Liver steatosis induces portal hypertension regardless of fibrosis in patients with NAFLD: A proof of concept case report

Esteatosi hepàtica; Hipertensió portalLiver steatosis; Portal hypertensionEsteatosis hepática; Hipertensión portalNo financial support was received for data analysis or writing assistance. JRE is a PhD student at Universitat Autònoma de Barcelona, Spain. JMP reports having received consulting fees from Boehringer Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898 (PI22/01770). JG has received consulting fees from Boehringer Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. All other authors: nothing to disclose

Proteomic Analysis of Dysfunctional Liver Sinusoidal Endothelial Cells Reveals Substantial Differences in Most Common Experimental Models of Chronic Liver Diseases

Animal models; Chronic liver disease; Endothelial dysfunctionModels animals; Malaltia hepàtica crònica; Disfunció endotelialModelos animales; Enfermedad hepática crónica; Disfunción endotelialMolecular markers of dedifferentiation of dysfunctional liver sinusoidal endothelial cells (LSEC) have not been fully elucidated. We aimed at deciphering the molecular profile of dysfunctional LSEC in different pathological scenarios. Flow cytometry was used to sort CD11b−/CD32b+ and CD11b−/CD32b− LSEC from three rat models of liver disease (bile duct ligation-BDL; inhaled carbon tetrachloride-CCl4; and high fat glucose/fructose diet-HFGFD). A full proteomic profile was performed applying nano-scale liquid chromatography tandem mass spectrometry (nLC-MS) and analyzed with PEAKS software. The percentage of CD32b− LSEC varied across groups, suggesting different capillarization processes. Both CD32+ and CD32b− LSEC from models are different from control LSEC, but differently expressed proteins in CD32b− LSEC are significantly higher. Heatmaps evidenced specific protein expression patterns for each model. Analysis of biological significance comparing dysfunctional CD32b− LSEC with specialized CD32b+ LSEC from controls showed central similarities represented by 45 common down-regulated proteins involved in the suppression of the endocytic machinery and 63 common up-regulated proteins associated with the actin-dependent cytoskeleton reorganization. In summary; substantial differences but also similarities in dysfunctional LSEC from the three most common models of liver disease were found, supporting the idea that LSEC may harbor different protein expression profiles according to the etiology or disease stage.This work was supported by grants PI18/00947 and AC18/00033 (ENM3 2018) and PI21/00691 from Instituto de Salud Carlos III (ISCIII) and cofounded by the European Union (ERDF/ESF, “Investing in your future”). J.G. is the recipient of a clinical intensification award and D.H. of a Sara Borrell grant, both from ISCIII. M.G. and A.B. have predoctoral fellowships from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) and ISCIII respectively. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is supported by ISCIII. The APC was funded by ISCIII

A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo

Bacterial consortium; Gut microbiome; Portal hypertensionConsorcio bacteriano; Microbioma intestinal; Hipertensión portalConsorci bacterià; Microbioma intestinal; Hipertensió portalThe gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression