24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ.

Background & Aims: Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods: NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results: NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1ß, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions: NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications: Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.

A gut bacterial signature in blood and liver tissue characterizes cirrhosis and hepatocellular carcinoma.

BACKGROUND: HCC is the leading cause of cancer in chronic liver disease. A growing body of experimental mouse models supports the notion that gut-resident and liver-resident microbes control hepatic immune responses and, thereby, crucially contribute to liver tumorigenesis. However, a comprehensive characterization of the intestinal microbiome in fueling the transition from chronic liver disease to HCC in humans is currently missing. METHODS: Here, we profiled the fecal, blood, and liver tissue microbiome of patients with HCC by 16S rRNA sequencing and compared profiles to nonmalignant cirrhotic and noncirrhotic NAFLD patients. RESULTS: We report a distinct bacterial profile, defined from 16S rRNA gene sequences, with reduced α-and ß-diversity in the feces of patients with HCC and cirrhosis compared to NAFLD. Patients with HCC and cirrhosis exhibited an increased proportion of fecal bacterial gene signatures in the blood and liver compared to NAFLD. Differential analysis of the relative abundance of bacterial genera identified an increased abundance of Ruminococcaceae and Bacteroidaceae in blood and liver tissue from both HCC and cirrhosis patients compared to NAFLD. Fecal samples from cirrhosis and HCC patients both showed a reduced abundance for several taxa, including short-chain fatty acid-producing genera, such as Blautia and Agathobacter. Using paired 16S rRNA and transcriptome sequencing, we identified a direct association between gut bacterial genus abundance and host transcriptome response within the liver tissue. CONCLUSIONS: Our study indicates perturbations of the intestinal and liver-resident microbiome as a critical determinant of patients with cirrhosis and HCC.

Liver Transplantation after Successful Downstaging of a Locally Advanced Hepatocellular Carcinoma with Systemic Therapy.

INTRODUCTION: Liver transplantation (LT) is potentially curative for patients with cirrhosis and hepatocellular carcinoma (HCC). However, this procedure is usually reserved for patients with early tumor stages or after successful downstaging with local regional therapies. In patients with locally advanced HCC, current guidelines recommend locoregional and palliative systemic therapies for tumor stages Barcelona Clinic Liver Cancer (BCLC) B and C, respectively. CASE REPORT: In this article, we describe a 63-year-old male patient with locally advanced HCC (BCLC C) and hepatitis C-associated cirrhosis. Following systemic treatment with the immune checkpoint inhibitor atezolizumab and the anti-VEGF antibody bevacizumab, significant downstaging to a tumor stage within the Milan criteria was achieved after which LT was successfully performed. CONCLUSION: As more effective systemic therapies become available, LT and potential curative treatment could become feasible for selected patients with locally advanced HCC.

Interleukin-11 drives human and mouse alcohol-related liver disease.

OBJECTIVE: Alcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide. Interleukin-11 (IL-11) is a profibrotic, proinflammatory cytokine with increasingly recognised toxicities in parenchymal and epithelial cells. We explored IL-11 serum levels and their prognostic value in patients suffering from AH and cirrhosis of various aetiology and experimental ALD. DESIGN: IL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort (n=186). Primary human hepatocytes exposed to ethanol were studied in vitro. Ethanol-fed wildtype mice were treated with a neutralising murine IL-11 receptor-antibody (anti-IL11RA) and examined for severity signs and markers of ALD. RESULTS: IL-11 serum concentration and hepatic expression increased with severity of liver disease, mostly pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 pg/mL was a model of end-stage liver disease independent risk factor for transplant-free survival in patients with compensated and decompensated cirrhosis. In mice, severity of alcohol-induced liver inflammation correlated with enhanced hepatic IL-11 and IL11RA expression. In vitro and in vivo, anti-IL11RA reduced pathogenic signalling pathways (extracellular signal-regulated kinases, c-Jun N-terminal kinase, NADPH oxidase 4) and protected hepatocytes and murine livers from ethanol-induced inflammation and injury. CONCLUSION: Pathogenic IL-11 signalling in hepatocytes plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signalling might be a therapeutic option in human ALD, particularly AH.

Multidisciplinary Treatment of Liver Metastases from Intracranial SFTs/HPCs: A Report of Three Consecutive Cases.

In the 2016 WHO classification of tumors of the central nervous system, hemangiopericytomas (HPCs) and solitary fibrous tumors (SFTs) were integrated into a new entity (SFT/HPC). Metastases to bone, liver, lung, and abdominal cavity are of concern. Only 37 cases of patients with liver metastases due to intracranial SFTs/HPCs have been reported. Herein, we present our experience in the management of patients with liver metastases from intracranial SFTs/HCPs. All consecutive patients who were treated for liver metastases from intracranial SFTs/HPCs from January 2014 to December 2020 were enrolled. Overall, three patients were treated for liver metastasis from SFTs/HPCs with curative intent. Two patients with bilobar metastases at presentation required surgical resection, transarterial embolization, stereotactic radiofrequency ablation (SRFA) and systemic therapy. One patient with a singular right liver lobe metastasis was treated with SRFA alone. This patient shows no evidence of liver metastases 39 months following diagnosis. Of the two patients with bilobar disease, one died 89 months following diagnosis, while one is still alive 73 months following diagnosis. Long-term survival can be achieved using a multimodal treatment concept, including surgery, loco-regional and systemic therapies. Referral to a specialized tertiary cancer center and comprehensive long-term follow-up examinations are essential.

Stereotactic radiofrequency ablation as a valid first-line treatment option for hepatocellular adenomas.

OBJECTIVES: This study aimed to assess the safety and efficacy of stereotactic radiofrequency ablation (SRFA) in patients with hepatocellular adenomas (HCA). METHODS: Retrospective analyses of all patients referred for SRFA treatment at our institution between January 2010 and October 2020 revealed 14 patients (10 women; mean age 34.4 [range, 17-73 years]) with 38 HCAs treated through 18 ablation sessions. Ablations were considered successful if a safety margin >5 mm was achieved. Demographic, interventional, and outcome data were collected and analyzed. Primary and secondary technical efficacy rates were assessed based on follow-up images consisting of contrast-enhanced CT or MR scans. RESULTS: The mean tumor size was 22 mm (range, 7-75 mm). Overall, 37/38 (97.4%) tumors were successfully ablated at the initial SRFA (primary efficacy rate of 97.4%). The median follow-up duration was 49.6 months. No deaths or adenoma-related complications (hemorrhage or malignant transformation) were observed. Disease-free survival rates at 1, 3, and 5 years from the date of the first SRFA were 100%, 85.8%, and 85.8%, respectively. Two patients developed new distant tumors retreated with consecutive re-ablation. No major complications occurred during any of the 18 ablation sessions. CONCLUSIONS: Percutaneous thermal ablation is efficient in the treatment of HCAs and may thus be considered a valid first-line treatment option. In addition, SRFA allows for an effective, minimally invasive treatment of large and multiple hepatic tumors within one session.

PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease.

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.

Distinct structural and dynamic components of portal hypertension in different animal models and human liver disease etiologies.

BACKGROUND AND AIMS: Liver fibrosis is the static and main (70%-80%) component of portal hypertension (PH). We investigated dynamic components of PH by a three-dimensional analysis based on correlation of hepatic collagen proportionate area (CPA) with portal pressure (PP) in animals or HVPG in patients. APPROACH AND RESULTS: Different animal models (bile duct ligation: n = 31, carbon tetrachloride: n = 12, thioacetamide: n = 12, choline-deficient high-fat diet: n = 12) and patients with a confirmed single etiology of cholestatic (primary biliary cholangitis/primary sclerosing cholangitis: n = 16), alcohol-associated (n = 22), and metabolic (NASH: n = 19) liver disease underwent CPA quantification on liver specimens/biopsies. Based on CPA-to-PP/HVPG correlation, potential dynamic components were identified in subgroups of animals/patients with lower-than-expected and higher-than-expected PP/HVPG. Dynamic PH components were validated in a patient cohort (n = 245) using liver stiffness measurement (LSM) instead of CPA. CPA significantly correlated with PP in animal models (Rho = 0.531; p < 0.001) and HVPG in patients (Rho = 0.439; p < 0.001). Correlation of CPA with PP/HVPG varied across different animal models and etiologies in patients. In models, severity of hyperdynamic circulation and specific fibrosis pattern (portal fibrosis: p = 0.02; septa width: p = 0.03) were associated with PH severity. In patients, hyperdynamic circulation (p = 0.04), vascular dysfunction/angiogenesis (VWF-Ag: p = 0.03; soluble vascular endothelial growth factor receptor 1: p = 0.03), and bile acids (p = 0.04) were dynamic modulators of PH. The LSM-HVPG validation cohort confirmed these and also indicated IL-6 (p = 0.008) and hyaluronic acid (HA: p < 0.001) as dynamic PH components. CONCLUSIONS: The relative contribution of "static" fibrosis on PH severity varies by type of liver injury. Next to hyperdynamic circulation, increased bile acids, VWF-Ag, IL-6, and HA seem to indicate a pronounced dynamic component of PH in patients.

Pediatric Malignant Peritoneal Mesothelioma With Meningeal Metastasis.

Malignant peritoneal mesothelioma (MPM) is an extremely rare entity with a poor prognosis. We report on a 16-year-old boy with ascites and abdominal distension. A computed tomography scan showed peritoneal thickening and a mass adjacent to the transverse colon. Neither repeated cytologic testing of ascitic fluid, nor peritoneal tissue biopsy detected malignant cells. After the patient became progressively comatose, a magnetic resonance imaging scan of the brain showed leptomeningeal enhancement. An autopsy showed MPM infiltrating the pleura and the meninges. This is the first report on meningeal metastasis of MPM in a pediatric patient illustrating the enigmatic behavior of the tumor and highlighting the diagnostic pitfalls.

When cardiac surgery comes to its limits: a case report of pericardial mesothelioma invading the myocardium.

BACKGROUND: Primary pericardial mesothelioma (PPM) is a rare form of highly aggressive cancer. Many patients are diagnosed only at an advanced stage. Therefore, the overall survival rate is poor with a median survival of 3 months. In some rare cases, the PPM infiltrates the myocardium causing lethal myocardial dysfunction. CASE SUMMARY: A 66-year-old patient was transferred to our centre with the provisional diagnose of pericarditis of unknown origin. Using extensive cardiac imaging [echocardiography, computed tomography (CT), positron emission tomography-CT, cardiac magnetic resonance imaging, left and right heart catheterization, coronary angiography], PPM was finally diagnosed. After consultation with the oncologists, the heart team decided to resect the tumour first due to impaired haemodynamics and then initiate adjuvant chemotherapy. Intraoperatively, myocardial infiltration of the tumour became apparent, which was not detected preoperatively despite intensive imaging. Complete resection of the PPM was not possible and effective decompression of the ventricle could not be achieved. The patient died on the first postoperative day. DISCUSSION: Surgical therapy is indicated in many forms of cardiac tumours. However, when a tumour invades the myocardium, surgery often comes to its limits. In this case, myocardial invasion of PPM could not be detected despite extensive imaging. We therefore suggest that possible myocardial infiltration by PPM, and thus potential limitations of cardiac surgery, should be considered independently of imaging results when therapeutic options are discussed.

Validation of the 'Inflammatory Bowel Disease-Distribution, Chronicity, Activity [IBD-DCA] Score' for Ulcerative Colitis and Crohn´s Disease.

BACKGROUND AND AIMS: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis [UC] and is also important in Crohn´s disease [CD]. Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease [IBD]-Distribution [D], Chronicity [C], Activity [A] score [IBD-DCA score] for histological disease activity assessment in IBD. METHODS: Inter- and intra-rater reliability were assessed by 16 observers on biopsy specimens from 59 patients with UC and 25 patients with CD. Construct validity and responsiveness to treatment were retrospectively evaluated in a second cohort of 30 patients. RESULTS: Inter-rater reliability was moderate to good for the UC cohort (intraclass correlation coefficients [ICCs] = 0.645, 0.623, 0.767 for D, C, and A, respectively) and at best moderate for the CD cohort [ICC = 0.690, 0.303, 0.733 for D, C, and A, respectively]. Intra-rater agreement ranged from good to excellent in both cohorts. Correlation with the Nancy Histological Index [NHI] was moderate and strong with the Simplified Geboes Score [SGS] and a Visual Analogue Scale [VAS], respectively. Large effect sizes were obtained for all three parameters. External responsiveness analysis revealed correlated changes between IBD-DCA score and NHI, SGS and VAS. CONCLUSIONS: The IBD-DCA score is a simple histological activity score for UC and CD, agreed and validated by a large group of IBD specialists. It provides reliable information on treatment response. Therefore, it has potential value for use in routine diagnostics as well as clinical studies.

