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Background Extensive intestinal resection may lead to short bowel syndrome resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones, GLP-1 and GLP-2. Two major problems of short bowel (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 combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and also slow intestinal transit. Methods The GLP-1 and GLP-2 specific effects of the novel dual GLP-1 and GLP-2 receptor 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 liquid diet intake. 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-1 and GLP-2 receptor 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. This article is protected by copyright. All rights reserved.

Introduction: Cholestatic liver disease (CLD) is associated with intestinal barrier dysfunction. The peptide hormone ghrelin may exert both hepatoprotective and barrier-strengthening effects. Here, we have evaluated these effects under the conditions of experimental cholestasis. Methods: C57BL/6J mice with bile duct ligation (BDL) or sham surgery were treated with ghrelin or solvent for 9 days. Liver injury was assessed by histological and laboratory analyses. Paracellular macromolecule permeability and transmural electrical resistance (TMER) of colonic tissues were measured using a Ussing chamber. Expression of tight junction (TJ) genes was quantified by real-time PCR. Amplicon metagenomic sequencing was employed to analyze bacterial 16S rRNA from colonic stool samples. Results: Mice with BDL exhibited weight loss and signs of severe liver injury. These changes were unaffected by ghrelin treatment. FITC-4-kDa-dextran flux was increased and TMER decreased after BDL. Treatment with ghrelin tended to reduce these effects. Furthermore, application of ghrelin was associated with higher mRNA levels of claudin-4, occludin, and ZO-1 in colonic tissues of mice with BDL. Reduced alpha-diversity of the microbiome was observed in solvent-treated mice with BDL but not in ghrelin-treated animals. Conclusion: Ghrelin treatment did not improve weight loss and liver damage but increased gene expression of colonic TJ proteins and restored the alpha-diversity of the microbiome. Since protective effects of ghrelin might be masked by the severity of the model, we suggest follow-up studies in models of milder CLD.

Pancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown.We took advantage of a model of accelerated aging, uncoupling protein 2-deficient (Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment.Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells.Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

Malnutrition is a common primary or secondary complication in gastrointestinal diseases. The patient’s nutritional status also influences muscle mass and function, which can be impaired up to the degree of sarcopenia. The molecular interactions in diseases leading to sarcopenia are complex and multifaceted, affecting muscle physiology, the intestine (nutrition), and the liver at different levels. Although extensive knowledge of individual molecular factors is available, their regulatory interplay is not yet fully understood. A comprehensive overall picture of pathological mechanisms and resulting phenotypes is lacking.In silicoapproaches that convert existing knowledge into computationally readable formats can help to unravel such complex systems. We compiled available experimental evidence for molecular interactions involved in the development of sarcopenia into a knowledge base, referred to as the Sarcopenia Map. By including specific diseases, namely liver cirrhosis, and intestinal dysfunction, and considering their effects on nutritional status and blood secretome, we investigated their contribution to the development of sarcopenia. The Sarcopenia Map is publicly available as an open-source, interactive online resource, providing tools that allow users to explore the information on the map and performin silicoperturbation experiments.

Disease-related malnutrition (MN) is common in patients with liver cirrhosis (LC), short bowel syndrome (SBS), and chronic pancreatitis (CP). Different MN risk screening tools and diagnostic criteria of the European Society for Clinical Nutrition and Metabolism (ESPEN) and Global Leadership Initiative on Malnutrition (GLIM) algorithms were analyzed for their diagnostic accuracy and role as specific drivers to diagnose MN in patients with LC, SBS, and CP.A total of 187 patients with LC, SBS, and CP, as well as control patients were prospectively recruited in a multicenter cross-sectional study. MN risk was screened using Nutritional Risk Screening 2002 (NRS-2002), the Malnutrition Universal Screening Tool (MUST), and the Royal Free Hospital Nutritional Prioritizing Tool (RFH-NPT), and diagnosed using the ESPEN, GLIM, and GLIMNRS-2002 was only sensitive in conjunction with ESPEN, while MUST was sensitive additionally with the GLIM algorithm. RFH-NPT worked the best for LC. GLIM and GLIMRFH-NPT and MUST performed better in conjunction with the GLIM algorithm than NRS-2002. MN was diagnosed more frequently by GLIM than the ESPEN algorithm in LC, SBS, and CP. Individual criteria acted as specific drivers in MN in chronic gastrointestinal diseases.