United European Gastroenterology Journal最新文献

Aim: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level.

Methods: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA.

Results: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD.

Conclusions: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.

Background: Gelsectan^® is a formulation of xyloglucan (XG), pea protein, grape seed extract (PPGS) and xylo-oligosaccharides (XOS). Our aim was to examine the effect of Gelsectan^® on rectal sensitivity in an animal model, abdominal pain in irritable bowel syndrome with diarrhoea (IBS-D) subjects and intestinal permeability in both conditions.

Methods: Animals: Wistar rats received gavage with XOS, XG + PPGS or XG + PPGS + XOS, as a single dose or for 7 days before a partial restraint stress (PRS). Visceromotor response to rectal distension and total gut paracellular permeability to ⁵¹Cr-EDTA were assessed. Humans: IBS-D and control patients were involved. After initial colonoscopy with biopsy sampling Gelsectan® was administered to IBS-D patients for 12 weeks. Stool count and pain scores were documented. After treatment, colonoscopy was repeated. The permeability of biopsy samples was measured in Ussing-chambers. Adherent mucus layer, Muc-2 expression as well as TNFα, Interferon IFNγ were evaluated by histology/immunohistochemistry and ELISA assays, respectively.

Results: Animal studies: In control rats, PRS significantly increased visceromotor response as well as gut paracellular permeability. Single dose administration of XG + PPGS + XOS failed to reverse PRS, but 7 days of oral treatment reversed PRS-induced rectal hypersensitivity and gut hyperpermeability. Human studies: Gelsectan^® treatment significantly reduced and abdominal pain. Intestinal permeability in IBS-D patients was elevated compared with controls, Gelsectan^® restored permeability in the ascendent colon. Periodic acid-Schiff-stained mucus layer was significantly thinner in IBS-D patients compared with controls, In both segments, mucus thickness and the proportion of Muc-2 positive cells were not affected by Gelsectan^® treatment. IFNγ tissue level in the sigmoid colon shows modest mucosal inflammation in IBS-D.

Conclusions: Gelsectan^® prevented rectal hypersensitivity in rats, abdominal pain in human and intestinal hyperpermeability in rat and human studies respectively. These effects involve restoration of gut permeability. Based on this translational study, Gelsectan^® can be considered as an effective therapy for IBS-D symptoms.

Background and aims: Deterioration of liver function is a leading cause of death in patients with advanced hepatocellular carcinoma (HCC). We evaluated the impact of immune checkpoint inhibitor (ICI)-treatment on liver function and outcomes.

Method: HCC patients receiving ICIs or sorafenib between 04/2003 and 05/2024 were included. Liver function (assessed by Child-Pugh score [CPS]) was evaluated at the start of ICI-treatment (baseline, BL) and 3 and 6 months thereafter. A ≥1 point change in CPS was defined as deterioration (-) or improvement (+), while equal CPS points were defined as stable (=).

Results: Overall, 182 ICI-treated patients (66.8 ± 11.8 years; cirrhosis: n = 134, 74%) were included. At BL, median CPS was 5 (IQR: 5-6; CPS-A: 147, 81%). After 3 months, liver function improved/stabilized in 102 (56%) and deteriorated in 61 (34%) patients, while 19 (10%) patients deceased/had missing follow-up (d/noFU). Comparable results were observed at 6 months (+/=: n = 82, 45%; -: n = 55, 30%; d/noFU: n = 45, 25%). In contrast, 54 (34%) and 33 (21%) out of 160 sorafenib patients achieved improvement/stabilization at 3 and 6 months, respectively. Radiological response was linked to CPS improvement/stabilization at 6 months (responders vs. non-responders, 73% vs. 50%; p = 0.007). CPS improvement/stabilization at 6 months was associated with better overall survival following landmark analysis (6 months: +/=: 28.4 [95% CI: 18.7-38.1] versus -: 14.2 [95% CI: 10.3-18.2] months; p < 0.001). Of 35 ICI-patients with CPS-B at BL, improvement/stabilization occurred in 16 (46%) patients, while 19 (54%) patients deteriorated/d/noFU at 3 months. Comparable results were observed at 6 months (CPS +/=: 14, 40%, -: 8, 23%). Importantly, 6/35 (17%) and 9/35 (26%) patients improved from CPS-B to CPS-A at 3 and 6 months.

Conclusion: Radiological response to ICI-treatment was associated with stabilization or improvement in liver function, which correlated with improved survival, even in patients with Child-Pugh class B at baseline.

Gastrointestinal angiodysplasia (GIA) is a common, acquired, vascular abnormality of the digestive tract, and a frequent cause of bleeding. Refractory GIA criteria usually include recurrent bleeding, transfusions and/or repeat endoscopy. Pharmacological and interventional treatments have been the subject of recent high-quality publications. This review provides an overview of the latest updates on non-endoscopic management of refractory GIA. Aortic valve replacement has shown its efficacy in Heyde syndrome and should be considered if indicated. Anti-angiogenic drugs, such as Octreotide and Thalidomide, are efficient treatments of refractory GIA-related bleeding. Somatostatin analogs should, based on efficacy and tolerance profile, be considered first. In the future, a better understanding of the physiopathology of GIA might help develop new-targeted therapies.