Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.

BACKGROUND & AIMS Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH

Central and eastern Bransfield basins (Antarctica) from high-resolution swath-bathymetry data

For the first time complete swath bathymetric maps of central and eastern Bransfield basins are presented at a medium scale and detailed morphological descriptions are provided. Bathymetry reveals morphological structures which provide important information about the structure, volcanism, and kinematics of these basins. The central basin is dominated by two roughly orthogonal sets of extensional faults (N065°the main set and N145°the secondary set), displays several discontinuous along-axis large volcanic cones and ridges trending about N059°, and undergoes extension roughly normal to the basin. The structure of the eastern basin has a roughly rhomboidal pattern (fault sets along N053°and N103°), displays four deep troughs and a much smaller amount of volcanism than the central basin, and is affected by extension with a significant sinistral strike-slip componentPeer Reviewe

Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites.

BACKGROUND The gut-liver-axis presents the pathophysiological hallmark for multiple liver diseases and has been proposed to be modulated during stress and shock. Access to the gut-liver-axis needs crossing of the mucus and gut-vascular barrier. The role of β-adrenoreceptor-activation for both barriers has not been defined and is characterized here. METHODS Splanchnic β-adrenergic stimulation was achieved by chronic intraperitoneal application of isoproterenol via alzet-pump in vivo. The intestinal permeability and gut-vascular barrier function was assessed in ileal loop experiments. The extravasation of predefined sizes of fluorescence isothiocyanate (FITC)-dextran molecules in ileal microcirculation was evaluated by intravital confocal laser endomicroscopy in vivo. Mucus parameters thickness, goblet cell count and mucin-expression were assessed by stereomicroscopy, immunostaining and RNA-sequencing respectively. Ileal lamina propria (LP) as well as mesenteric lymph node mononuclear cells was assessed by FACS. RESULTS Healthy mice lack translocation of 4 kDa-FITC-dextran from the small intestine to the liver, whereas isoproterenol-treated mice demonstrate pathological translocation (PBT). Mucus layer is reduced in thickness with loss of goblet-cells and mucin-2-staining and -expression in isoproterenol-treated animals under standardized gnotobiotic conditions. Isoproterenol disrupts the gut vascular barrier displaying Ileal extravasation of large-sized 70- and 150 kDa-FITC-dextran. This pathological endothelial permeability and accessibility induced by isoproterenol associates with an augmented expression of plasmalemmal-vesicle-associated-protein-1 in intestinal vessel. Ileal LP after isoproterenol treatment contains more CD11c+-dendritic cells (DC) with increased appearance of CCR7+ DC in mesenteric lymph nodes. CONCLUSIONS Isoproterenol impairs the intestinal muco-epithelial and endothelial-vascular barrier promoting PBT to the liver. This barrier dysfunction on multiple levels potentially can contribute to liver injury induced by catecholamines during states of increased β-adrenergic drive

Caracterización y observación del fondo marino con un nuevo sistema de sonar de barrido frontal

V Congreso Geológico de España, 10-14 julio 2000, Alicante.-- 5 pages, 5 figures[EN] A prototype multi-beam front-scan sonar system has been defined for the characterization and observation of the seafloor. This system has been developed within the framework of COSMOS Project (Ref. MAS3-CT97-0090). The first sea trial to test the capabilities of the COSMOS sonartook place recently in the Catalan continental shelf. Three areas were selected (Blanes, Barcelona and Vilanova) based on the huge volume of geological background information of these areas, which has allowed the accomplishement of the following objetives: seabed characterization, mapping of relief, and seafloor imaging.The Blanes area has been useful to determine the validity of the COSMOS system for sediment classification on a wide scale. The Barcelona area has been chosen to determine the capabilities of the COSMOS system for sediment classification on a detail scale i.e, where sediment variation occurs on subtle or gradual changes in textural types; in this area also pipeline andsurficial seafloor morphologies caused by fishing activity and sewage deposits have beenimaging. The Vilanova area has been specifically selected to test the capabilities of the COSMOS system due to the precise delimitation of the artificial reef and antisfishing structures[ES] La investigación marina requiere siempre la utilización de buques como plataformas para la obtención de datos, pero además el desarrollo de esta ciencia precisa de constantes desarrollos tecnológicos, construcción de nuevos o más precisos instrumentos, y mediciones novedosas que proporcionen el avance en el conocimiento de los procesos oceánicos. El interés científico del estudio del fondo marino comprende un amplio espectro de características que incluyen, no sólo la morfología de los mismos, sino también la naturaleza del material que lo conforma y su distribución espacio-temporal. [...]Peer reviewe

