pathways were differentially enriched (P &lt; .05) in the categories of amino acid, glycan, carbohydrate, energy, and vitamin/cofactor metabolism. Finally, chemicals and pathways were integrated to derive exposure–effect correlation networks by site. These networks demonstrate the shared and differential chemical–metabolome associations by site and highlight important pathways that are likely relevant to PSC. The USA patients demonstrated higher environmental chemical bile content and increased associations between chemicals and metabolic pathways than those in Norway. Polychlorinated biphenyl (PCB)-118 and PCB-101 were identified as chemicals of interest for additional investigation in PSC given broad associations with metabolomic pathways in both the USA and Norway patients. Associated pathways include glycan degradation pathways, which play a key role in microbiome regulation and thus may be implicated in PSC pathophysiology.
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Mayer, Carlotta; Nehring, Sophie; Kücken, Michael; Repnik, Urska; Seifert, Sarah & Sljukic, Aleksandra
[Vis alle 18 forfattere av denne artikkelen]
(2023).
Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.
EMBO Reports.
ISSN 1469-221X.
24(9).
doi:
10.15252/embr.202357181.
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Abstract Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.
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Lapitz, Ainhoa; Azkargorta, Mikel; Milkiewicz, Piotr; Olaizola, Paula; Zhuravleva, Ekaterina & Grimsrud, Marit Mæhle
[Vis alle 35 forfattere av denne artikkelen]
(2023).
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma.
Journal of Hepatology.
ISSN 0168-8278.
79(1),
s. 93–108.
doi:
10.1016/j.jhep.2023.02.027.
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Background & Aims Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. Results High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients’ survival, respectively. Conclusions Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine. Impact and implications The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.
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Wacker, Eike Matthias; Uellendahl-Werth, Florian; Bej, Saptarshi; Wolkenhauer, Olaf; Vesterhus, Mette Nåmdal & Lieb, Wolfgang
[Vis alle 10 forfattere av denne artikkelen]
(2023).
Whole blood RNA sequencing identifies transcriptional differences between primary sclerosing cholangitis and ulcerative colitis.
JHEP Reports.
6(2).
doi:
10.1016/j.jhepr.2023.100988.
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Background & Aims: Genetic and microbiome studies across patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have indicated that UC in PSC is a separate disease entity to primary UC, but expression studies for PSC are lacking. Methods: We conducted whole blood RNA sequencing experiments for 495 patients with UC, 220 patients with PSC (including 177 with UC), and 320 healthy controls from Germany and Norway. Differential expression analyses, gene ontology and coexpression analyses and random forest machine learning were performed to identify genes, ontologies and transcriptional features that discriminate diagnoses. Results: The blood transcriptome in UC and PSC is dominated by neutrophil activation genes (e.g. S100A12). In UC, but not in PSC (neither PSC alone nor patients with an additional diagnosis of UC [PSC/UC]), ribosomal, mitochondrial, and energy metabolism genes are upregulated in conjunction with antibody transcript expression (MZB1, IGJ). In PSC, there is an increase in modules related to apoptosis and expression of genes of interferon-I-related ontologies. Random forest analysis could poorly discriminate PSC alone from PSC/UC (AUROC 0.56), but could discriminate PSC, UC, and controls with high accuracy (AUROC UC vs. controls 0.95, PSC vs. controls 0.88, UC vs. PSC 0.986). The main coexpression modules relevant for distinguishing PSC, UC, and controls are enriched in neutrophil degranulation and antibody production genes. Conclusions: Supported by machine learning results, PSC and UC appear to be separate entities on a molecular level, while PSC/UC and PSC are indistinguishable. Impact and implications: Clinical and genetic studies suggest that the colitis-like symptoms in primary sclerosing cholangitis (PSC) represent a different disease entity from primary ulcerative colitis (UC). The present study supports this assumption with transcriptomic data from whole blood and describes notable differences in gene expression between primary UC and PSC, providing insights into the still unclear pathophysiology of both diseases. These findings are of interest to scientists seeking to decipher the molecular pathophysiology of both diseases and provide evidence that a redefinition of the PSC-UC phenotype should be considered. The study practically supports future molecular research by providing a large transcriptomic whole blood reference cohort.
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Han, Younghun; Byun, Jinyoung; Zhu, Catherine; Sun, Ryan; Roh, Julia Y. & Cordell, Heather J.
[Vis alle 26 forfattere av denne artikkelen]
(2023).
Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.
Nature Communications.
14(1),
s. 1–13.
doi:
10.1038/s41467-023-36678-8.
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Abstract Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5 . Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.
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Baumdick, Marin E; Niehrs, Annika; Degenhardt, Frauke; Schwerk, Maria; Hinrichs, Ole & Jordan-Paiz, Ana
[Vis alle 33 forfattere av denne artikkelen]
(2023).
HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis.
Gastroenterology.
ISSN 0016-5085.
165(4),
s. 946–962.
doi:
10.1053/j.gastro.2023.06.034.
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Background & Aims Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.
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Meer, Dennis van der; Gurholt, Tiril Pedersen; Sønderby, Ida Elken; Shadrin, Alexey; Hindley, Guy Frederick Lanyon & Rahman, Zillur
[Vis alle 18 forfattere av denne artikkelen]
(2022).
The link between liver fat and cardiometabolic diseases is highlighted by genome-wide association study of MRI-derived measures of body composition.
Communications Biology.
5(1).
doi:
10.1038/s42003-022-04237-4.
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Abstract Obesity and associated morbidities, metabolic associated fatty liver disease (MAFLD) included, constitute some of the largest public health threats worldwide. Body composition and related risk factors are known to be heritable and identification of their genetic determinants may aid in the development of better prevention and treatment strategies. Recently, large-scale whole-body MRI data has become available, providing more specific measures of body composition than anthropometrics such as body mass index. Here, we aimed to elucidate the genetic architecture of body composition, by conducting genome-wide association studies (GWAS) of these MRI-derived measures. We ran both univariate and multivariate GWAS on fourteen MRI-derived measurements of adipose and muscle tissue distribution, derived from scans from 33,588 White European UK Biobank participants (mean age of 64.5 years, 51.4% female). Through multivariate analysis, we discovered 100 loci with distributed effects across the body composition measures and 241 significant genes primarily involved in immune system functioning. Liver fat stood out, with a highly discoverable and oligogenic architecture and the strongest genetic associations. Comparison with 21 common cardiometabolic traits revealed both shared and specific genetic influences, with higher mean heritability for the MRI measures (h 2 = .25 vs. .13, p = 1.8x10 −7 ). We found substantial genetic correlations between the body composition measures and a range of cardiometabolic diseases, with the strongest correlation between liver fat and type 2 diabetes (r g = .49, p = 2.7x10 −22 ). These findings show that MRI-derived body composition measures complement conventional body anthropometrics and other biomarkers of cardiometabolic health, highlighting the central role of liver fat, and improving our knowledge of the genetic architecture of body composition and related diseases.
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Braadland, Peder Rustøen; Schneider, Kai Markus; Bergquist, Annika; Molinaro, Antonio; Lövgren-Sandblom, Anita & Henricsson, Marcus
[Vis alle 11 forfattere av denne artikkelen]
(2022).
Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis.
JHEP Reports.
4(11),
s. 1–10.
doi:
10.1016/j.jhepr.2022.100561.
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Background & Aims: Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods: Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results: The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions: Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation.
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Singh, Yashbir; Jons, William A.; Eaton, John E.; Vesterhus, Mette Nåmdal; Karlsen, Tom Hemming & Bjørk, Ida Torunn
[Vis alle 21 forfattere av denne artikkelen]
(2022).
Algebraic topology-based machine learning using MRI predicts outcomes in primary sclerosing cholangitis.
European Radiology Experimental.
6.
doi:
10.1186/s41747-022-00312-x.
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Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that can lead to cirrhosis and hepatic decompensation. However, predicting future outcomes in patients with PSC is challenging. Our aim was to extract magnetic resonance imaging (MRI) features that predict the development of hepatic decompensation by applying algebraic topology-based machine learning (ML). Methods: We conducted a retrospective multicenter study among adults with large duct PSC who underwent MRI. A topological data analysis-inspired nonlinear framework was used to predict the risk of hepatic decompensation, which was motivated by algebraic topology theory-based ML. The topological representations (persistence images) were employed as input for classification to predict who developed early hepatic decompensation within one year after their baseline MRI. Results: We reviewed 590 patients; 298 were excluded due to poor image quality or inadequate liver coverage, leaving 292 potentially eligible subjects, of which 169 subjects were included in the study. We trained our model using contrast-enhanced delayed phase T1-weighted images on a single center derivation cohort consisting of 54 patients (hepatic decompensation, n = 21; no hepatic decompensation, n = 33) and a multicenter independent validation cohort of 115 individuals (hepatic decompensation, n = 31; no hepatic decompensation, n = 84). When our model was applied in the independent validation cohort, it remained predictive of early hepatic decompensation (area under the receiver operating characteristic curve = 0.84). Conclusions: Algebraic topology-based ML is a methodological approach that can predict outcomes in patients with PSC and has the potential for application in other chronic liver diseases.
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Chung, Brian K.; Øgaard, Jonas; Reims, Henrik Mikael; Karlsen, Tom Hemming & Melum, Espen
(2022).
Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis.
Hepatology communications..
6(9),
s. 2538–2550.
doi:
10.1002/hep4.2001.
