Secondary Sclerosing Cholangitis in Critically Ill Patients Alters the Gut–Liver Axis: A Case Control Study

Secondary sclerosing cholangitis in critically ill patients (SC-CIP) occurs after long-term intensive care treatment. This study aimed to assess the gut–liver axis in SC-CIP. Stool microbiome composition, gut permeability, bacterial translocation and serum bile acid profiles of 18 SC-CIP patients compared to 11 patients after critical illness without liver disease (CIP controls), 21 patients with cirrhosis and 21 healthy controls were studied. 16S rDNA was isolated from stool and sequenced using the Illumina technique. Diamine oxidase, zonulin, soluble CD14 (sCD14) and lipopolysaccharide binding protein were measured in serum and calprotectin in stool. Serum bile acids were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Reduced microbiome alpha diversity and altered beta diversity were seen in SC-CIP, CIP controls and cirrhosis compared to healthy controls. SC-CIP patients showed a shift towards pathogenic taxa and an oralization. SC-CIP, CIP controls and cirrhotic patients presented with impaired gut permeability, and biomarkers of bacterial translocation were increased in SC-CIP and cirrhosis. Total serum bile acids were elevated in SC-CIP and cirrhosis and the bile acid profile was altered in SC-CIP, CIP controls and cirrhosis. In conclusions, observed alterations of the gut–liver axis in SC-CIP cannot solely be attributed to liver disease, but may also be secondary to long-term intensive care treatment

Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis

IntroductionEosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4+ T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing.MethodsIn this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus.ResultsOur results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4+ T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4+ and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4+ T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE.DiscussionHerein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models

Hematopoietic Stem Cell Transplantation in Refractory Crohn’s Disease: Should It Be Considered?

Hematopoietic stem cell transplantation (HSCT) is widely used in benign and malignant hematological diseases. During the last decade, HSCT, mainly autologous, also gained increasing attention in the treatment of refractory autoimmune diseases. Crohn’s disease (CD) is an inflammatory bowel disease leading to transmural inflammation potentially affecting all parts of the luminal gastrointestinal tract. Despite improving therapeutic options, including various biologics, some patients are refractory to all lines of available conservative therapy, leading to increased morbidity and reduced quality of life. Apart from surgery, HSCT might be a reasonable treatment alternative for refractory CD patients. This review aims to describe the current role of HSCT in CD and discusses the procedure, the correct patient selection, the clinical efficacy from initial remission to following relapse rates, and complications of this treatment

Baden Württemberg Heat Atlas - Preparation of the Guidelines and Their Implementation for Exemplary Regions

Ziel des Vorhabens ist die Erstellung eines Wärmeatlanten für Baden-Württemberg zur Darstellung der räumlichen und zeitlichen Verteilung des Wärmebedarfs auf lokaler Ebene. Zur Visualisierung des räumlichen Wärmebedarfs als auch der Bereitstellungspotenziale unterschiedlicher Energieträger, insbesondere der leitungsgebundenen Energieträger (Fernwärme, Gas), dient ein Geographisches Informationssystem (GIS). In einem ersten Schritt der Forschungsarbeit wird zunächst ein Leitfaden erarbeitet, der die notwendigen Datengrundlagen, die prinzipielle Vorgehensweise bei der Erstellung, die Aufbereitung der Daten in Geographischen Informationssystemen und die Nutzungsmöglichkeiten eines Wärmeatlas darstellt. Neben den Wärmepotenzialen im Siedlungsbereich werden auch die entsprechenden Bedarfswerte der industriellen und kommunalen Objektversorgung erfasst. Zudem werden auch Informationen zum Angebot an Energieträgern, z. B. Biomasse, Geothermie oder Solarthermie, bereitgestellt, so dass auch energieträgerbezogene Potenziale ermittelt werden können. Außerdem wird die Vorgehensweise zur Beurteilung der Wirtschaftlichkeit von konkurrierenden Wärmeerzeugungsanlagen erläutert. Damit wird den Entscheidungsträgern eine Basis für die Beurteilung lokaler Versorgungskonzepte zur Verfügung gestellt. Im zweiten Arbeitsschritt wird auf der Basis des erarbeiteten Leitfadens für Modellregionen in Baden-Württemberg ein Wärmeatlas erstellt. Basierend auf diesen Ergebnissen werden notwendige Parameter für einen Ausbau oder Neubau der Nah-/Fernwärmeversorgung festgelegt und in den GIS-Karten kenntlich gemacht. Dadurch sollen die Voraussetzungen geschaffen werden, Versorgungsgebiete zu identifizieren, für die eine leitungsgebundene Wärmeversorgung, möglichst auf KWK-Basis, sinnvoll erscheint. Die Ergebnisse für die Modellregionen dienen als Grundlage für die näherungsweise Hochskalierung des Wärmebedarfs und der Potenziale auf Baden-Württemberg insgesamt. Auch hier werden GIS-Darstellungen genutzt, um die räumliche Verteilung über die Landesfläche anschaulich präsentieren zu können.The objective of the project is to build up a heat map for Baden-Wuerttemberg to illustrate the spatial and temporal distribution of the heat demand on a local scale. A geographic information system (GIS) is used to visualize the spatial heat demand and also the potential to allocate any heat for different energy carriers, particular of those which are pipeline-bound, as district heat and gas. In the first work package a guidebook will be created, wherein the necessary data bases, the proceeding in principle with the generation, the presentation of the data in geographical information systems, and the possible usage of a heat map will be represented. Besides the heat potential within the settlement area, the appropriate demand values will be seized also for the industrial and the local object supply. Also information about the existing potentials of biomass, geothermal or solar energy will be made available, so that energy carrier related potentials can be determined. The second stage of the project comprises the construction of a heat map for selected exemplary regions of Baden-Württemberg, according to the guidelines set up in the first stage. Based upon these results the parameters necessary for an expansion or installation of district heat supply systems are fixed and marked within the GIS system. This shall enable the identification of areas that might be suitable for a pipeline-based heat supply, ideally with a CHP backbone. The results for the exemplary regions serve as basis for the high scaling of the potentials on Baden-Wuerttemberg altogether. GIS representations are used also here, in order to be able to present the spatial distribution over the landscape

Downgrading of a G3 Neuroendocrine Tumor to a G2 Tumor: Can First-Line Cytotoxic Chemotherapy Change the Tumor Biology?

The antiproliferative treatment options for neuroendocrine tumors (NET)/neuroendocrine carcinomas of the gastrointestinal tract critically depend on the proliferation rate, evaluated by immunohistochemical staining for Ki-67. According to their grading, tumors are treated with somatostatin analogs, mTOR inhibitors, or cytotoxic substances. This case illustrates downgrading of a primarily highly proliferative NET achieved by a variation of cytotoxic chemotherapy regimens, followed by a combination therapy using everolimus together with lanreotide. The latter medication might lead to a good clinical response as far as tumor growth is concerned

Members of the endocannabinoid system are distinctly regulated in inflammatory bowel disease and colorectal cancer

Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI

Increased Pancreatic Protease Activity in Response to Antibiotics Impairs Gut Barrier and Triggers Colitis

Background & Aims: Antibiotic (ABx) therapy is associated with increased risk for Crohn’s disease but underlying mechanisms are unknown. We observed high fecal serine protease activity (PA) to be a frequent side effect of ABx therapy. The aim of the present study was to unravel whether this rise in large intestinal PA may promote colitis development via detrimental effects on the large intestinal barrier. Methods: Transwell experiments were used to assess the impact of high PA in ABx-treated patients or vancomycin/metronidazole-treated mice on the epithelial barrier. Serine protease profiling was performed using liquid chromatography–mass spectrometry/mass spectrometry analysis. The impact of high large intestinal PA on the intestinal barrier in wild-type and interleukin (IL)10-/- mice and on colitis development in IL10-/- mice was investigated using vancomycin/metronidazole with or without oral serine protease inhibitor (AEBSF) treatment. Results: The ABx-induced, high large intestinal PA was caused by significantly increased levels of pancreatic proteases and impaired epithelial barrier integrity. In wild-type mice, the rise in PA caused a transient increase in intestinal permeability but did not affect susceptibility to chemically induced acute colitis. In IL10-/- mice, increased PA caused a consistent impairment of the intestinal barrier associated with inflammatory activation in the large intestinal tissue. In the long term, the vancomycin/metronidazole-induced lasting increase in PA aggravated colitis development in IL10-/- mice. Conclusions: High large intestinal PA is a frequent adverse effect of ABx therapy, which is detrimental to the large intestinal barrier and may contribute to the development of chronic intestinal inflammation in susceptible individuals. Keywords: Epithelial Barrier, Serine Proteases, Gut Microbiota, Inflammatory Bowel Disease

A single alcohol binge impacts on neutrophil function without changes in gut barrier function and gut microbiome composition in healthy volunteers.

Alcohol binge drinking is a dangerous drinking habit, associated with neurological problems and inflammation. The impact of a single alcohol binge on innate immunity, gut barrier and gut microbiome was studied. In this cohort study 15 healthy volunteers received 2 ml vodka 40% v/v ethanol/kg body weight. Neutrophil function was studied by flow cytometry; markers of gut permeability and inflammation (lactulose/mannitol/sucrose test, zonulin, calprotectin, diamino-oxidase) were studied with NMR spectroscopy and enzyme-linked immunosorbent assay in urine, stool and serum respectively. Bacterial products in serum were quantified using different reporter cell lines. Gut microbiome composition was studied by 16S rDNA sequencing and bioinformatics analysis. After a single alcohol binge, neutrophils were transiently primed and the response to E.coli stimulation with reactive oxygen species (ROS) production was transiently increased, on the other hand the percentage of neutrophils that did not perform phagocytosis increased. No changes in gut permeability, inflammatory biomarker, bacterial translocation and microbiome composition could be detected up to 4 hours after a single alcohol binge or on the next day. A single alcohol binge in young, healthy volunteers transiently impacts on neutrophil function. Although the exact biological consequence of this finding is not clear yet, we believe that this strengthens the importance to avoid any alcohol binge drinking, even in young, otherwise healthy persons