Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. DRM and sarcopenia often coexist in cirrhotic patients and are associated with increased morbidity and mortality. The clinical manifestation of both comorbidities are triggered by multifactorial mechanisms including reduced nutrient and energy intake caused by dietary restrictions, anorexia, neuroendocrine deregulation, olfactory and gustatory deficits. Maldigestion and malabsorption due to small intestinal bacterial overgrowth, pancreatic insufficiency or cholestasis may also contribute to DRM and sarcopenia. Decreased protein synthesis and increased protein degradation is the cornerstone mechanism to muscle loss, among others mediated by disease- and inflammation-mediated metabolic changes, hyperammonemia, increased myostatin and reduced human growth hormone. The concise pathophysiological mechanisms and interactions of DRM and sarcopenia in liver cirrhosis are not completely understood. Furthermore, most knowledge in this field are based on experimental models, but only few data in humans exist. This review summarizes known and proposed molecular mechanisms contributing to malnutrition and sarcopenia in liver cirrhosis and highlights remaining knowledge gaps. Since, in the prevention and treatment of DRM and sarcopenia in cirrhotic patients, more research is needed to identify potential biomarkers for diagnosis and development of targeted therapeutic strategies.

Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. NCT03065699.

Einleitung: Beim Kurzdarmsyndrom und beim Darmversagen sind enterale und parenterale Ernährung die Basis der Therapie. Die rekonstruktive Chirurgie vermag die anatomische Situation zu verbessern. Die Darmtransplantation stellt gegenwärtig eine Therapieoption beim drohenden Scheitern der parenteralen Ernährung dar. Methodik: Es wurde eine systematische Literatursuche zum Kurzdarmsyndrom und zum Darmversagen, gekoppelt mit einer Literatursuche zur enteralen und parenteralen Ernährung, zur rekonstruktiven Chirurgie und zur Darmtransplantation durchgeführt. In der Arbeitsgruppe wurden auf dieser Basis Empfehlungen formuliert und hinsichtlich der Empfehlungsstärke bewertet. Sie wurden anschließend in einem Delphi-Verfahren und einer Konsensuskonferenz vorgestellt, diskutiert und verabschiedet. Ergebnisse: Die Leitlinie bezieht sich spezifisch auf das Kurzdarmsyndrom bei Erwachsenen. Sie enthält einen allgemeinen Teil mit Definitionen sowie Empfehlungen zur Dokumentation der anatomischen Situation und des Ernährungszustands, zur Indikation, Zusammensetzung und Durchführung einer parenteralen Ernährung (unter besonderer Berücksichtigung der meist im Vordergrund stehenden Flüssigkeits- und Elektrolytverluste), zu den Prinzipien der spezifischen Diät, zu den Kathetern und deren Infektionsmanagement, zur spezifischen und symptomatischen Pharmakotherapie, zur rekonstruktiven Chirurgie und zur Darmtransplantation. Schlussfolgerung: Kontrollierte Studien sind beim Darmversagen spärlich wegen der Seltenheit des Krankheitsbilds und der großen individuellen Unterschiede. Die prognostizierte Kurzdarmsituation auf der Basis einer möglichst detailliert beschriebenen anatomischen Ausgangssituation stellt die Indikation zur Ernährungsintervention dar. Die ergänzend intendierte, individualisierte parenterale Ernährung, die Prophylaxe und Therapie der Komplikationen und die rekonstruktiv-operativen Ansätze sollen konsequent umgesetzt werden. Spezifische und symptomatische pharmakologische Ansätze können ebenfalls genutzt werden. Die Darmtransplantation stellt eine Option beim drohenden Scheitern der parenteralen Ernährung dar. Introduction: Enteral and parenteral nutrition are the cornerstone for the therapy of short bowel syndrome and intestinal failure. The underlying anatomic situation may be amendable to reconstructive surgery. Intestinal transplantation is currently an option in case of failure of parenteral nutrition. Methods: A systematic literature search for short bowel syndrome or intestinal failure coupled with a literature search for enteral or parenteral nutrition, reconstructive surgery or intestinal transplantation was performed. Based on this the working group developed recommendations, which were presented, discussed and confirmed in a consensus conference. Results: The guideline addresses only short bowel syndrome (intestinal failure) in adults. It contains a general part with definitions and a specific part with recommendations for the documentation of the postoperative anatomy and the nutritional status, for the indication, the compounding and the administration of parenteral nutrition (with special emphasis on the predominant fluid and electrolyte losses), for the principles of a specific diet, for the catheters and the management of their infectious complications, for the specific and symptomatic pharmacotherapy, for reconstructive surgery and for intestinal transplantation. Conclusion: Controlled studies addressing intestinal failure are sparse due to the orphan nature of the disease and due to the large interindividual variation. The anticipated short bowel situation (based on a detailed description of the postoperative situation) is the indication for nutritional intervention. Individually tailored (compounded) parenteral nutrition, prophylaxis and treatment of complications and reconstructive surgery should all be applied. Specific and symptomatic pharmacologic approaches can be used as well. Intestinal transplantation is a therapeutic option if parenteral nutrition fails. ^* DGEM Steering Committee: Bischoff SC, Lochs H, Weimann A sowie das DGEM-Präsidium

Background: Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon‐derived hormones glucagon‐like peptide‐1 (GLP‐1) and GLP‐2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP‐2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP‐1 and GLP‐2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit.Methods: The GLP‐1– and GLP‐2–specific effects of the novel dual GLP‐1 receptor (GLP‐1R) and GLP‐2 receptor (GLP‐2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and sham‐operated male mice.Results: Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone.Conclusion: Dapiglutide possesses specific and potent GLP‐1R and GLP‐2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP‐1R and GLP‐2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF.

“Quorum sensing” (QS) is the phenomenon which allows single bacterial cells to measure the concentration of bacterial signal molecules. Two principle different QS systems are known, the Autoinducer 1 system (AI-1) for the intraspecies communication using different Acyl-homoserine lactones (AHL) and AI-2 for the interspecies communication. Aim of this study was to investigate QS of Escherichia coli Nissle 1917 (Mutaflor). While E. coli Nissle is producing AI-2 in a density dependent manner, no AI-1 was produced. To study the effect of AI-2 in the DSS (dextran sulphate sodium) induced mouse model of acute colitis, we silenced the corresponding gene lux S by intron insertion. The mutant bacterium E. coli Nissle::lux S was equally effective in colonizing the colon and the mutation turned out to be 100% stable during the course of the experiment. Isolating RNA from the colon mucosa and performing semiquantitative RT PCR, we were able to show that the expression of the pro-inflammatory cytokine IFN-y was suppressed in mice being infected with the E. coli Nissle wild type. Mice infected with the E. coli Nissle::lux S mutant showed a suppressed expression of IL-10 compared to uninfected mice, while the expression of the pro-inflammatory cytokines IL-6 and TNF-α was higher in these mice. The expression of mBD-1 was suppressed in mice being infected with the mutant in comparison to the mice not infected or infected with the wild type. No differences were seen in the histological examination of the colon sections in the different groups of mice. E. coli Nissle is producing AI-2 molecules, which are influencing the expression of cytokines in the mucosa of the colon in the DSS mice. However, if QS has a direct influence on the probiotic properties of E. coli Nissle remains to be elucidated.