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Liver fibrosis and cirrhosis have limited therapeutic options and represent a serious unmet patient need. Recent use of single-cell RNA sequencing (scRNAseq) has identified enriched cell types infiltrating cirrhotic livers but without defining the microanatomical location of these lineages thoroughly. To assess whether fibrotic liver regions specifically harbor enriched cell types, we explored whether whole-tissue spatial transcriptomics combined with scRNAseq and gene deconvolution analysis could be used to localize cell types in cirrhotic explants of patients with end-stage liver disease (total n = 8; primary sclerosing cholangitis, n = 4; primary biliary cholangitis, n = 2, alcohol-related liver disease, n = 2). Spatial transcriptomics clearly identified tissue areas of distinct gene expression that strongly correlated with the total area (Spearman r = 0.97, p = 0.0004) and precise location (parenchyma, 87.9% mean congruency; range, 73.1%–97.1%; fibrosis, 68.5% mean congruency; range, 41.0%–91.7%) of liver regions classified as parenchymal or fibrotic by conventional histology. Deconvolution and enumeration of parenchymal and fibrotic gene content as measured by spatial transcriptomics into distinct cell states revealed significantly higher frequencies of ACTA2+ FABP4+ and COL3A1+ mesenchymal cells, IL17RA+ S100A8+ and FCER1G+ tissue monocytes, VCAM1+ SDC3+ Kupffer cells, CCL4+ CCL5+ KLRB1+ and GZMA+ IL17RA+ T cells and HLA-DR+, CD37+ CXCR4+ and IGHM+ IGHG+ B cells in fibrotic liver regions compared with parenchymal areas of cirrhotic explants. Conclusion: Our findings indicate that spatial transcriptomes of parenchymal and fibrotic liver regions express unique gene content within cirrhotic liver and demonstrate proof of concept that spatial transcriptomes combined with additional RNA sequencing methodologies can refine the localization of gene content and cell lineages in the search for antifibrotic targets.
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Kaarbø, Mari; Yang, Mingyi; Hov, Johannes Espolin Roksund; Holm, Kristian; Sousa, Mirta & Macpherson, Magnhild Eide
[Vis alle 15 forfattere av denne artikkelen]
(2022).
Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses.
Journal of Allergy and Clinical Immunology.
ISSN 0091-6749.
doi:
10.1016/j.jaci.2022.09.029.
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Background
A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism.
Objective
We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID.
Methods
DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry–based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed.
Results
CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls—DBNL, TRMT11, GCHFR, and IGHA2—independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls.
Conclusion
Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID.
Key words
CVID
RNA sequencing
proteomics
microbiome
gut microbiota
microbiota
gastrointestinal tract
duodenum
celiac disease
Primary immunodeficiency
IgA
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Hole, Mikal Jacob; Jørgensen, Kristin Kaasen; Holm, Kristian; Braadland, Peder Rustøen; Meyer-Myklestad, Malin Holm & Medhus, Asle Wilhelm
[Vis alle 13 forfattere av denne artikkelen]
(2022).
A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation.
Hepatology.
ISSN 0270-9139.
doi:
10.1002/hep.32773.
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Background and Aims Several characteristic features of the fecal microbiota have been described in primary sclerosing cholangitis (PSC), whereas data on mucosal microbiota are less consistent. We aimed to use a large colonoscopy cohort to investigate key knowledge gaps, including the role of gut microbiota in PSC with inflammatory bowel disease (IBD), the effect of liver transplantation (LT), and whether recurrent PSC (rPSC) may be used to define consistent microbiota features in PSC irrespective of LT. Approach and Results We included 84 PSC and 51 liver transplanted PSC patients (PSC-LT) and 40 healthy controls (HCs) and performed sequencing of the 16S ribosomal RNA gene (V3–V4) from ileocolonic biopsies. Intraindividual microbial diversity was reduced in both PSC and PSC-LT versus HCs. An expansion of Proteobacteria was more pronounced in PSC-LT (up to 19% relative abundance) than in PSC (up to 11%) and HCs (up to 8%; QFDR < 0.05). When investigating PSC before (PSC vs. HC) and after LT (rPSC vs. no-rPSC), increased variability (dispersion) in the PSC group was found. Five genera were associated with PSC before and after LT. A dysbiosis index calculated from the five genera, and the presence of the potential pathobiont, Klebsiella, were associated with reduced LT-free survival. Concomitant IBD was associated with reduced Akkermansia. Conclusions Consistent mucosal microbiota features associated with PSC, PSC-IBD, and disease severity, irrespective of LT status, highlight the usefulness of investigating PSC and rPSC in parallel, and suggest that the impact of gut microbiota on posttransplant liver health should be investigated further.
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Valestrand, Laura Cecilie; Zheng, Fei; Hansen, Simen Hyll; Øgaard, Jonas; Hov, Johannes Espolin Roksund & Björkström, Niklas K.
[Vis alle 9 forfattere av denne artikkelen]
(2022).
Bile from Patients with Primary Sclerosing Cholangitis Contains Mucosal-Associated Invariant T-Cell Antigens.
American Journal of Pathology.
ISSN 0002-9440.
192(4),
s. 629–641.
doi:
10.1016/j.ajpath.2021.12.008.
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Primary sclerosing cholangitis (PSC) is associated with altered microbiota of the gut and bile. Mucosal-associated invariant T (MAIT) cells, enriched in human liver, uniquely recognize microbial-derived metabolites. This study aimed to determine whether bile from patients with PSC contains antigens activating MAIT cells. Bile was collected at the time of liver transplantation from patients with PSC (n = 28). The bile samples were either directly incubated with peripheral blood mononuclear cells from healthy donors or with antigen-presenting cells followed by co-culture with peripheral blood mononuclear cells. MAIT cell activation was assessed by flow cytometry. An anti-MR1 antibody was used to determine whether the activation was major histocompatibility complex class I–related protein (MR1) restricted. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing, and the abundance of the bacterial gene ribD was predicted. Eight of 28 bile samples could activate MAIT cells. This activation was partly MR1-dependent in five of eight bile samples. Microbial DNA was detected in 15 of 28 bile samples, including the five bile samples leading to MR1-dependent activation. A higher abundance of the ribD gene expression in the group of bile samples that could activate MAIT cells was predicted on the basis of the 16S sequencing. In co-culture experiments, cholangiocytes could take up and present biliary antigens to MAIT cells. These findings suggest a pathophysiological pathway in PSC connecting the immune system and the microbiome.
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Hov, Johannes Espolin Roksund & Karlsen, Tom Hemming
(2022).
The microbiota and the gut–liver axis in primary sclerosing cholangitis.
Nature reviews: Gastroenterology & hepatology.
ISSN 1759-5045.
doi:
10.1038/s41575-022-00690-y.
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Degenhardt, Frauke; Ellinghaus, David; Juzenas, Simonas; Lerga-Jaso, Jon; Wendorff, Mareike & Maya-Miles, Douglas
[Vis alle 51 forfattere av denne artikkelen]
(2022).
Detailed stratified GWAS analysis for severe COVID-19 in four European populations.
Human Molecular Genetics.
ISSN 0964-6906.
31(23),
s. 3945–3966.
doi:
10.1093/hmg/ddac158.
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Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution
to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended
genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488
population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease
severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2
peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ∼0.9-Mb inversion polymorphism that creates
two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th
release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new
locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
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Cruz, Raquel; Almeida, Silvia Diz-de; Heredia, Miguel López de; Quintela, Inés; Ceballos, Francisco C. & Pita, Guillermo
[Vis alle 165 forfattere av denne artikkelen]
(2022).
Novel genes and sex differences in COVID-19 severity.
Human Molecular Genetics.
ISSN 0964-6906.
31(22),
s. 3789–3806.
doi:
10.1093/hmg/ddac132.
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Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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Uellendahl-Werth, Florian; Maj, Carlo; Borisov, Oleg; Juzenas, Simonas; Wacker, Eike Matthias & Jørgensen, Isabella Friis
[Vis alle 21 forfattere av denne artikkelen]
(2022).
Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease.
Communications Biology.
5(1).
doi:
10.1038/s42003-022-03031-6.
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Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies for 23 tissues of the gut-brain-axis using genome-wide association studies data sets (total 180,592 patients) for Crohn’s disease, ulcerative colitis, primary sclerosing cholangitis, schizophrenia, bipolar disorder, major depressive disorder and attention-deficit/hyperactivity disorder. We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory ulcerative colitis) as shared susceptibility genes with transcriptome-wide significance both for Crohn’s disease, ulcerative colitis and schizophrenia, largely explaining fine-mapped association signals at nearby genome-wide association study susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the gut-brain-axis. PPP3CA together with three further suggestive loci can be linked to calcineurin-related signaling pathways such as NFAT activation or Wnt.
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Hammer, Quirin; Dunst, Josefine; Christ, Wanda; Picarazzi, Francesca; Wendorff, Mareike & Momayyezi, Pouria
[Vis alle 51 forfattere av denne artikkelen]
(2022).
SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells.
Cell reports.
38(10).
doi:
10.1016/j.celrep.2022.110503.
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Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.
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Niemi, Mari E.K.; Karjalainen, Juha; Liao, Rachel G.; Neale, Benjamin M.; Daly, Mark & Ganna, Andrea
[Vis alle 84 forfattere av denne artikkelen]
(2021).
Mapping the human genetic architecture of COVID-19.
Nature.
ISSN 0028-0836.
600(7889),
s. 472–477.
doi:
10.1038/s41586-021-03767-x.
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The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
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Vedeld, Hege Marie; Grimsrud, Marit Mæhle; Andresen, Kim; Pharo, Heidi Dietrichson; Seth, Erik von & Karlsen, Tom Hemming
[Vis alle 15 forfattere av denne artikkelen]
(2021).
Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile.
Hepatology.
ISSN 0270-9139.
doi:
10.1002/hep.32125.
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Background and Aims Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. Approach and Results Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77–0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow-up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSC ≤ 12 patients, all positive for the biomarkers, included both early-stage and late-stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19-9 levels. Conclusions Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.
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Dhillon, Amandeep Kaur; Rupp, Christian; Bergquist, Annika; Voitl, Robert; Folseraas, Trine & Trøseid, Marius
[Vis alle 12 forfattere av denne artikkelen]
(2021).
Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis.
Scandinavian Journal of Gastroenterology.
ISSN 0036-5521.
56(4),
s. 443–452.
doi:
10.1080/00365521.2021.1880627.
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Background and aims Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine–tryptophanratio (KT-ratio) in PSC. Methods Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. Results Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50–0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23–0.42) in all cohorts. Conclusions Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.
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Degenhardt, Frauke; Mayr, Gabriele; Wendorff, Mareike; Boucher, Gabrielle; Ellinghaus, Eva & Ellinghaus, David
[Vis alle 51 forfattere av denne artikkelen]
(2021).
Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.
Human Molecular Genetics.
ISSN 0964-6906.
30(5),
s. 356–369.
doi:
10.1093/hmg/ddab017.
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Abstract Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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Vesterhus, Mette; Nielsen, Mette Juul; Hov, Johannes Roksund; Saffioti, Francesca; Manon-Jensen, Tina & Leeming, Diana Julie
[Vis alle 12 forfattere av denne artikkelen]
(2021).
Comprehensive assessment of ECM turnover using serum biomarkers establishes PBC as a high-turnover autoimmune liver disease.
JHEP Reports.
3(1),
s. 1–11.
doi:
10.1016/j.jhepr.2020.100178.
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Background & Aims: Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover. Methods: Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM). Results: Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH (p <0.01). PRO-C3 correlated well with liver stiffness and showed the most striking differences between advanced and non-advanced liver disease; several of the other ECM markers were also associated with stage. PRO-C3 and other ECM markers were inversely associated with ursodeoxycholic acid treatment response in PBC and remission in AIH. All ECM remodelling markers were significantly elevated (p <0.05) in patients with PSC, PBC, or AIH compared with ulcerative colitis. Conclusions: In this first study comparing ECM turnover in autoimmune liver diseases, we found increased ECM turnover in PBC compared with either PSC or AIH. The study indicates that ECM remodelling is different in PSC, PBC, and AIH, suggesting differing opportunities for therapeutic intervention.
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Fossdal, Guri; Mjelle, Anders Batman; Wiencke, Kristine; Bjørk, Ida Torunn; Gilja, Odd Helge & Folseraas, Trine
[Vis alle 10 forfattere av denne artikkelen]
(2021).
Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF.
JHEP Reports.
3(5),
s. 1–10.
doi:
10.1016/j.jhepr.2021.100328.
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Background & Aims Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. Methods We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. Results At baseline, the median (range) ELF test was 9.3 (7.5–12.9) and median LSM 1.26 m/s (0.66–3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). Conclusions ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC.
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Bossen, Lars; Vesterhus, Mette Nåmdal; Hov, Johannes Espolin Roksund; Färkkilä, Martti; Rosenberg, William & Møller, Holger J.
[Vis alle 9 forfattere av denne artikkelen]
(2021).
Circulating Macrophage Activation Markers Predict Transplant-Free Survival in Patients With Primary Sclerosing Cholangitis.
Clinical and Translational Gastroenterology.
12(3),
s. e00315–e00315.
doi:
10.14309/ctg.0000000000000315.
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INTRODUCTION: Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC. METHODS: We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison. RESULTS: Median (interquartile range) sCD163 was 3.32 (2.27–5.60) and 1.96 (1.47–2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22–0.44) and 0.28 mg/L (0.20–0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients. DISCUSSION: Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516).
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Pagano, Ester; Elias, Joshua E.; Schneditz, Georg Thomas; Saveljeva, Svetlana; Holland, Lorraine M. & Borrelli, Francesca
[Vis alle 9 forfattere av denne artikkelen]
(2021).
Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment.
Gut.
ISSN 0017-5749.
doi:
10.1136/gutjnl-2020-323363.
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Objective Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers. Design Mice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays. Results Here, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors. Conclusions Activation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.
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Zheng, Thenghao; Ellinghaus, David; Juzenas, Simonas; Cossais, François; Burmeister, Greta & Mayr, Gabriele
[Vis alle 86 forfattere av denne artikkelen]
(2021).
Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.
Gut.
ISSN 0017-5749.
70(8),
s. 1538–1549.
doi:
10.1136/gutjnl-2020-323868.
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Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.
Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.
Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.
Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
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Reich, Maria; Spomer, Lina; Klindt, Caroline; Fuchs, Katharina; Stindt, Jan & Deutschmann, Kathleen
[Vis alle 33 forfattere av denne artikkelen]
(2021).
Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis.
Journal of Hepatology.
ISSN 0168-8278.
75(3),
s. 634–646.
doi:
10.1016/j.jhep.2021.03.029.
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Background & Aims Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis. Methods TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4-/-, Abcb4-/-/Tgr5Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4-/- mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models. Results TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4-/- livers, in Abcb4-/- extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4-/- mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4-/- BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4-/- livers. Conclusions Reduced TGR5 levels in BECs from patients with PSC and Abcb4-/- mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA.
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Valestrand, Laura Cecilie; Berntsen, Natalie Lie; Fei, Zheng; Schrumpf, Erik; Hansen, Simen Hyll & Karlsen, Tom Hemming
[Vis alle 10 forfattere av denne artikkelen]
(2020).
Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells.
Clinical and Experimental Immunology.
ISSN 0009-9104.
doi:
10.1111/cei.13541.
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Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non‐invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end‐stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non‐invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non‐invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT‐reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology.
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Lohse, Ansgar W.; Sebode, Marcial; Jørgensen, Marianne H.; Ytting, Henriette; Karlsen, Tom Hemming & Kelly, Deirdre
[Vis alle 8 forfattere av denne artikkelen]
(2020).
Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group.
Journal of Hepatology.
ISSN 0168-8278.
s. 1–12.
doi:
10.1016/j.jhep.2020.07.023.
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Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10–20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications.
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Kummen, Martin; Thingholm, Louise B.; Rühlemann, Malte C.; Holm, Kristian; Hansen, Simen Hyll & Moitinho-Silva, Lucas
[Vis alle 22 forfattere av denne artikkelen]
(2020).
Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.
Gastroenterology.
ISSN 0016-5085.
160(5).
doi:
10.1053/j.gastro.2020.12.058.
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Background & Aims To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). Methods Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. Results Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation–free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. Conclusions The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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Thaventhiran, James; Allen, Hana Lango; Burren, Oliver S; Rae, William; Greene, Daniel & Staples, Emily
[Vis alle 50 forfattere av denne artikkelen]
(2020).
Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
Nature.
ISSN 0028-0836.
583(7814),
s. 90–95.
doi:
10.1038/s41586-020-2265-1.
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Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1,2,3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
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Mousa, Omar Y; Juran, Brian D; McCauley, Bryan M.; Vesterhus, Mette; Folseraas, Trine & Turgeon, Coleman T.
[Vis alle 19 forfattere av denne artikkelen]
(2020).
Bile Acid Profiles in Primary Sclerosing Cholangitis and their Ability to Predict Hepatic Decompensation.
Hepatology.
ISSN 0270-9139.
74(1).
doi:
10.1002/hep.31652.
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Background and Aims: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). Conclusions: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.
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Vesterhus, Mette & Karlsen, Tom Hemming
(2020).
Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities.
Journal of gastroenterology.
ISSN 0944-1174.
55,
s. 588–614.
doi:
10.1007/s00535-020-01681-z.
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Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics.
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Kummen, Martin; Solberg, Ole Geir; Larsen, Christopher Storm; Holm, Kristian; Ragnarsson, Asgrimur & Trøseid, Marius
[Vis alle 18 forfattere av denne artikkelen]
(2020).
Rosuvastatin alters the genetic composition of the human gut microbiome.
Scientific Reports.
10:5397,
s. 1–9.
doi:
10.1038/s41598-020-62261-y.
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The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.
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Goeppert, Benjamin; Folseraas, Trine; Roessler, Stephanie; Kloor, Matthias; Volckmar, Anna-Lena & Endris, Volker
[Vis alle 36 forfattere av denne artikkelen]
(2020).
Genomic characterization of cholangiocarcinoma in primary sclerosing cholangitis reveals therapeutic opportunities.
Hepatology.
ISSN 0270-9139.
72(4),
s. 1253–1266.
doi:
10.1002/hep.31110.
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Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC‐associated BTC (PSC‐BTC). Approach and Results We analyzed formalin‐fixed, paraffin‐embedded tumor tissue from 186 patients with PSC‐BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC‐BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC‐BTC include a significant number of putative actionable therapeutic targets. Notably, PSC‐BTC shows a distinct extrahepatic morpho‐molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC‐associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome‐based personalized treatment strategies in PSC‐BTC.
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Liwinski, Timur; Zenouzi, Roman; John, Clara; Ehlken, Hanno; Rühlemann, Malte C. & Bang, Corinna
[Vis alle 18 forfattere av denne artikkelen]
(2019).
Alterations of the bile microbiome in primary sclerosing cholangitis.
Gut.
ISSN 0017-5749.
s. 1–8.
doi:
10.1136/gutjnl-2019-318416.
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Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC.Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1–V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20).The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10−5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021).PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.
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Dhillon, Amandeep Kaur; Kremer, Andreas E.; Kummen, Martin; Boberg, Kirsten Muri; Elferink, Ronald P. Oude & Karlsen, Tom Hemming
[Vis alle 9 forfattere av denne artikkelen]
(2019).
Autotaxin activity predicts transplant-free survival in primary sclerosing cholangitis.
Scientific Reports.
9(1).
doi:
10.1038/s41598-019-44762-7.
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Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n=165) and one validation panel (n=87). Serum activity of autotaxin was measured in diluted sera by a fuorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n=118 [71.5%]; validation panel: n=35 [40.2%]), showed higher autotaxin activity compared with the other patients, P<0.001 and P=0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P<0.001, validation panel: P=0.001). There was no relationship between autotaxin activity and the presence of infammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confdence interval 1.21–3.40), P<0.01), independent from Mayo risk score, an in-house enhanced liver fbrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplantfree survival independent from Mayo risk score and markers of infammation and fbrosis.
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Melum, Espen; Jiang, Xiaojun; Baker, Kirsti B; Macedo, M Fatima; Fritsch, Jürgen & Dowds, C Marie
[Vis alle 21 forfattere av denne artikkelen]
(2019).
Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.
Nature Immunology.
ISSN 1529-2908.
20(12),
s. 1644–1655.
doi:
10.1038/s41590-019-0504-0.
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Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann–Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.
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Rühlemann, Malte C.; Liwinski, Timur; Heinsen, Femke-Anouska; Bang, Corinna; Zenouzi, Roman & Kummen, Martin
[Vis alle 17 forfattere av denne artikkelen]
(2019).
Consistent alterations in faecal microbiomes of patients with primary sclerosing cholangitis independent of associated colitis.
Alimentary Pharmacology and Therapeutics.
ISSN 0269-2813.
50(5),
s. 580–589.
doi:
10.1111/apt.15375.
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Background Single‐centre studies reported alterations of faecal microbiota in patients with primary sclerosing cholangitis (PSC). As regional factors may affect microbial communities, it is unclear if a microbial signature of PSC exists across different geographical regions. Aim To identify a robust microbial signature of PSC independent of geography and environmental influences. Methods We included 388 individuals (median age, 47 years; range, 15‐78) from Germany and Norway in the study, 137 patients with PSC (n = 75 with colitis), 118 with ulcerative colitis (UC) and 133 healthy controls. Faecal microbiomes were analysed by 16S rRNA gene sequencing (V1‐V2). Differences in relative abundances of single taxa were subjected to a meta‐analysis. Results In both cohorts, microbiota composition (beta‐diversity) differed between PSC patients and controls (P < 0.001). Random forests classification discriminated PSC patients from controls in both geographical cohorts with an average area under the curve of 0.88. Compared to healthy controls, many new cohort‐spanning alterations were identified in PSC, such as an increase of Proteobacteria and the bile‐tolerant genus Parabacteroides, which were detected independent from geographical region. Associated colitis only had minor effects on microbiota composition, suggesting that PSC itself drives the faecal microbiota changes observed. Conclusion Compared to healthy controls, numerous microbiota alterations are reproducible in PSC patients across geographical regions, clearly pointing towards a microbiota composition that is shaped by the disease itself and not by environmental factors. These reproducibly altered microbial populations might provide future insights into the pathophysiology of PSC.
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Bergquist, Annika; Seth, Erik von; Karlsen, Tom Hemming; Tanaka, Atsushi & Ponsioen, Cyriel
(2026).
Advances in primary sclerosing cholangitis care – Authors' reply.
The Lancet.
ISSN 0140-6736.
408(10562),
s. 1311–1312.
doi:
10.1016/S0140-6736(26)01802-7.
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Hov, Johannes Espolin Roksund; Molberg, Øyvind & Karlsen, Tom Hemming
(2024).
Tubulin beta 5 is not the target of antineutrophil antibodies in primary sclerosing cholangitis.
Clinical and Experimental Immunology.
ISSN 0009-9104.
218(1),
s. 75–77.
doi:
10.1093/cei/uxae053.
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Jørgensen, Silje Fjellgård; Macpherson, Magnhild Eide; Bjørnetrø, Tonje; Holm, Kristian; Kummen, Martin & Rashidi, Azita
[Vis alle 18 forfattere av denne artikkelen]
(2024).
Retraction to: Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency (Scientific Reports, (2019), 9, 1, (167), 10.1038/s41598-018-35367-7).
Scientific Reports.
14(1).
doi:
10.1038/s41598-024-54117-6.
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Haukeland, John Willy; Vesterhus, Mette Nåmdal; Jørgensen, Kristin Kaasen; Frigstad, Svein Oskar & Karlsen, Tom Hemming
(2023).
FIB-4-testen som beslutningsverktøy.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
143(5).
doi:
10.4045/tidsskr.23.0176.
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Hole, Mikal Jacob; Jørgensen, Kristin Kaasen; Holm, Kristian; Braadland, Peder Rustøen; Meyer-Myklestad, Malin Holm & Medhus, Asle Wilhelm
[Vis alle 13 forfattere av denne artikkelen]
(2023).
Reply: The mucosal gut signature in primary sclerosing cholangitis before and after liver transplantation. Is the dysbiosis index really predictive for the recurrence of PSC?
Hepatology.
ISSN 0270-9139.
77(6),
s. E188–E189.
doi:
10.1097/HEP.0000000000000340.
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Graupera, Isabel; Thiele, Maja; Ma, Ann T.; Serra-Burriel, Miquel; Pich, Judit & Fabrellas, Núria
[Vis alle 47 forfattere av denne artikkelen]
(2023).
Correction: LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries (BMC Public Health, (2022), 22, 1, (1385), 10.1186/s12889-022-13724-6).
BMC Public Health.
23.
doi:
10.1186/s12889-023-15867-6.
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Krag, Aleksander & Karlsen, Tom Hemming
(2022).
Er leversygdomme et overset problem i Europa?
Ugeskrift for Læger.
ISSN 0041-5782.
184(4).
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Vesterhus, Mette Nåmdal; Jørgensen, Kristin Kaasen; Frigstad, Svein Oskar; Haukeland, John Willy & Karlsen, Tom Hemming
(2022).
Vi trenger en ny strategi for leversykdom.
142(3).
doi:
10.4045/tidsskr.21.0892.
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Thaventhiran, James E. D.; Allen, Hana Lango; Burren, Oliver S.; Rae, William; Greene, Daniel & Staples, Emily
[Vis alle 632 forfattere av denne artikkelen]
(2020).
Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort (Nature, (2020), 583, 7814, (90-95), 10.1038/s41586-020-2265-1).
Nature.
ISSN 0028-0836.
584(7819),
s. E2–E2.
doi:
10.1038/s41586-020-2556-6.
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Karlsen, Tom Hemming & Newsome, Phil N
(2019).
The dawn of a new EASL – A new chapter in the history of the European Association for the Study of the liver.
Journal of Hepatology.
ISSN 0168-8278.
71(1),
s. 5–8.
doi:
10.1016/j.jhep.2019.03.010.
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Tronstad, Rune Rose; Fiskerstrand, Torunn; Karlsen, Tom Hemming; Knappskog, Per & Hellard, Stephanie Le
(2019).
Clinical and molecular effects of guanylate cyclase C-activation.
Universitetet i Bergen.
ISSN 9788230843970.
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We studied a large Norwegian family who had been affected by chronic diarrhoea and other symptoms from the digestive tract throughout several generations. Our genetic studies showed that family members with diarrhoea shared markers on the short arm of chromosome 12. In this part of the genome we discovered a new genetic variant in GUCY2C. This variant was present in 32 family members with diarrhoea, but not in the healthy family members. We performed functional assays of the GUCY2C variant in a cell-model. These studies showed that the genetic variant encodes an increased activity of guanylate cyclase C (GC-C), a protein known to be involved in infectious diarrhoea. Apart from diarrhoea many family members had also experienced acute intestinal obstructions and/or inflammatory bowel disease (IBD) categorized as Crohn’s disease (CD). To our knowledge the constellation of symptoms experienced by our patients had not been reported previously and we assumed that we were dealing with a new disorder. We called this disorder Familial GUCY2C diarrhoea syndrome (FGDS). The publication in 2012 of our research constituted the first report of a human disorder caused by a change in the GUCY2C gene. The further work on this thesis aimed at discovering factors involved in the pathogenesis of FGDS with a main focus on its link to IBD. In parallel with our project multinational case-control studies were charting the genetic basis for IBD, and by 2015 more than 200 genetic associations had been identified. While GUCY2C has not been flagged by these population-based studies we hypothesised that common genetic variants within the GC-C pathway may still contribute to the risk of developing IBD. Rather than assessing single genes, we tested whether an aggregation of genes within the GC-C pathway was associated with IBD. For this analysis we used genetic association statistics made publicly available from the largest IBD case-control studies. The GC-C gene list did indeed show significant enrichment of association in IBD. We then looked at common IBD genetic risk variants in FGDS patients and found that genetic variants in the NOD2 gene distinguished FGDS patients affected by IBD from those not developing IBD. NOD2 encodes a protein involved in sensing and removal of bacteria in the intestinal wall. We studied which genes were differentially expressed in the distal small bowel of FGDS compared to healthy controls as well as patients with CD. Down regulation of metallothionein genes was found in FGDS patients regardless of concomitant IBD when compared to healthy but not when compared to CD. Metallothioneins may serve as signal transducers in the interplay between the human host and its resident bacteria (microbiota). Paucity of these antioxidant proteins may perturb epithelial sensing and clearance of microbes and has been reported in IBD. We hypothesised that GUCY2C related changes of the gut hydration could also impact on its bacterial composition. Using sequencing of the 16S ribosomal RNA gene we analysed the microbial composition in stool from adult FGDS patients, related and unrelated healthy controls as well as patients with IBD. Overall microbiota composition of FGDS patients was different from the other groups, but similar between healthy relatives and unrelated healthy controls. The microbiota of the FGDS patients displayed increased abundance of Enterobacteriaceae and loss of Faecalibacterium, findings that may have a pro-inflammatory potential and are found in IBD. In conclusion we here identified activating mutations of the GUCY2C gene as the cause of familial diarrhoea and defined a new disorder, Familial GUCY2C diarrhoea syndrome. Our work indicates that genetic testing for mutations in GUCY2C should be considered in patients presenting with early onset secretory diarrhoea. Apart from diarrhoea we also highlighted clinical complications potentially linked to hyperactivation of GUCY2C, such as IBD, intestinal obstruction and dysfunctional gut peristalsis. Our subsequent studies suggested that GUCY2C is involved in the crosstalk between the gut mucosa and the adjacent microbiota, providing a potential clue to the link between GUCY2C and IBD.
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