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans.

OBJECTIVE: Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD. DESIGN: An unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models. RESULTS: Cirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis. CONCLUSION: Cirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

Faecal Biomarkers in Inflammatory Bowel Diseases: Calprotectin Versus Lipocalin-2-a Comparative Study.

BACKGROUND AND AIMS: Faecal biomarkers, particularly calprotectin [FCAL], have become important diagnostic and monitoring tools in inflammatory bowel diseases [IBD]. As FCAL is mainly produced by neutrophils, we hypothesised that faecal lipocalin-2 [FLCN2], also expressed by intestinal epithelial cells [IEC], could be beneficial in specific clinical situations. METHODS: We compared clinical and endoscopic activity-related correlations between FCAL and FLCN2, assayed from the same sample, in a cohort of 132 patients (72 Crohn's disease [CD]) and 40 controls. A detailed analysis of cellular origins was done by confocal microscopy and flow cytometry. To evaluate the potential to detect low-grade inflammation, we studied faecal and tissue concentrations in a cohort with clinical, endoscopic, and histological remission. RESULTS: There was an excellent correlation between FCAL and FLCN2 [rS = 0.87, p <0.001] and comparable sensitivity and specificity to predict clinical and endoscopic disease activity, with optimal thresholds for endoscopic activity of 73.4 and 1.98 µg/g in ulcerative colitis [UC] and 78.4 and 0.56 µg/g in Crohn's disease for FCAL and FLCN2, respectively. Strong co-expression of both proteins was observed in granulocytes and macrophages. IECs expressed LCN2 but not CAL. In our IBD cohort in deep remission neither FCAL nor FLCN2 was different from controls; yet mucosal LCN2 but not CAL expressions remained elevated in the rectum of UC and the ileum of CD patients. CONCLUSIONS: This study corroborates the diagnostic equivalence of FLCN2 and FCAL in IBD. In remission, persistent mucosal overexpression renders LCN2 an attractive candidate for molecular inflammation warranting further investigation.

The role of gut vascular barrier in experimental alcoholic liver disease and A. muciniphila supplementation.

The translocation of bacterial components from the intestinal lumen into the portal circulation is crucial in the pathogenesis of alcoholic liver disease (ALD). Recently the important role of the gut vascular barrier (GVB) was elucidated in alcoholic liver disease. Here we report about the influence of A. muciniphila supplementation in experimental ALD on the GVB. Ethanol feeding was associated with increased Pv-1, indicating altered endothelial barrier function, whereas A. muciniphila administration tended to restore GVB. To further investigate GVB in experimental ALD, ß-catenin gain-of-function mice, which display an enhanced GVB, were ethanol-fed. ß-catenin gain-of-function mice were not protected from ethanol-induced liver injury, suggest an alternative mechanism of ethanol-induced GVB disruption. The description of the GVB in ALD could pave the way for new therapeutic options in the future.

Erratum: Gruber, E.S.; et al. The Oncogene AF1Q is Associated with WNT and STAT Signaling and Offers a Novel Independent Prognostic Marker in Patients with Resectable Esophageal Cancer. Cells 2019, 8, 1357.

The authors wish to make the following change to their paper [...].

Stereotactic radiofrequency ablation of a variety of liver masses in children.

BACKGROUND AND AIMS: Surgical resection is currently the cornerstone of liver tumor treatment in children. In adults radiofrequency ablation (RFA) is an established minimally invasive treatment option for small focal liver tumors. Multiprobe stereotactic RFA (SRFA) with intraoperative image fusion to confirm ablation margins allows treatment for large lesions. We describe our experience with SRFA in children with liver masses. METHODS: SRFA was performed in 10 patients with a median age of 14 years (range 0.5-17.0 years) suffering from liver adenoma (n = 3), hepatocellular carcinoma (n = 1), hepatoblastoma (n = 2), myofibroblastic tumor (n = 1), hepatic metastases of extrahepatic tumors (n = 2) and infiltrative hepatic cysts associated with alveolar echinococcosis (n = 1). Overall, 15 lesions with a mean lesion size of 2.6 cm (range 0.7-9.5 cm) were treated in 11 sessions. RESULTS: The technical success rate was 100%, as was the survival rate. No transient adverse effects higher than grade II (Clavien and Dindo) were encountered after interventions. The median hospital stay was 5 d (range 2-33 d). In two patients who subsequently underwent transplant hepatectomy complete ablation was histologically confirmed. Follow-up imaging studies (median 55 months, range 18-129 months) revealed no local or distant recurrence of disease in any patient. CONCLUSIONS: SRFA is an effective minimal-invasive treatment option in pediatric patients with liver tumors of different etiologies.

Soluble guanylyl cyclase stimulation and phosphodiesterase-5 inhibition improve portal hypertension and reduce liver fibrosis in bile duct-ligated rats.

BACKGROUND: In cirrhosis, the nitric oxide-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired, which contributes to increased intrahepatic vascular resistance (IHVR) and fibrogenesis. We investigated if sGC stimulation (riociguat (RIO)), sGC activation (cinaciguat (CINA)) or phosphodiesterase (PDE)-5 inhibition (tadalafil (TADA)) improves portal hypertension (PHT) and liver fibrosis. METHODS: Fifty male Sprague-Dawley rats underwent bile-duct ligation (BDL) or sham operation. RIO (0.5 mg/kg), CINA (1 mg/kg), TADA (1.5 mg/kg) or vehicle (VEH) was administered from weeks 2 to 4 after BDL. At week 4, invasive haemodynamic measurements were performed, and liver fibrosis was assessed by histology (chromotrope-aniline blue (CAB), Picro-Sirius red (PSR)) and hepatic hydroxyproline content. RESULTS: Cirrhotic bile duct-ligated rats presented with PHT (13.1 ± 1.0 mmHg) and increased IHVR (4.9 ± 0.5 mmHg⋅min/mL). Both RIO (10.0 ± 0.7 mmHg, p = 0.021) and TADA (10.3 ± 0.9 mmHg, p = 0.050) decreased portal pressure by reducing IHVR (RIO: -41%, p = 0.005; TADA: -21%, p = 0.199) while not impacting heart rate, mean arterial pressure and portosystemic shunting. Hepatic cGMP levels increased upon RIO (+239%, p = 0.006) and TADA (+32%, p = 0.073) therapy. In contrast, CINA dosed at 1 mg/kg caused weight loss, arterial hypotension and hyperlactataemia in bile duct-ligated rats. Liver fibrosis area was significantly decreased by RIO (CAB: -48%, p = 0.011; PSR: -27%, p = 0.121) and TADA (CAB: -21%, p = 0.342; PSR: -52%, p = 0.013) compared to VEH-treated bile duct-ligated rats. Hepatic hydroxyproline content was reduced by RIO (from 503 ± 20 to 350 ± 30 µg/g, p = 0.003) and TADA (282 ± 50 µg/g, p = 0.003), in line with a reduction of the hepatic stellate cell activation markers smooth-muscle actin and phosphorylated moesin. Liver transaminases decreased under RIO (AST: -36%; ALT: -32%) and TADA (AST: -24%; ALT: -27%) treatment. Hepatic interleukin 6 gene expression was reduced in the RIO group (-56%, p = 0.053). CONCLUSION: In a rodent model of biliary cirrhosis, the sGC stimulator RIO and the PDE-5 inhibitor TADA improved PHT. The decrease of sinusoidal vascular resistance was paralleled by a reduction in liver fibrosis and hepatic inflammation, while systemic haemodynamics were not affected.

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.