Geological evolution of the Pacific margin of Western Antarctica: sea-floor spreading and plate tectonics Cruise GEBRAP 96/97

Canals, Miquel... et al.-- 17 pages, 5 figures, 1 table[EN] The main activity of the project has been the cruise GEBRAP 96/97, carried out onboard RV Hesperides from 03.12.96 to 06.01.97 in the northern Bellinghausen Sea, the Gerlache Strait and the Bransfield Basin, Western Antarctica. [...][ES] De acuerdo con la propuesta presentada en su momento, los objetivos de la campaña GEBRAP 96/97 pueden agruparse en los siguientes apartados: [...]Peer reviewe

Morphostructure and evolution of the Central and Eastern Bransfield Basins (NW Antarctic Peninsula)

The Bransfield Basin is a narrow and elongated active rift basin located between the Antarctic Peninsula and the South Shetland Islands. The Bransfield Basin is composed of three small basins, and two of them, the Central and Eastern Bransfield Basins, were surveyed during a recent cruise (GEBRA 93). The full swath bathymetry coverage as well as the single-channel seismic reflection and magnetic profiles that have been acquired, help us to better understand the morphostructure and recent evolution of the Bransfield Basin. Six large volcanic edifices aligned with the basin axis stick out of the sedimented seafloor of the Central Bransfield Basin. In contrast, the Eastern Bransfield Basin is characterised by four deep troughs displaying a rhombic-shape, and small, scattered volcanic cones located in the southwestern half basin. Seamount volcanism plays an important role in the formation of new crust in the Bransfield Basin. The larger seamounts of the Central Bransfield Basin are located al the intersection of the two main orthogonal sets of faults (longitudinal ENE-WSW and transversal NNW-SSE). Morphological analysis of the seamounts indicates a multi-staged volcano-tectonic construction. The distribution and shape of these edifices suggests that both volcanism and extension are concentrated at the same preferential areas through time. This might be related to the fracturation style of the continental crust. The Central and Eastern Bransfield Basins are very different in morphostructure, volcanism, and sedimentary cover. The Central Bransfield Basin shows evidence of NW-SE extensional faulting and focused active MORB-volcanism interpreted as result of incipient seafloor spreading. The Eastern Bransfield Basin is still in a rifting stage, mainly dominated by a NW-SE extension and some left-lateral strike-slip component probably related to the South Scotia Ridge

Evolución geológica de la cuenca de Bransfield y de la dorsal sur del mar de Scotia (GEBRA'93)

Canals, Miquel... et al.-- Proyecto ANT93-1008-C03-01.-- 25 pages, 6 figures[EN] The GEBRA '93 survey was carried out in December 1993 in the waters of Bransfield Strait and adjacent areas, on board B.I.O. Hespérides. [...][ES] La campaña GEBRA '93 se ha desarrollado en aguas del Estrecho de Bransfield y zonas próximas entre los días 3 y 24 de Diciembre de 1993, a bordo del B.I.O. Hespérides. [...]Peer reviewe

FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.

BACKGROUND & AIMS Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria. MATERIALS Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl4. Pre-hepatic portal-hypertension was induced by partial portal vein ligation (PPVL). Intestinal permeability was compared in these mice after GFP-Escherichia coli or different sized FITC-dextrans were injected into the intestine. RESULTS Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl4-induced cirrhotic mice demonstrate pathological translocation, which is not altered by prior thoracic-duct ligation. The mucus layer is reduced in thickness, with loss of goblet cells and Muc2-staining and expression in cirrhotic but not PPVL mice. These changes are associated with bacterial overgrowth in the inner mucus layer and pathological translocation of GFP-E. coli through the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran, but only slightly altered in PPVL mice. This pathological endothelial permeability and accessibility in cirrhotic mice is associated with augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB, whereas both FXR-agonists ameliorate gut to liver translocation of GFP-E. coli. CONCLUSIONS Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. LAY SUMMARY For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis

Paneth cells promote angiogenesis and regulate portal hypertension in response to microbial signals.

BACKGROUND & AIMS Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. METHODS We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. RESULTS Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. CONCLUSIONS These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. LAY SUMMARY Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches