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- Alberts, R, et al.
(author)
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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
- 2018
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:8, s. 1517-1524
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Journal article (peer-reviewed)abstract
- Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
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- Brevini, T, et al.
(author)
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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7950, s. 134-
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Journal article (peer-reviewed)abstract
- Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
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- Lissing, M, et al.
(author)
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Liver Transplantation for Acute Intermittent Porphyria
- 2021
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In: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. - : Ovid Technologies (Wolters Kluwer Health). - 1527-6473. ; 27:4, s. 491-501
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Journal article (peer-reviewed)
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- Schrumpf, E., et al.
(author)
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The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation
- 2017
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In: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 66:2, s. 382-389
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Journal article (peer-reviewed)abstract
- Background & Aims: A strong association between human inflammatory biliary diseases and gut inflammation has led to the hypothesis that gut microbes and lymphocytes activated in the intestine play a role in biliary inflammation. The NOD.c3c4 mouse model develops spontaneous biliary inflammation in extra- and intrahepatic bile ducts. We aimed to clarify the role of the gut microbiota in the biliary disease of NOD.c3c4 mice. Methods: We sampled cecal content and mucosa from conventionally raised (CONV-R) NOD.c3c4 and NOD control mice, extracted DNA and performed 16S rRNA sequencing. NOD.c3c4 mice were rederived into a germ free (GF) facility and compared with CONV-R NOD.c3c4 mice. NOD.c3c4 mice were also co-housed with NOD mice and received antibiotics from weaning. Results: The gut microbial profiles of mice with and without biliary disease were different both before and after rederivation (unweighted UniFrac-distance). GF NOD.c3c4 mice had less distended extra-hepatic bile ducts than CONV-R NOD.c3c4 mice, while antibiotic treated mice showed reduction of biliary infarcts. GF animals also showed a reduction in liver weight compared with CONV-R NOD.c3c4 mice, and this was also observed in antibiotic treated NOD.c3c4 mice. Co-housing of NOD and NOD. c3c4 mice indicated that the biliary phenotype was neither transmissible nor treatable by co-housing with healthy mice. Conclusions: NOD.c3c4 and NOD control mice show marked differences in the gut microbiota. GF NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice. Our findings suggest that the intestinal micro biota contributes to disease in this murine model of biliary inflammation. Lay summary: Mice with liver disease have a gut microflora (microbiota) that differs substantially from normal mice. In a normal environment, these mice spontaneously develop disease in their bile ducts. However, when these mice, are raised in an environment devoid of bacteria, the disease in the bile ducts diminishes. Overall this clearly indicates that the bacteria in the gut (the gut microbiota) influences the liver disease in these mice. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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- Bergsmark, T., et al.
(author)
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Long-term survival after liver transplantation for alcohol-related liver disease in the Nordic countries
- 2023
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 58:8, s. 923-30
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Journal article (peer-reviewed)abstract
- ObjectivesAlcohol-related liver disease (ALD) is among the most common indications for liver transplantation (LTX) in Europe and North America, with good five-year survival rates post-LTX. Here we evaluated survival up to and beyond 20 years after LTX for patients with ALD compared to a comparison group.MethodsPatients with ALD and a comparison group transplanted in the Nordic countries between 1982 and 2020 were included. Data were analyzed using descriptive statistics, Kaplan-Meier curves and predictors of survival were assessed with Cox-regressions.Results831 patients with ALD and 2979 patients in the comparison group were included in the study. Patients with ALD were older at the time of LTX (p < .001) and more likely to be male (p < .001). The estimated median follow-up time was 9.1 years for the ALD-group and 11.1 years for the comparison group. 333 (40.1%) patients with ALD and 1010 (33.9%) patients in the comparison group died during follow-up. The overall survival was impaired for patients with ALD compared to the comparison group (p < .001) and was evident for male and female patients, patients transplanted before and after 2005, and observed in all age-groups except patients over 60 years. Age at transplant, waiting time, year of LTX and country of LTX were associated with decreased survival after LTX for patients with ALD.ConclusionsPatients with ALD have a decreased long-term survival following LTX. This difference was evident in most sub-groups of patients and warrants close follow-up of liver transplanted patients with ALD with focus on risk reduction.
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